WO2026006830A1 - Compositions and methods of treating diseases and disorders characterized by blood-brain barrier deterioration or reactive oxygen species generation - Google Patents

Compositions and methods of treating diseases and disorders characterized by blood-brain barrier deterioration or reactive oxygen species generation

Info

Publication number
WO2026006830A1
WO2026006830A1 PCT/US2025/035911 US2025035911W WO2026006830A1 WO 2026006830 A1 WO2026006830 A1 WO 2026006830A1 US 2025035911 W US2025035911 W US 2025035911W WO 2026006830 A1 WO2026006830 A1 WO 2026006830A1
Authority
WO
WIPO (PCT)
Prior art keywords
pgdh
alkyl
subject
alkylene
brain
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/035911
Other languages
French (fr)
Inventor
Sanford Markowitz
Andrew Pieper
Min-Kyoo SHIN
Yeojung Koh
Edwin VAZQUEZ-ROSA
Farrah GAO
Hongyun LI
Dawn Dawson
Ramachandra KATABATHULA
Salendra Singh
Bindu PAUL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Case Western Reserve University
Johns Hopkins University
US Department of Veterans Affairs
University Hospitals Cleveland Medical Center
Original Assignee
Case Western Reserve University
Johns Hopkins University
US Department of Veterans Affairs
University Hospitals Cleveland Medical Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Case Western Reserve University, Johns Hopkins University, US Department of Veterans Affairs, University Hospitals Cleveland Medical Center filed Critical Case Western Reserve University
Publication of WO2026006830A1 publication Critical patent/WO2026006830A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine

Definitions

  • a prominent and early feature of Alzheimer’s Disease (AD) is deterioration in blood-brain barrier (BBB) structure and function, which impairs neurovascular coupling and increases permeability of blood-borne substances and peripheral immune cells into the brain parenchyma, triggering perivascular inflammation.
  • BBB blood-brain barrier
  • BBB dysfunction occurs in the earliest pathological stages of AD and has been proposed as an early biomarker for the disease. Aging further contributes to BBB deterioration, especially in the hippocampus, a region essential for learning and memory that is particularly vulnerable in AD.
  • TBI traumatic brain injury
  • Common causes of TBI include falls, motor vehicle accidents, explosions, interpersonal violence, and sports injuries.
  • Embodiments described herein relate to compositions and methods of treating diseases or disorders characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species within the nervous system of a subject in need thereof.
  • 15-hydroxyprostaglandin dehydrogenase 15-hydroxyprostaglandin dehydrogenase
  • BBB blood brain barrier
  • 15-PGDH 15-hydroxyprostaglandin dehydrogenase
  • AD Alzheimer’s disease
  • TBI traumatic brain injury
  • aging 15-hydroxyprostaglandin dehydrogenase
  • Pathological increase in 15-PGDH correlates with pronounced oxidative stress, neuroinflammation, and neurodegeneration, alongside profound BBB structural degeneration characterized by astrocytic endfeet swelling and functional impairment.
  • Pharmacologic inhibition or genetic reduction of 15-PGDH in AD and TBI models strikingly mitigates cognitive decline, oxidative damage, suppresses neuroinflammation, and restores BBB integrity.
  • inhibiting 15-PGDH not only blocks damage to the brain by blocking microglial generation of reactive oxygen in 15-PGDH positive microglial cells and halts neurodegeneration but also preserves cognitive function at levels indistinguishable from healthy controls.
  • these neuroprotective effects in AD are achieved without affecting amyloid pathology, underscoring a non-canonical mechanism for treating AD.
  • our findings position 15-PGDH inhibition as a novel and broad-spectrum strategy to treat oxidative stress, neuroinflammation, and neurodegeneration, alongside profound BBB structural degeneration, associated with pathological increases in 15-PGDH.
  • a method of treating diseases or disorders characterized by structural deterioration of the blood-brain barrier in a subject in need thereof can include administering to the subject an amount of a 15-PGDH inhibitor and/or 15-PGDH substrate effective to prevent the onset of deterioration and/or the progression of further deterioration of the blood-brain barrier and/or prevent the neurodegeneration associated with blood-brain barrier deterioration and/or prevent the impaired neuronal function associated with blood- brain barrier deterioration and/or restore the integrity and/or structure and/or function of the blood-brain barrier.
  • a method of treating diseases or disorders characterized by increased generation of reactive oxygen species within the nervous system, and particularly, central nervous system, of a subject in need thereof can include administering to the subject an amount of a 15-PGDH inhibitor and/or 15-PGDH substrate effective to prevent and/or decrease reactive oxygen species generation and/or neurodegeneration and/or impaired neuronal function associated with reactive oxygen species.
  • the subject has memory loss and/or cognitive decline and the 15-PGDH inhibitor and/or 15-PGDH substrate is administered at an amount effective to improve memory and/or cognition.
  • the 15-PGDH inhibitor and/or 15-PGDH substrate is administered to the subject at an amount effective to block aberrantly increased 15-PGDH enzymatic activity and prevent perivascular inflammation.
  • the subject is asymptomatic for Alzheimer’s dementia, has preclinical Alzheimer’s disease, or prodromal Alzheimer’s disease.
  • the 15-PGDH inhibitor and/or 15-PGDH substrate is administered to the subject at an amount effective to decrease 4-hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or more.
  • the 15-PGDH inhibitor is a small molecule that binds to 15-PGDH protein.
  • the 15-PGDH inhibitor can inhibit enzymatic activity of recombinant 15-PGDH at an IC 50 of less than 1 ⁇ M, or preferably at an IC 50 of less than 250 nM, or more preferably at an IC 50 of less than 50 nM, or more preferably at an IC 50 of less than 10 nM, or more preferably at an IC 50 of less than 5 nM at a recombinant 15-PGDH concentration of about 5 nM to about 10 nM.
  • the 15-PGDH inhibitor has the following formula (V): (V) or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein n is 0-2 X 6 is independently is N or CR c R 1 , R 6 , R 7 , and R c are the same or different each independently hydrogen or a substituted or unsubstituted group selected from C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C 3 -C 20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C 6 -C 24 alkaryl, C6-C24 aralkyl, halo, -Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20
  • the 15-PGDH inhibitor is a molecule or generates a molecule that binds to 15-PGDH mRNA to promote degradation 15-PGDH mRNA and/or inhibit expression of 15-PGDH.
  • the molecule can include an RNA interference (RNAi) molecule, preferably at least one of a small interfering RNA (siRNA) or microRNA (miRNA).
  • RNAi RNA interference
  • the 15-PGDH inhibitor can include an agent or method of gene editing that inactivates or alters the HPGD gene that encodes 15-PGDH.
  • the 15-PGDH inhibitor can include at least one nuclease that can remove, cut, or alter a target nucleic acid sequence of the HPGD gene.
  • the 15-PGDH inhibitor is an agent that promotes the degradation of 15-PGDH protein.
  • the agent can include at least one of a small molecule-assisted shutoff (SMASh) system, a Shield-1-inducible degron, an auxin inducible degron, an IMid-inducible degron, a peptidic degron, a proteolysis targeting chimera, or an antibody for targeted 15-PGDH degradation.
  • the 15-PGDH substrate can include at least one of PGE2, PGF2 ⁇ , RvD1, LXA4, or 15-HETE.
  • the method can include measuring at least one biomarker of reactive oxygen species generation in the brain of the subject and comparing the at least one biomarker of reactive oxygen species generation to a control to determine the efficacy of the 15-PGDH inhibitor and/or PGDH substrate in treating neurodegeneration and/or impaired neuronal function in the subject.
  • the method can include measuring 4-hydroxy- 2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels of the subject following administration of the 15-PGDH inhibitor and/or 15-PGDH substrate and comparing the measured 4-hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels to a control, wherein a decrease in 4-hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels is indicative of efficacy of the 15-PGDH inhibitor and/or PGDH substrate in treating neurodegeneration and/or impaired neuronal function in the subject.
  • the control is the 4-hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels of the subject prior to administration of the 15-PGDH inhibitor and/or 15-PGDH substrate.
  • the method can include measuring blood-brain barrier (BBB) permeability of the subject following administration of the 15-PGDH inhibitor and/or 15-PGDH substrate and comparing the measured BBB permeability to a control, wherein a decrease in BBB permeability is indicative of efficacy of the 15-PGDH inhibitor and/or PGDH substrate in treating neurodegeneration and/or impaired neuronal function in the subject.
  • BBB blood-brain barrier
  • the control is the BBB permeability of the subject prior to administration of the 15-PGDH inhibitor and/or 15-PGDH substrate.
  • BRIEF DESCRIPTION OF THE DRAWINGS [0023] Figs.1(A-J) illustrate brain 15-PGDH increases in human and mouse AD, TBI, and aging, and is enriched in brain myeloid cells.
  • Figs.1(A-J) illustrate brain 15-PGDH increases in human and mouse AD, TBI, and aging, and is enriched in brain myeloid cells.
  • A qPCR data from human cortex reveals that 15-PGDH mRNA (HPGD expression) is increased in subjects with Alzheimer’s disease (AD), compared to control subjects without dementia. HPGD was normalized to the geometric mean of ACTB, POLR1B, and LDHA (* p ⁇ 0.05, unpaired t-test).
  • ERP015139 reveals that 15-PGDH mRNA (HPGD expression) is increased in subjects with chronic traumatic encephalopathy (CTE), compared to control subjects (* p ⁇ 0.05, unpaired t-test). Data are shown from both superior parietal cortex and posterior visual cortex.
  • E Mouse hippocampal 15-PGDH enzymatic activity is increased 3 weeks after TBI, relative to sham-injury (**** p ⁇ 0.0001, unpaired t-test).
  • FISH Fluorescent in situ hybridization
  • Hpgd expressing myeloid cells are composed of Mrc1 positive PVMs and Tmem119 positive microglia.
  • a heatmap of cortical myeloid cells depicting expression (log2(SCT)) of 15-PGDH mRNA (Hpgd), Mrc1 (perivascular macrophages), Lyve1 (perivascular macrophages), Aif1 (microglia and macrophages), and Tmem119 (microglia) is shown.
  • RNA FISH in mouse brain shows an increase in Hpgd-expressing microglia [double positive for 15-PGDH mRNA, Hpgd, (red) and Tmem119 mRNA (green)], in symptomatic 5xFAD mice (6 months old), compared to WT littermates, in cortex and hippocampus (** p ⁇ 0.01, unpaired t-test; 4-8 brain sections/mouse).
  • RNA FISH shows an increase in Hpgd-expressing PVMs [double positive for 15-PGDH mRNA, Hpgd (red) and Mrc1 mRNA (green)] in symptomatic 5xFAD mice (6 months old), compared to WT littermates, in cortex and hippocampus (* p ⁇ 0.05, ** p ⁇ 0.01, unpaired t-test; 2-7 brain sections/mouse). Expanded view of boxed region shown at lower right. In all graphs (A-J), datapoints indicate values of individual human subjects or individual mice. [0024] Figs.2(A-L) illustrate 15-PGDH inhibition protects 5xFAD mice from cognitive impairment and BBB deterioration without reducing amyloid pathology.
  • Tg-WT and Tg-5xFAD refer to 5xFAD genotypes, respectively designating absence or presence of the 5xFAD transgene, and Hpgd +/+ and Hpgd +/- denote Hpgd genotype.
  • Mice were injected with a bolus of BrdU (150 mg/kg) 1 month before sacrifice to label newborn hippocampal neurons. MWM testing of cognition was conducted one week before brain tissue was harvested for analysis at nine months of age.
  • Hpgd haploinsufficiency fully blocks the increase in 15-PGDH enzyme activity in symptomatic 5xFAD mice.
  • Brain 15-PGDH enzyme activity is highly elevated in Tg-5xFAD Hpgd +/+ mice compared to control Tg-WT Hpgd +/+ mice and is preserved at control levels in Tg-5xFAD Hpgd +/- mice, with no difference detected between Tg-WT Hpgd +/+ and Tg-5xFAD Hpgd +/- mice (** p ⁇ 0.01, one-way ANOVA and Tukey’s post hoc analysis).
  • Hpgd haploinsufficiency prevents cognitive impairment in 5xFAD mice in the MWM.
  • Tg-5xFAD Hpgd +/+ mice performed significantly worse than control Tg-WT Hpgd +/+ mice, as shown by significantly longer latency to first cross the platform area.
  • Tg-5xFAD Hpgd +/- mice were protected from memory deficits, as evidenced by latency to first cross the platform area in the memory test being significantly lower than Tg-5xFAD Hpgd +/+ mice and not significantly different from Tg-WT Hpgd +/+ mice (Interaction p ⁇ 0.05, * p ⁇ 0.05, **** p ⁇ 0.0001, two-way ANOVA and Tukey’s post hoc analysis).
  • TEM Transmission electron microscopy
  • (J) TEM shows structural damage of the BBB, as measured by the percentage of brain capillaries affected by astrocyte endfeet swelling in Tg-5xFAD Hpgd +/+ mice as compared to control Tg-WT Hpgd +/+ mice.
  • (L) IgG staining shows functional impairment and increased permeability of the BBB as evidenced by IgG infiltration into the brain parenchyma in Tg- 5xFAD Hpgd +/+ mice, compared to control Tg-WT Hpgd +/+ mice.
  • FIG.3(A-J) illustrate 15-PGDH inhibition protects 5xFAD mice from decreased survival of newborn hippocampal neurons, neuroinflammation, and oxidative stress.
  • FIG.3(A-J) illustrate 15-PGDH inhibition protects 5xFAD mice from decreased survival of newborn hippocampal neurons, neuroinflammation, and oxidative stress.
  • FIG.3(A-J) illustrate 15-PGDH inhibition protects 5xFAD mice from decreased survival of newborn hippocampal neurons, neuroinflammation, and oxidative stress.
  • FIG.3(A-J) illustrate 15-PGDH inhibition protects 5xFAD mice from decreased survival of newborn hippocampal neurons, neuroinflammation, and oxidative stress.
  • A 6- month-old symptomatic 5xFAD mice have impaired survival of BrdU-labeled newborn hippocampal neurons (black arrows), compared to WT littermates, as assessed 28 days post- BrdU injection.
  • Each graphed dot represents the average value of BrdU-labelled cells from an individual mouse as determined from 5-6 sections spaced at least 400 ⁇ m apart across the hippocampus.
  • Tg- 5xFAD Hpgd +/+ mice have impaired survival of BrdU-labeled newborn hippocampal neurons (black arrows), versus Tg-WT Hpgd +/+ littermates, as assessed 28 days post-BrdU injection.
  • (C) 5xFAD mice show increased hippocampal GFAP expression, which is significantly reduced by treatment with (+)-SW033291 (Interaction p ⁇ 0.001, ** p ⁇ 0.01, **** p ⁇ 0.0001, two-way ANOVA and Tukey’s post hoc analysis).
  • (D) Tg-5xFAD Hpgd +/+ mice show increased whole brain GFAP expression compared to Tg-WT Hpgd +/+ mice, which is significantly prevented in Tg-5xFAD Hpgd +/- mice (** p ⁇ 0.01, *** p ⁇ 0.001, one-way ANOVA and Tukey’s post hoc analysis).
  • FIGs.4(A-K) illustrate 15-PGDH inhibition protects mice from TBI-induced cognitive impairment, oxidative stress, neurodegeneration, and BBB damage.
  • FIG. 1 Schematic diagram of experimental procedure for evaluating the protective efficacy of genetic 15-PGDH inhibition in TBI.
  • Control 8-week-old Hpgd +/+ (WT) and Hpgd -/- (KO) mice were subjected to multimodal TBI. Brain tissue was harvested for analysis 3 weeks after TBI.
  • FIGs.5(A-E) illustrate Brain 15-PGDH is elevated in human and rodent Alzheimer’s disease.
  • A RNA sequencing data from the Allen brain atlas shows higher 15- PGDH mRNA (HPGD expression, 203913_s_at (ID_Ref)) in the hippocampus of human Alzheimer’s disease (AD) subjects, compared to no dementia matched control subjects (* p ⁇ 0.05, unpaired t-test).
  • B 15-PGDH whole brain enzymatic activity is increased in symptomatic TgF344-AD rats (6 months old), compared to WT littermates (* p ⁇ 0.05, unpaired t-test).
  • FIG. 6(A-G) illustrate Brain 15-PGDH expression is enriched in PVMs and microglia.
  • A UMAP depiction of single cell RNA sequencing data reanalyzed from Yao et al. reveals 15-PGDH mRNA (Hpgd expression) is most highly enriched in a brain PVM plus microglia cell cluster (bold arrow), along with lesser enrichment in a minority neuronal subpopulation (thin arrow). Increased Hpgd expression level is indicated by increased dot size and color intensity.
  • FIG. 7 The mean log2(SCT) expression level of Hpgd in each cluster of the hippocampus shows that the PVM/microglia population has the highest mean expression of Hpgd, followed by neurons in CA3 and IG-FC.
  • Figs.7(A-C) illustrate 15-PGDH expressing myeloid cells are proximal to blood vessels.
  • A Mouse brain 15-PGDH enzymatic activity in WT mice (6 months old) is enriched ⁇ 200-fold in CD11b (+) myeloid cells, compared to CD11b (-) non-myeloid cells (* p ⁇ 0.05, paired t-test). Data points indicate values of individual mice.
  • RNA FISH for Hpgd and Itgam combined with CD31 immunofluorescence (IF) in mouse brain shows 15- PGDH positive brain myeloid cells (Hpgd+ Itgam+ cells) close to blood vessel (CD31) in cortex and hippocampus of 6-month-old WT mouse. Histogram shows the number of Hpgd and Itgam double positive cells in each distance category from the nearest CD31 marked cell.
  • a total of 12 images per brain section (6 from the cortex, 6 from the hippocampus) were analyzed. Two brain sections from each mouse were used, with a total of 6 WT mice included in the study.
  • FIG.8(A-J) illustrate Pharmacokinetics of (+)-SW033291 in the plasma and the brain; 15-PGDH inhibition protects 5xFAD mice from cognitive impairment, with similar swim speed in Morris water maze (MWM) across all groups.
  • (+)-SW033291 fully prevents cognitive deficits in 5XFAD mice in the MWM, in which vehicle-treated 5xFAD mice performed significantly worse than vehicle-treated WT littermates, as evidenced by significantly fewer platform area crossings. This was preserved at normal WT littermate vehicle levels in 5xFAD mice treated with (+)-SW033291 (Treatment (vehicle vs. (+)- SW033291) p ⁇ 0.01, * p ⁇ 0.05, two-way ANOVA and Tukey’s post hoc analysis).
  • Tg- 5xFAD Hpgd +/+ mice performed significantly worse than control Tg-WT Hpgd +/+ mice, as evidenced by significantly fewer platform area crossings.
  • Hpgd haploinsufficient Tg-5xFAD Hpgd +/- mice were protected from memory deficit, as evidenced by a normal level of platform area crossings.
  • Tg-5xFAD Hpgd +/+ mice displayed learning deficit during the training phase, as evidenced by longer time to find the platform (escape latency) than the other groups on days 2 and 3 of training, which was significantly protected by Hpgd haploinsufficiency in Tg-5xFAD Hpgd +/+ mice.
  • Tg-5xFAD Hpgd +/- mice performed comparably to Tg-WT Hpgd +/+ and Tg-WT Hpgd +/- mice (Time x group Interaction p ⁇ 0.001, ** p ⁇ 0.01, **** p ⁇ 0.0001, repeated measures two-way ANOVA and Tukey’s post hoc analysis).
  • Tg-5xFAD mice showed significant difference in swim speed versus Tg-WT mice (Genotype (Tg-WT vs Tg- 5xFAD) p ⁇ 0.05, two-way ANOVA and Tukey’s post hoc analysis; no difference between other groups were observed, including no difference in swim speed as a function of haploinsuffiency of Hpgd).
  • Tg-5xFAD Hpgd +/+ and Tg-5xFAD Hpgd +/- mice weighed significantly less compared to Tg-WT Hpgd +/+ and Tg-WT Hpgd +/- mice (Genotype (Tg-WT vs Tg-5xFAD) p ⁇ 0.01, two-way ANOVA and Tukey’s post hoc analysis). Males are shown as filled circles or filled squares and females are shown as open circles or open squares, here and in all subsequent panels.
  • FIG. 10(A-E) illustrate pharmacologic or genetic 15-PGDH inhibition increases survival of newborn hippocampal neurons.
  • Hpgd -/- Genetic inhibition of 15-PGDH increases survival of BrdU-labeled newborn hippocampal neurons (black arrows) in male and female adult mice, assayed 15 days post-BrdU injection (Genotype p ⁇ 0.0001, **** p ⁇ 0.0001, two-way ANOVA and Tukey’s post hoc analysis). No difference was detected between males and females.
  • (+)-SW033291 inhibition of 15-PGDH increases survival of BrdU-labeled newborn hippocampal neurons (black arrows) in adult wild type (Hpgd +/+ ) mice.
  • Hpgd -/- mice show increased survival of BrdU-labeled new hippocampal neurons (versus control Hpgd +/+ ), but do not show any additional response to (+)-SW033291 treatment, confirming that (+)-SW033291 potentiates the net magnitude of hippocampal neurogenesis by an on-target effect of inhibiting 15-PGDH.
  • BrdU-labeled cells were quantified 28 days post-BrdU injection.
  • FIG.3C Western blot of GFAP protein, quantified in Fig.3C, with each lane on the gel representing an individual mouse.
  • a to B 5xFAD mice also show characteristic over-expression of APP and induction of IBA1, neither of which are prevented by treatment with (+)-SW033291 (Genotype p ⁇ 0.0001, ** p ⁇ 0.01, two-way ANOVA and Tukey’s post hoc analysis).
  • C Western blot of GFAP protein, quantified in Fig.3D, with each lane on the gel representing an individual mouse.
  • Tg-5xFAD Hpgd +/+ mice also show overexpression of APP and IBA1, as compared to control Tg-WT Hpgd +/+ mice, and neither of these are prevented in Tg-5xFAD Hpgd +/- mice. (* p ⁇ 0.05, one-way ANOVA and Tukey’s post hoc analysis). In all graphs (A-D), data points indicate values of individual mice.
  • Figs.12(A-C) illustrate A ⁇ oligomer-induced generation of reactive oxygen species (ROS) in BV2 microglia cells is suppressed by treatment with 15-PGDH substrates.
  • ROS reactive oxygen species
  • compositions are described as having, including, or comprising, specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components.
  • methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps.
  • order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
  • pharmaceutically acceptable means suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use within the scope of sound medical judgment.
  • salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc.
  • acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • salts also includes those obtained by reacting the active compound functioning as an acid, with an inorganic or organic base to form a salt, for example salts of ethylenediamine, N-methyl- glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, and the like.
  • Non limiting examples of inorganic or metal salts include lithium, sodium, calcium, potassium, magnesium salts and the like.
  • the salts of the compounds described herein can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • Non-limiting examples of hydrates include monohydrates, dihydrates, etc.
  • Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
  • solvates means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.
  • the solvent is water the solvate formed is a hydrate
  • the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 O, such combination being able to form one or more hydrate.
  • the compounds and salts described herein can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present application includes all tautomers of the present compounds.
  • a tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism. [0047] Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.
  • Tautomerizations can be catalyzed by: Base: 1. deprotonation; 2. formation of a delocalized anion (e.g., an enolate); 3. protonation at a different position of the anion; Acid: 1. protonation; 2. formation of a delocalized cation; 3. deprotonation at a different position adjacent to the cation.
  • Base 1. deprotonation; 2. formation of a delocalized anion (e.g., an enolate); 3. protonation at a different position of the anion
  • Acid 1. protonation; 2. formation of a delocalized cation; 3. deprotonation at a different position adjacent to the cation.
  • Amino refers to the -NH2 radical.
  • Cyano refers to the -CN radical.
  • Halo or halogen refers to bromo, chloro, fluoro or iodo radical.
  • An alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl
  • an alkyl comprising up to 10 carbon atoms is a C 1 -C 10 alkyl
  • an alkyl comprising up to 6 carbon atoms is a C1-C6 alkyl
  • an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl.
  • a C1- C 5 alkyl includes C 5 alkyls, C 4 alkyls, C 3 alkyls, C 2 alkyls and C 1 alkyl (i.e., methyl).
  • a C 1 - C6 alkyl includes all moieties described above for C1-C5 alkyls but also includes C6 alkyls.
  • a C 1 -C 10 alkyl includes all moieties described above for C 1 -C 5 alkyls and C 1 -C 6 alkyls, but also includes C7, C8, C9 and C10 alkyls.
  • a C1-C12 alkyl includes all the foregoing moieties, but also includes C 11 and C 12 alkyls.
  • Non-limiting examples of C 1 -C 12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t- amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl.
  • an alkyl group can be optionally substituted.
  • Alkylene or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms.
  • C 1 -C 12 alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
  • alkylene chain can be optionally substituted.
  • alkenyl or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included.
  • An alkenyl group comprising up to 12 carbon atoms is a C 2 -C 12 alkenyl
  • an alkenyl comprising up to 10 carbon atoms is a C 2 -C 10 alkenyl
  • an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl
  • an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl.
  • a C2- C 5 alkenyl includes C 5 alkenyls, C 4 alkenyls, C 3 alkenyls, and C 2 alkenyls.
  • a C 2 -C 6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes C6 alkenyls.
  • a C2- C 10 alkenyl includes all moieties described above for C 2 -C 5 alkenyls and C 2 -C 6 alkenyls, but also includes C7, C8, C9 and C10 alkenyls.
  • a C2-C12 alkenyl includes all the foregoing moieties, but also includes C 11 and C 12 alkenyls.
  • Non-limiting examples of C 2 -C 12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1- propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4- heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6- octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-n
  • alkyl group can be optionally substituted.
  • alkenylene or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds.
  • C 2 -C 12 alkenylene include ethene, propene, butene, and the like.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
  • alkenylene chain can be optionally substituted.
  • alkynyl or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included.
  • An alkynyl group comprising up to 12 carbon atoms is a C2-C12 alkynyl
  • an alkynyl comprising up to 10 carbon atoms is a C 2 -C 10 alkynyl
  • an alkynyl group comprising up to 6 carbon atoms is a C 2 -C 6 alkynyl
  • an alkynyl comprising up to 5 carbon atoms is a C 2 -C 5 alkynyl.
  • a C 2 -C 5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls.
  • a C2-C6 alkynyl includes all moieties described above for C 2 -C 5 alkynyls but also includes C 6 alkynyls.
  • a C 2 -C 10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C 7 , C 8 , C 9 and C 10 alkynyls.
  • a C 2 -C 12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls.
  • Non-limiting examples of C2-C12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like.
  • alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds.
  • C 2 -C 12 alkynylene include ethynylene, propargylene and the like.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
  • alkynylene chain can be optionally substituted.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl, alkenyl or alknyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.
  • Alkylamino refers to a radical of the formula -NHR a or -NR a R a where each R a is, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms.
  • alkylamino group can be optionally substituted.
  • R a is an alkyl, alkenyl or alkynyl radical as defined above.
  • a non-limiting example of an alkyl carbonyl is the methyl carbonyl (“acetal”) moiety.
  • Alkylcarbonyl groups can also be referred to as “C w -C z acyl” where w and z depicts the range of the number of carbon in Ra, as defined above.
  • C 1 -C 10 acyl refers to alkylcarbonyl group as defined above, where R a is C 1 -C 10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl radical as defined above. Unless stated otherwise specifically in the specification, an alkyl carbonyl group can be optionally substituted.
  • Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
  • the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from phenyl (benzene), aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • aryl is meant to include aryl radicals that are optionally substituted.
  • “Aralkyl” or “arylalkyl” refers to a radical of the formula -Rb-Rc where Rb is an alkylene group as defined above and R c is one or more aryl radicals as defined above.
  • Aralkyl radicals include, but are not limited to, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.
  • “Aralkenyl” or “arylalkenyl” refers to a radical of the formula -R b -R c where R b is an alkenylene group as defined above and Rc is one or more aryl radicals as defined above.
  • an aralkenyl group can be optionally substituted.
  • “Aralkynyl” or “arylalkynyl” refers to a radical of the formula -R b -R c where R b is an alkynylene group as defined above and R c is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkynyl group can be optionally substituted.
  • Carbocyclyl “carbocyclic ring” or “carbocycle” refers to a ring structure, wherein the atoms which form the ring are each carbon.
  • Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring.
  • Carbocyclic rings include aryls and cycloalkyl. Cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.
  • Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.
  • Cycloalkenyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like.
  • Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.
  • Cycloalkynyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.
  • “Cycloalkylalkyl” refers to a radical of the formula -R b -R d where R b is an alkylene, alkenylene, or alkynylene group as defined above and R d is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group can be optionally substituted.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.
  • Haloalkenyl refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.
  • Haloalkynyl refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropynyl, 1-fluorobutynyl, and the like.
  • Heterocyclyl refers to a stable 3- to 20-membered non-aromatic, partially aromatic, or aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclycl or heterocyclic rings include heteroaryls as defined below.
  • the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, and spiral ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated.
  • heterocyclyl radicals include, but are not limited to, aziridinyl, oextanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thia
  • Heterocyclylalkyl refers to a radical of the formula -R b -R e where R b is an alkylene group as defined above and R e is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group can be optionally substituted.
  • Heterocyclylalkenyl refers to a radical of the formula -R b -R e where R b is an alkenylene group as defined above and Re is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkenyl group can be optionally substituted.
  • Heterocyclylalkynyl refers to a radical of the formula -R b -R e where R b is an alkynylene group as defined above and Re is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkynyl group can be optionally substituted.
  • N-heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a N-heterocyclyl group can be optionally substituted.
  • Heteroaryl refers to a 5- to 20-membered ring system radical one to thirteen carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, as the ring member.
  • the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems, wherein at least one ring containing a heteroatom ring member is aromatic.
  • the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized and the nitrogen atom can be optionally quaternized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
  • heteroaryl group can be optionally substituted.
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group can be optionally substituted.
  • Heteroarylalkyl refers to a radical of the formula -R b -R f where R b is an alkylene chain as defined above and Rf is a heteroaryl radical as defined above.
  • heteroarylalkyl group can be optionally substituted.
  • “Heteroarylalkenyl” refers to a radical of the formula -R b -R f where R b is an alkenylene, chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkenyl group can be optionally substituted.
  • “Heteroarylalkynyl” refers to a radical of the formula -R b -R f where R b is an alkynylene chain as defined above and Rf is a heteroaryl radical as defined above.
  • heteroarylalkynyl group can be optionally substituted.
  • “Thioalkyl” refers to a radical of the formula -SR a where R a is an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted.
  • substituted means any of the above groups (e.g., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, etc.) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in
  • “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • a higher-order bond e.g., a double- or triple-bond
  • nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • Rg and R h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
  • “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N- heteroaryl and/or heteroarylalkyl group.
  • a point of attachment bond denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond.
  • “ ” indicates that the chemical entity “A” is bonded to another chemical entity via the point of attachment bond.
  • the specific point of attachment to the non-depicted chemical entity can be specified by inference.
  • parenteral administration and “administered parenterally” are art-recognized terms, and include modes of administration other than enteral and topical administration, such as injections, and include, without limitation, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra- articular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • treating is art-recognized and includes inhibiting a disease, disorder or condition in a subject, e.g., impeding its progress; and relieving the disease, disorder or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected.
  • preventing is art-recognized and includes stopping a disease, disorder or condition from occurring in a subject, which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it.
  • Preventing a condition related to a disease includes stopping the condition from occurring after the disease has been diagnosed but before the condition has been diagnosed.
  • a "patient,” “subject,” or “host” to be treated by the subject method may mean either a human or non-human animal, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is a mammal.
  • a patient refers to a subject afflicted with a disease or disorder.
  • the terms "prophylactic” or “therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the unwanted condition e.g., disease or other unwanted state of the host animal
  • therapeutic agent include molecules and other agents that are biologically, physiologically, or pharmacologically active substances that act locally or systemically in a patient or subject to treat a disease or condition.
  • the terms include without limitation pharmaceutically acceptable salts thereof and prodrugs.
  • agents may be acidic, basic, or salts; they may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; they may be prodrugs in the form of ethers, esters, amides and the like that are biologically activated when administered into a patient or subject.
  • terapéuticaally effective amount or “pharmaceutically effective amount” is an art-recognized term.
  • the term refers to an amount of a therapeutic agent that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the term refers to that amount necessary or sufficient to eliminate, reduce or maintain a target of a particular therapeutic regimen.
  • the effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject or the severity of the disease or condition.
  • One of ordinary skill in the art may empirically determine the effective amount of a particular compound without necessitating undue experimentation.
  • a therapeutically effective amount of a therapeutic agent for in vivo use will likely depend on a number of factors, including: the rate of release of an agent from a polymer matrix, which will depend in part on the chemical and physical characteristics of the polymer; the identity of the agent; the mode and method of administration; and any other materials incorporated in the polymer matrix in addition to the agent.
  • ED50 is art-recognized. In certain embodiments, ED50 means the dose of a drug, which produces 50% of its maximum response or effect, or alternatively, the dose, which produces a pre-determined response in 50% of test subjects or preparations.
  • LD50 is art-recognized.
  • LD50 means the dose of a drug, which is lethal in 50% of test subjects.
  • therapeutic index is an art-recognized term, which refers to the therapeutic index of a drug, defined as LD50/ED50.
  • IC50 half maximal inhibitory concentration
  • IC50 half maximal inhibitory concentration
  • the phrase "optionally substituted” means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.
  • the term “or” as used herein should be understood to mean “and/or”, unless the context clearly indicates otherwise.
  • the term "about” or “approximately” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.
  • the term "about” or “approximately” refers a range of quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length ⁇ 15%, ⁇ 10%, ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, or ⁇ 1% about a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. [0096] All percentages and ratios used herein, unless otherwise indicated, are by weight.
  • brain injury includes traumatic injuries and injuries as a result of disease, in particular neurodegenerative diseases and dementias.
  • brain injury includes, but is not limited to mild, moderate, or severe trauma to the brain such as that received in military conflict, sports injury, accidents and falls, and the like, and also includes but is not limited to injury to the brain as a result of any tauopathy or dementia.
  • the brain injury is accompanied by, associated with, or mediated by astrogliosis or astroglial activation.
  • Glasgow Coma Scale or “GCS” as used herein refers to a 15 point scale for estimating and categorizing the outcomes of brain injury on the basis of overall social capability or dependence on others.
  • the test measures the motor response, verbal response and eye opening response with these values: I. Motor Response (6--Obeys commands fully; 5--Localizes to noxious stimuli; 4--Withdraws from noxious stimuli; 3--Abnormal flexion, i.e., decorticate posturing; 2--Extensor response, i.e. decerebrate posturing; and 1--No response); II.
  • Verbal Response (5--Alert and Oriented; 4--Confused, yet coherent, speech; 3-- Inappropriate words and jumbled phrases consisting of words; 2--Incomprehensible sounds; and 1--No sounds); and III. Eye Opening (4--Spontaneous eye opening; 3--Eyes open to speech; 2--Eyes open to pain; and 1--No eye opening). The final score is determined by adding the values of I+II+III.
  • the final score can be categorized into four possible levels for survival, with a lower number indicating a more severe injury and a poorer prognosis: Mild (13-15); Moderate Disability (9-12) (Loss of consciousness greater than 30 minutes; Physical or cognitive impairments which may or may resolve: and Benefit from Rehabilitation); Severe Disability (3-8) (Coma: unconscious state. No meaningful response, no voluntary activities); and Vegetative State (Less Than 3) (Sleep wake cycles; Arousal, but no interaction with environment; No localized response to pain).
  • Moderate brain injury is defined as a brain injury resulting in a loss of consciousness from 20 minutes to 6 hours and a Glasgow Coma Scale of 9 to 12.
  • Severe brain injury is defined as a brain injury resulting in a loss of consciousness of greater than 6 hours and a Glasgow Coma Scale of 3 to 8.
  • "Glasgow Outcome Scale” as used herein refers to a global scale for functional outcome that rates patient status into one of five categories: Dead, Vegetative State, Severe Disability, Moderate Disability or Good Recovery.
  • Primary brain injuries occur during the initial insult and result from displacement of the physical structures of the brain. More specifically, a primary brain injury is the physical damage to parenchyma (tissue, vessels) that occurs during the traumatic event, resulting in shearing and compression of the surrounding brain tissue. Secondary brain injuries occur subsequent to the primary injury and may involve an array of cellular processes.
  • a secondary brain injury refers to the changes that evolve over a period of time (from hours to days) after the primary brain injury. It includes an entire cascade of cellular, chemical, tissue, or blood vessel changes in the brain that contribute to further destruction of brain tissue.
  • An injury to the head can be either closed or open (penetrating).
  • a closed head injury refers to a trauma to the scalp, skull or brain where there is no penetration of the skull by a striking object.
  • An open head injury refers a trauma to the scalp, skull or brain where there is penetration of the skull by a striking object.
  • An injury to the head may be caused by physical shaking of a person, by blunt impact by an external mechanical or other force that results in a closed or open head trauma (e.g., vehicle accident, such as with an automobile, plane, train, etc.; blow to the head, such as with a baseball bat, or from a firearm), a cerebral vascular accident (e.g., stroke), one or more falls (e.g., as in sports or other activities), explosions or blasts (collectively, "blast injuries”) and by other types of blunt force trauma.
  • a closed or open head trauma e.g., vehicle accident, such as with an automobile, plane, train, etc.; blow to the head, such as with a baseball bat, or from a firearm
  • a cerebral vascular accident e.g., stroke
  • one or more falls e.g., as in sports or other activities
  • explosions or blasts collectively, "blast injuries”
  • an injury to the head may be caused by the ingestion and/or exposure to a chemical, toxin or
  • Examples of such chemicals and/or toxins include fires, molds, asbestos, pesticides and insecticides, organic solvents, paints, glues, gases (such as carbon monoxide, hydrogen sulfide, and cyanide), organic metals (such as methyl mercury, tetraethyl lead and organic tin) and/or one or more drugs of abuse.
  • gases such as carbon monoxide, hydrogen sulfide, and cyanide
  • organic metals such as methyl mercury, tetraethyl lead and organic tin
  • an injury to the head may be caused as a result of a subject suffering from an autoimmune disease, a metabolic disorder, a brain tumor, one or more viruses, meningitis, hydrocephalus, hypoxia or any combinations thereof. In some cases, it is not possible to be certain whether any such event or injury has occurred or taken place.
  • TBI Traumatic Brain Injury
  • TBI can be classified as "mild,” “moderate,” or “severe.”
  • the causes of TBI are diverse and include, for example, physical shaking by a person, a car accident, injuries from firearms, cerebral vascular accidents (e.g., strokes), falls, explosions or blasts and other types of blunt force trauma.
  • Other causes of TBI include the ingestion and/or exposure to one or more chemicals or toxins (such as fires, molds, asbestos, pesticides and insecticides, organic solvents, paints, glues, gases (such as carbon monoxide, hydrogen sulfide, and cyanide), organic metals (such as methyl mercury, tetraethyl lead and organic tin), one or more drugs of abuse or combinations thereof).
  • TBI can occur in subjects suffering from an autoimmune disease, a metabolic disorder, a brain tumor, hypoxia, one or more viruses, meningitis, hydrocephalus or combinations thereof. Young adults and the elderly are the age groups at highest risk for TBI.
  • traumatic brain injury or TBI does not include and specifically excludes cerebral vascular accidents such as strokes.
  • Mild TBI refers to a brain injury where loss of consciousness is brief and usually a few seconds or minutes and/or confusion and disorientation is shorter than 1 hour. Mild TBI is also referred to as a concussion, minor head trauma, minor TBI, minor brain injury, and minor head injury.
  • Mild TBI is the most prevalent TBI and is often missed at time of initial injury. Typically, a subject has a Glasgow Coma scale number of between 13-15 (such as 13-15 or 14-15). Fifteen percent (15%) of people with mild TBI have symptoms that last 3 months or more. Mild TBI is defined as the result of the forceful motion of the head or impact causing a brief change in mental status (confusion, disorientation or loss of memory) or loss of consciousness for less than 30 minutes.
  • Modemize TBI refers to a brain injury where loss of consciousness and/or confusion and disorientation is between 1 and 24 hours and the subject has a Glasgow Coma scale number of between 9-12. The individual with moderate TBI have abnormal brain imaging results.
  • “Severe TBI” as used herein refers to a brain injury where loss of consciousness is more than 24 hours and memory loss after the injury or penetrating skull injury longer than 24 hours and the subject has a Glasgow Coma scale number between 3-8. The deficits range from impairment of higher level cognitive functions to comatose states. Survivors may have limited function of arms or legs, abnormal speech or language, loss of thinking ability or emotional problems. Individuals with severe injuries can be left in long-term unresponsive states. For many people with severe TBI, long-term rehabilitation is often necessary to maximize function and independence.
  • Common symptoms of moderate to severe TBI include cognitive deficits including difficulties with attention, concentration, distractibility, memory, speed of processing, confusion, perseveration, impulsiveness, language processing, and/or "executive functions", not understanding the spoken word (receptive aphasia), difficulty speaking and being understood (expressive aphasia), slurred speech, speaking very fast or very slow, problems reading, problems writing, difficulties with interpretation of touch, temperature, movement, limb position and fine, discrimination, the integration or patterning of sensory impressions into psychologically meaningful data, partial or total loss of vision, weakness of eye muscles and double vision (diplopia), blurred vision, problems judging distance, involuntary eye movements (nystagmus), intolerance of light (photophobia), hearing, such as decrease or loss of hearing, ringing in the ears (tinnitus), increased sensitivity to sounds, loss or diminished sense of smell (anosmia), loss or diminished sense of taste, the convulsions associated with epilepsy that can be several types and can
  • neurodegenerative disease is used interchangeably herein to refer to a varied assortment of central nervous system diseases, disorders, and conditions characterized by gradual and progressive loss of neural tissue and/or neural tissue function.
  • a neurodegenerative disease is a class of neurological disorder or disease, and where the neurological disease is characterized by a gradual and progressive loss of neural tissue, and/or altered neurological function, typically reduced neurological function as a result of a gradual and progressive loss of neural tissue.
  • vascular dementia is also referred to as "multi-infarct dementia” in the art refers to a group of syndromes caused by different mechanisms all resulting in vascular lesions in the brain.
  • vascular dementia The main subtypes of vascular dementia are, for example vascular mild cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct (affecting the thalamus, the anterior cerebral artery, the parietal lobes or the cingulate gyrus), vascular dementia due to hemorrhagic lesions, small vessel disease (including, e.g., vascular dementia due to lacunar lesions and Binswanger disease), and mixed Alzheimer's Disease with vascular dementia.
  • vascular mild cognitive impairment vascular mild cognitive impairment
  • multi-infarct dementia vascular dementia due to a strategic single infarct (affecting the thalamus, the anterior cerebral artery, the parietal lobes or the cingulate gyrus)
  • vascular dementia due to hemorrhagic lesions
  • small vessel disease including, e.g., vascular dementia due to lacunar lesions and Binswanger disease
  • mixed Alzheimer's Disease with vascular dementia
  • disease refers to any alteration in state of the body or of some of the organs, interrupting or disturbing the performance of the functions and/or causing symptoms such as discomfort, dysfunction, distress, or even death to the person afflicted or those in contact with a person.
  • a disease or disorder can also relate to a distemper, ailing, ailment, malady, disorder, sickness, illness, complaint, or affectation.
  • blood-brain barrier or "BBB” are used interchangeably herein, and are used to refer to the permeability barrier that exists in blood vessels as they travel through the brain tissue that severely restricts and closely regulates what is exchanged between the blood and the brain tissue.
  • the blood brain barrier components include the endothelial cells that form the innermost lining of all blood vessels, the tight junctions between adjacent endothelial cells that are the structural correlate of the BBB, the basement membrane of endothelial cells and the expanded foot processes of nearby astrocytes which cover nearly all of the exposed outer surface of the blood vessel.
  • the BBB prevents most substances in the blood from entering brain tissue, including most large molecules such as Ig, antibodies, complement, albumin and drugs and small molecules.
  • abnormal BBB is used to refer to a dysfunctional BBB, for example, where the BBB does not allow transit of molecules that normally transit a functional BBB, for example nutrients and sugars such as glucose.
  • An abnormal BBB can also refer to when the BBB is permeable to molecules that a normally functioning BBB would typically exclude, which is typically referred to "BBB permeability" herein.
  • BBB permeability or “permeable BBB” are commonly referred to by persons in the art as “leaky BBB”. The terms are used interchangeably herein to refer to impaired BBB integrity and increased vascular permeability.
  • a permeable BBB allows transit of molecules through the BBB that an intact BBB would normally exclude from the brain tissue, for example, Ig molecules, complement proteins, serum albumin and numerous other proteins.
  • An assay to determine the presence of a permeable BBB can be, for example, to assess the presence of extravascular Ig in the brain tissue which is normally be restricted to the lumen of blood vessels when the BBB is functioning normally (i.e., when the BBB is not permeable).
  • 15-hydroxyprostaglandin dehydrogenase 15-hydroxyprostaglandin dehydrogenase
  • BBB blood brain barrier
  • 15-PGDH 15-hydroxyprostaglandin dehydrogenase
  • AD Alzheimer’s disease
  • TBI traumatic brain injury
  • aging 15-hydroxyprostaglandin dehydrogenase
  • Pathological increase in 15-PGDH correlates with pronounced oxidative stress, neuroinflammation, and neurodegeneration, alongside profound BBB structural degeneration characterized by astrocytic endfeet swelling and functional impairment.
  • Pharmacologic inhibition or genetic reduction of 15-PGDH in AD and TBI models strikingly mitigates cognitive decline, oxidative damage, suppresses neuroinflammation, and restores BBB integrity.
  • inhibiting 15-PGDH not only blocks damage to the brain by blocking microglial generation of reactive oxygen in 15-PGDH positive microglial cells and halts neurodegeneration but also preserves cognitive function at levels indistinguishable from healthy controls.
  • Generation of reactive oxygen species by microglial cells can also be blocked with multiple substrates that 15-PGDH enzymatically degrades and limits, including PGE2, PGF2a, 15-HETE, RvD1, and LXA4 (respectively prostaglandin E2, prostaglandin F2 alpha, 15-HETE, resolving D1, and lipoxin A4).
  • these neuroprotective effects in AD are achieved without affecting amyloid pathology, underscoring a non-canonical mechanism for treating AD.
  • the cognitive decline, neuroinflammation, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, diseases and/or disorders characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species within the nervous system can also be associated with enhanced or aberrant 15-PGDH activity in a subject in need thereof.
  • a method of treating diseases or disorders characterized by structural deterioration of the blood-brain barrier can include administering to the subject an amount of a 15-PGDH inhibitor and/or 15-PGDH substrate effective to prevent the onset of deterioration and/or the progression of further deterioration of the blood-brain barrier and/or prevent the neurodegeneration associated with blood-brain barrier deterioration and/or prevent the impaired neuronal function associated with blood-brain barrier deterioration and/or restore the integrity and/or structure and/or function of the blood-brain barrier.
  • a method of treating diseases or disorders characterized by increased generation of reactive oxygen species within the nervous system or central nervous system of a subject in need thereof, including cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions can include administering to the subject an amount of a 15-PGDH inhibitor and/or 15-PGDH substrate effective to prevent and/or decrease reactive oxygen species generation and/or neurodegeneration and/or impaired neuronal function associated with reactive oxygen species.
  • the subject has memory loss and/or cognitive decline and the 15-PGDH inhibitor and/or 15-PGDH substrate is administered at amount effective to improve memory and/or cognition.
  • the 15-PGDH inhibitor and/or 15-PGDH substrate is administered to the subject at amount effective to block aberrantly increased 15-PGDH enzymatic activity and prevent perivascular inflammation.
  • Other embodiments described herein relate to a method of treating cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, diseases, and/or disorders characterized by increased generation of reactive oxygen species within the nervous system in a subject in need thereof.
  • the 15-PGDH inhibitor and/or 15-PGDH substrate can be administered to the subject at an amount effective to decrease at least one biomarker of reactive oxygen species generation, such as 4-hydroxy-2-nonenal (4-HNE) and/or 3- nitrotyrosine (3-NT) levels, by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or more.
  • at least one biomarker of reactive oxygen species generation such as 4-hydroxy-2-nonenal (4-HNE) and/or 3- nitrotyrosine (3-NT) levels
  • the method includes measuring at least one biomarker of reactive oxygen species generation in the brain of the subject and administering to the subject an amount of a 15-PGDH inhibitor and/or 15-PGDH substrate effective to decrease reactive oxygen species generation in the brain of the subject.
  • Methods of measuring reactive oxygen species generation in the brain can include, for example, measuring 4-hydroxy-2-nonenal (4- HNE) and/or 3-nitrotyrosine (3-NT) levels as described in Domenico et al., Free Radic. Biol. Med.111, 253–261 (2017); Shin et al., Biomedicines 8, 326 (2020); and Sultana, et al., Neurobiol. Dis.22, 76–87 (2006).
  • the method includes measuring at least one biomarker of reactive oxygen species generation, such as 4-hydroxy-2-nonenal (4-HNE) and/or 3- nitrotyrosine (3-NT) levels, in blood of the subject following administration of the 15-PGDH inhibitor and comparing the measured biomarker of reactive oxygen species generation to a control, wherein a decrease in 4-hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels is indicative of efficacy of the 15-PGDH inhibitor and/or PGDH substrate in treating neurodegeneration and/or impaired neuronal function in the subject.
  • a biomarker of reactive oxygen species generation such as 4-hydroxy-2-nonenal (4-HNE) and/or 3- nitrotyrosine (3-NT) levels
  • the control can be, for example, the 4-hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels of the subject prior to administration of the 15-PGDH inhibitor and/or 15-PGDH substrate.
  • the cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, diseases and/or disorders are associated with an increase in reactive oxygen species in neurotissue, such as brain tissue, of at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% relative to normal or healthy neurotissue.
  • administration of a 15-PGDH inhibitor and/or 15- PGDH substrate can be used to decrease reactive oxygen species in neurotissue of the subject from about 5% to about 200%, about 5% to about 180%, about 5% to about 160%, about 5% to about 140%, about 5% to about 120%, about 5% to about 100%, about 5% to about 80%, about 5% to about 60%, about 5% to about 40%, about 10% to about 200%, about 10% to about 180%, about 10% to about 160%, about 10% to about 140%, about 10% to about 120%, about 10% to about 100%, about 10% to about 80%, about 10% to about 60%, about 30% to about 200%, about 30% to about 180%, about 30% to about 160%, about 30% to about 140%, about 30% to about 120%, about 30% to about 100%, about 30% to about 80%, about 40% to about 200%, about 40% to about 180%, about 40% to about 160%, about 40% to about 140%, about 40% to about 120%, about 40% to about 100%, about 50% to about
  • Still other embodiments described herein relate to a method of treating cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, diseases, and/or disorders characterized by structural deterioration of the blood- brain barrier in a subject in need thereof.
  • the 15-PGDH inhibitor and/or 15-PGDH substrate can be administered to the subject at an amount effective to decrease BBB permeability by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or more.
  • the method includes measuring BBB permeability of the subject and administering to the subject an amount of a 15-PGDH inhibitor and/or 15-PGDH substrate effective to decrease the measured BBB permeability of the subject.
  • Methods of measuring BBB permeability can include, for example, tracer-based techniques using dyes, fluorescent tracers, or radiolabeled tracers, magnetic resonance imaging (MRI) techniques using dynamic contrast-enhanced MRI imaging and chelated metal contrast agents, PET/SPECT imaging using radiolabeled small molecules, and/or measurement of albumin CSF/serum ratio.
  • the method includes measuring BBB permeability of the subject following administration of the 15-PGDH inhibitor and/or 15-PGDH substrate and comparing the measured BBB permeability a control, wherein a decrease in BBB permeability is indicative of efficacy of the 15-PGDH inhibitor and/or PGDH substrate in treating neurodegeneration and/or impaired neuronal function in the subject.
  • the control can be, for example, the BBB permeability of the subject prior to administration of the 15-PGDH inhibitor and/or 15-PGDH substrate.
  • the cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, diseases and/or disorders are associated with an increase in BBB permeability of at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% relative to normal or healthy BBB.
  • administration of a 15-PGDH inhibitor and/or 15-PGDH substrate can be used to decrease BBB permeability of the subject from about 5% to about 200%, about 5% to about 180%, about 5% to about 160%, about 5% to about 140%, about 5% to about 120%, about 5% to about 100%, about 5% to about 80%, about 5% to about 60%, about 5% to about 40%, about 10% to about 200%, about 10% to about 180%, about 10% to about 160%, about 10% to about 140%, about 10% to about 120%, about 10% to about 100%, about 10% to about 80%, about 10% to about 60%, about 30% to about 200%, about 30% to about 180%, about 30% to about 160%, about 30% to about 140%, about 30% to about 120%, about 30% to about 100%, about 30% to about 80%, about 40% to about 200%, about 40% to about 180%, about 40% to about 160%, about 40% to about 140%, about 40% to about 120%, about 40% to about 100%, about 50% to about 200%,
  • the diseases or disorders characterized by structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species include brain injuries.
  • Brain injuries that can be treated include any brain injury that is mediated by structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species.
  • TBI traumatic brain injury
  • stroke ischemic and hemorrhagic
  • spinal cord injury SCI
  • brain hemorrhage for example intracerebral hemorrhage and subarachnoid hemorrhage
  • CTE chronic traumatic encephalopathy
  • AD Alzheimer’s disease
  • FTD frontotemporal dementia
  • PD Parkinson’s disease
  • MS multiple sclerosis
  • MS amyloid lateral sclerosis
  • ALS amyloid lateral sclerosis
  • CTE prodromal chronic traumatic encephalopathy
  • AD prodromal Alzheimer’s disease
  • TBI occurs due to a fall, vehicle collision, work injury, sports injury, violence, and the like. TBI can result in various physical, cognitive and behavioral symptoms, depending on the area of the brain affected and its severity, symptoms which may be permanent. It is a major cause of death and disability. Current treatment focusses on minimizing the damage caused, and prevention.
  • CTE also referred to as traumatic encephalopathy syndrome or dementia pugilisitca, is a neurodegenerative condition caused by repeated head injuries, and tends to get worse over time, resulting in dementia. The cause frequently is repeated injury in contact sports, the military, domestic violence, or repeated banging of the head. Firm diagnosis often is made only at autopsy, and no treatment is available and focusses on maintenance and support only.
  • Neurodegenerative diseases are those which involve progressive loss of neurons or their function, including death of neurons, and which result in a progressive loss of brain function.
  • Neurodegenerative diseases associated with a tauopathy include Alzheimer's disease, FTD, and the like.
  • CTE also sometimes also is classified as this type of neurodegenerative disease.
  • the cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, diseases, and/or disorders characterized by structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species can include at least one of subarachnoid hemorrhage, schizophrenia, depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury and/or a visual symptom associated therewith, post-traumatic stress disorder, Parkinson’s disease, Parkinson Plus syndromes, Lewy Body Dementia, multiple system atrophy, corticobasal neurodegeneration, progressive supranuclear palsy, Alexander’s disease, Alzheimer’s disease, Alzheimer's disease related dementias, prodromal Alzheimer’s disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington’s disease, stroke, brain radiation therapy, chronic stress, abuse or cellular toxicity of a neuro-active drug, retinal degeneration, spinal cord injury, peripheral nerve
  • the cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, diseases and/or disorders characterized by structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species is also associated with an aberrant level (e.g., decrease or increase in the level) of at least one eicosanoid selected from PGE2, 15-keto-PGE2, PGF2 ⁇ , 6-keto-PGF1 ⁇ , PGD2, PGJ2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5- HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, 14,15-DHET, or 11,12-DHET in neurotissue of the subject.
  • an aberrant level e.g., decrease or increase in the level
  • the neurodegenerative condition, disease, or disorder can be characterized by structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species and an increase or decrease in the level of at least one eicosanoid selected from PGE2, 15-keto-PGE2, PGF2 ⁇ , 6-keto-PGF1 ⁇ , PGD2, PGJ2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10- DiHOME, 14,15-DHET, or 11,12-DHET of at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, or more in neurotissue of the subject relative to a normal or healthy subject.
  • the 15-PGDH inhibitor and/or 15-PGDH substrate can be administered to the subject to decrease structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species and modulate the level of the aberrant eicosanoid to a normal or healthy level in the neurotissue.
  • the neurodegeneration and/or neurodegenerative condition, disease, or disorder can be associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species and an increase in the level of at least one of 15-keto-PGE2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, or 14,15-DHET in neurotissue (e.g., brain tissue) of the subject, and the 15-PGDH inhibitor and/or 15-PGDH substrate can be administered to the subject at amount effective to decrease structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species and the levels of the at least one of 15-keto-PGE2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, or 14,15-
  • the neurodegeneration and/or neurodegenerative condition, disease, or disorder can be associated with an increase in structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species and a decrease in the levels of at least one of PGJ2, TNE, 15-HETE, or 9,10- DiHOME in neurotissue (e.g., brain tissue) of the subject, and the 15-PGDH inhibitor and/or 15-PGDH substrate can be administered to the subject at amount effective to decrease structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species and increase the levels of the at least one of PGJ2, TNE, 15-HETE, or 9,10-DiHOME in neurotissue (e.g., brain tissue) of the subject.
  • neurotissue e.g., brain tissue
  • FIG. 1 Another embodiments described herein relate to a method of treating and/or inhibiting memory loss and/or cognitive decline associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species in a subject in need thereof by administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor and/or 15-PGDH substrate.
  • the memory loss and/or cognitive decline associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species in a subject in need thereof can be caused by and/or associated with neural injuries, neurodegeneration, neurodegenerative and/or neuropsychiatric conditions, diseases, and/or disorders.
  • neurodegenerative condition, disease, or disorder can include at least one of Alzheimer's disease, prodromal Alzheimer’s disease, Lewy body dementia, prodromal Lewy body dementia, Vascular dementia, prodromal Vascular dementia, Age-related dementia, Frontotemporal dementia, prodromal Frontotemporal dementia, mixed dementia, prodromal mixed dementia, or traumatic brain injury.
  • the memory loss and/or cognitive decline associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system is also associated with an aberrant level (e.g., decrease or increase in the level) of at least one eicosanoid selected from PGE2, 15-keto-PGE2, PGF2 ⁇ , 6-keto-PGF1 ⁇ , PGD2, PGJ2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, 14,15-DHET, or 11,12-DHET in brain tissue of the subject.
  • an aberrant level e.g., decrease or increase in the level
  • the 15-PGDH inhibitor can be administered to the subject to lower GFAP levels and modulate the level of the aberrant eicosanoid to a normal or healthy level in the brain tissue.
  • the memory loss and/or cognitive decline can be associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system and an increase in the level of at least one of 15-keto-PGE2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, or 14,15-DHET in brain tissue of the subject, and the 15-PGDH inhibitor can be administered to the subject at amount effective to decrease the structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species within the nervous system and the level of the at least one of 15-keto-PGE2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE,
  • the memory loss and/or cognitive decline can be associated with an increase structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system and a decrease in the level of at least one of PGJ2, TNE, 15-HETE, or 9,10-DiHOME in brain tissue of the subject, and the 15-PGDH inhibitor can be administered to the subject at amount effective to decrease the structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species within the nervous system and increase the levels of the at least one of PGJ2, TNE, 15-HETE, or 9,10-DiHOME in e.g., brain tissue of the subject.
  • small molecule 15-PGDH inhibitors used to decrease structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species within the nervous system can be identified using assays in which putative inhibitor compounds are applied to cells expressing 15-PGDH and then the functional effects on 15- PGDH activity are determined. Samples or assays comprising 15-PGDH that are treated with a potential inhibitor are compared to control samples without the inhibitor to examine the extent of effect. Control samples (untreated with modulators) are assigned a relative 15- PGDH activity value of 100%.
  • 15-PGDH activity value relative to the control is about 80%, optionally 50% or 25%, 10%, 5% or 1%.
  • Small molecules tested as 15-PGDH inhibitors can be any small chemical molecule or compound.
  • the assays are designed to screen large chemical libraries by automating the assay steps and providing compounds from any convenient source to assays, which are typically run in parallel (e.g., in microtiter formats on microtiter plates in robotic assays).
  • the 15-PGDH inhibitor can include a compound having the following formula (I): pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein n is 0-2; Y 1 , Y 2 , and R 1 are the same or different and are independently hydrogen or a substituted or unsubstituted group selected from C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C 3 -C 20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C 6 -C 24 alkaryl, C6-C24 aralkyl, halo, -Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl, acyloxy
  • the 15-PGDH inhibitor can include a compound having the following formula (II): pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein n is 0-2 X 4 , X 5 , X 6 , and X 7 are independently N or CR c ; R 1 , R 6 , R 7 , and R c are the same or different and independently hydrogen or a substituted or unsubstituted group selected from C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C 6 -C 24 aralkyl, halo, -Si(C 1 -C 3 alkyl) 3 , hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C2-C24 al
  • the 15-PGDH inhibitor can include a compound having the following formula (III) or (IV): (IV) or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein n is 0-2 X 6 is independently N or CR c ; R 1 , R 6 , R 7 , and R c are the same or different and independently hydrogen or a substituted or unsubstituted group selected from C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, -Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy,
  • R 6 and R 7 can each independently be one of the following:
  • R 73 , and R74 are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C 3 -C 20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C1-C6 alkyl), NC(O)(C1-C6 alkyl), O, and S), heteroaryl or heterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C1-C3 alkyl), O, and S), C6-C24 alkaryl, C 6 -C 24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -
  • R 6 and R 7 can independently be a group that improves aqueous solubility, for example, a phosphate ester (-OPO3H2), a phenyl ring linked to a phosphate ester (-OPO 3 H 2 ), a phenyl ring substituted with one or more methoxyethoxy groups, or a morpholine, or an aryl or heteroaryl ring substituted with such a group.
  • the 15-PGDH inhibitor can include a compound having the following formula (V): pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein n is 0-2 X 6 is independently is N or CR c R 1 , R 6 , R 7 , and R c are the same or different each independently hydrogen or a substituted or unsubstituted group selected from C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C 3 -C 20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, halo, -Si(C 1 -C 3 alkyl) 3 , hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C2-C24 alkynyloxy, C5-
  • V pharmaceutically acceptable salt,
  • R 6 and R 7 can each independently be one of the following: each R 8 R9 R10 R11 R12 R13 R14 R15 16 17 18 19 20 21 22 23 24 25 26 27 28 , , , , , , , , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R
  • R 6 and R 7 can independently be a group that improves aqueous solubility, for example, a phosphate ester (-OPO3H2), a phenyl ring linked to a phosphate ester (-OPO 3 H 2 ), a phenyl ring substituted with one or more methoxyethoxy groups, or a morpholine, or an aryl or heteroaryl ring substituted with such a group.
  • the 15-PGDH inhibitor can include a compound having a structure of formula (IA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; R 2 is –NH 2 , CN, or -NHC(O)alkyl; R 6 is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R 3 ; R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR 5 -alkyl, each of which is optionally substituted with one or more R 4 ; R 3 is ox
  • the 15-PGDH inhibitor can include a compound having a structure of formula (IIA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; R 2 is –NH 2 , CN, or -NHC(O)alkyl; R 6 is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R 3 ; R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR 5 -alkyl, each of which is optionally substituted with one or more R 4 ; R 3 is ox
  • R 1 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, -(C 1 -C 6 alkylene)-(3- to 6-membered cycloalkyl), -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), 3- to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl).
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) p -cyclopropyl, -(CH 2 ) p -cyclobutyl, -(CH 2 ) p -cyclopentyl, or -(CH 2 ) p -cyclohexyl; wherein p is 1, 2, or 3.
  • R 2 is –NH 2 .
  • R 6 is 5- to 6-membered heterocyclyl or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more R 3 .
  • R 6 is 5- to 6-membered heteroaryl optionally substituted with one or more R 3 .
  • R 6 is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more R 3 .
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(O)(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), or -C(O)NR 5 (C 1 -C 6 alkyl), each of which is optionally substituted with one or more R 4 .
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R 4 .
  • R 7 is C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 10-membered heteroaryl each of which is optionally substituted with one or more R 4 .
  • R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2, -N(R 5 )(C1-C6 alkylene-OH), -C(O)N(R 5 ) 2 , -C(O)N(R 5 )(C 1 -C 6 alkylene-OH), -C(O)(C 1 -C 6 alkyl), - C(O)O(C1-C6 alkyl), or -S(O)m(C1-C6 alkyl).
  • R 3 is -(C 1 -C 3 alkyl)OH, -NH 2 , -N(C 1 -C 3 alkyl) 2 , -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C 1 -C 3 alkyl)CH 2 CH(CH 2 OH) 2 , -NHCH 2 CH 2 OCH 2 CH 2 OH, -NHCH 2 CH 2 OCH 2 CH 2 NH 2 , -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH(C1-C3 alkyl), -NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1 -C 3 alkyl)CH 2 CH 2 NH(
  • R 3 is -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 , -NHCH 2 CH(CH 2 OH) 2 , -N(C 1 -C 3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH 2 CH 2 NH 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH(C 1 -C 3 alkyl), -NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl)CH 2 CH 2
  • R 3 is -NHCH 2 CH 2 OH or –N(CH 3 )CH 2 CH 2 OH.
  • R 4 is halogen, -CN, -N(R 5 ) 2 , -OH, -O-(C 1 -C 6 alkylene)- OH, -S(O) m (C 1 -C 6 alkyl), -C(O)(C 1 -C 6 alkyl), -C(O)-(3- to 6-membered cycloalkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl.
  • n is 1.
  • the compound has the structure of formula (IIIA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 is 3- to 6-membered cycloalkyl, -(C 1 -C 6 alkylene)-(3- to 6-membered cycloalkyl), 3-to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl); R 2 is –NH2, CN, or -NHC(O)alkyl; R 6 is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R 3 ; R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, - C(O)O-alkyl, or -C(O)NR 5
  • R 1 is 3- to 5-membered cycloalkyl or -(C1-C6 alkylene)- (3- to 5-membered cycloalkyl).
  • R 1 is cyclobutyl.
  • R 1 is a bicyclic 4- to 6-membered cycloalkyl.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(O)(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), or -C(O)NR 5 (C 1 -C 6 alkyl), each of which is optionally substituted with one or more R 4 .
  • R 7 is C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R 4 .
  • R 7 is C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more R 4 .
  • R 7 is C1-C3 alkyl, C1-C3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R 4 .
  • R 7 is C1-C3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R 4 .
  • R 7 is -CF 3 , isopropyl, cyclopropyl, phenyl, pyridyl, pyrazole, or triazole, each of which is optionally substituted with one or more R 4 .
  • R 7 is -CF 3 , cyclopropyl, phenyl, pyridyl, pyrazole, or triazole, each of which is optionally substituted with one or more R 4 .
  • R 3 is -O-(C 1 -C 6 alkylene)-N(R 5 ) 2 , -N(R 5 ) 2 , -N(R 5 )(C 1 -C 6 alkylene-OH), -C(O)N(R 5 ) 2 , -C(O)N(R 5 )(C 1 -C 6 alkylene-OH), -C(O)(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), or -S(O) m (C 1 -C 6 alkyl).
  • R 3 is -NH 2 , -N(C 1 -C 3 alkyl) 2 , -NHCH 2 CH 2 OH, -N(C 1 -C 3 alkyl)CH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 , -NHCH 2 CH(CH 2 OH) 2 , -N(C 1 -C 3 alkyl)CH 2 CH(CH 2 OH) 2 , -NHCH 2 CH 2 OCH 2 CH 2 OH, -NHCH 2 CH 2 OCH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH(C 1 -C 3 alkyl), -NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1
  • R 3 is -NHCH2CH2OH or –N(CH3)CH2CH2OH.
  • substituents at the R 7 position could be modified to improve hERG activity, including hERG inhibition (IC 50 ), blockade, and efflux ratio.
  • IC 50 hERG inhibition
  • certain 6- to 10-membered aryls e.g., optionally substituted phenyl
  • 5-to 10-membered heteroaryls e.g., optionally substituted pyridyls, pyrazoles, and triazoles
  • the compound has the structure of formula (IVA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; R 2 is –NH 2 , CN, or -NHC(O)alkyl; R 6 is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R 3 ; R 7 is C1-C6 haloalkyl, aryl or heteroaryl, each of which is optionally substituted with one or more R 4 ; R 3 is oxo, –OH, -O-alkylene-N(R 5 ).
  • R 7 is –CF 3 , pyridyl, pyrazole, phenyl, or triazole, each of which is optionally substituted with R 4 .
  • R 7 is –CF 3 , pyridyl, fluorophenyl, or a triazole optionally substituted with halogen or methyl.
  • R 7 is –CF 3. 7
  • R is .
  • R7 is [00190]
  • R 6 is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more R 3 .
  • the compound has the structure of formula (VA): (VA) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclyl, or -alkylene-heterocyclyl; R 2 is –NH 2 , CN, or -NHC(O)alkyl; R 6 is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R 3 ; R 7 is 3- to 6-membered cycloalkyl, optionally substituted with one or more R 4 ; R 3 is oxo, –OH, -O-alkylene-N(R 5 ).
  • R 7 is cyclopropyl.
  • R 1 is 3- to 6-membered cycloalkyl, -(C1-C6 alkylene)-(3- to 6-membered cycloalkyl), -(C1-C6 alkylene)-(C1-C6 alkoxy), 3- to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl).
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2)p-cyclopropyl, -(CH2)p-cyclobutyl, -(CH2)p-cyclopentyl, or -(CH2)p-cyclohexyl; wherein p is 1, 2, or 3.
  • R 3 is -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 , -NHCH 2 CH(CH 2 OH) 2 , -N(C 1 -C 3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH 2 CH 2 NH 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH(C 1 -C 3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH 2 CH2NH(C1-C3
  • R 3 is -NHCH 2 CH 2 OH or –N(CH 3 )CH 2 CH 2 OH.
  • R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2 or -N(R 5 )(C1- C 6 alkylene-OH).
  • R 5 is H, C1-C6 alkyl, -(C1-C6 alkylene)-OH, or -S(O)2(C1- C 3 alkyl).
  • R 3 is -NH 2 , -N(C 1 -C 3 alkyl) 2 , -NHCH 2 CH 2 OH, -N(C 1 -C 3 alkyl)CH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 , -NHCH 2 CH(CH 2 OH) 2 , -N(C 1 -C 3 alkyl)CH 2 CH(CH 2 OH) 2 , -NHCH 2 CH 2 OCH 2 CH 2 OH, -NHCH 2 CH 2 OCH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH(C 1 -C 3 alkyl), -NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1
  • R 3 is -NHCH 2 CH 2 OH or –N(CH 3 )CH 2 CH 2 OH. [00205] In still other embodiments, R 3 is –NHCH 2 CH 2 OH. [00206] In some embodiments, R 6 is 5- to 6-membered heterocyclyl or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more R 3 . [00207] In other embodiments, R 6 is 5- to 6-membered heteroaryl optionally substituted with one or more R 3 .
  • R 6 is furan, thiophene, pyrrole, thiazole, isothiazole, oxazole, isooxazole, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyridazine, or pyrazine, each optionally substituted with one or more R 3 .
  • R 6 is thiazole, imidazole, oxazole, pyridine, or pyrimidine.
  • R 6 is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more R 3 .
  • R 6 is 5- to 6-membered heterocyclyl, optionally substituted with one or more R 3 , selected from morpholine, pyridine-one, or piperidine.
  • R 7 is C1-C3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R 4 .
  • R 7 is -CF 3 , cyclopropyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more R 4 .
  • the compound has the structure of formula (VIIA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; R 2 is –NH2, CN, or -NHC(O)alkyl; R 6 is fused bicyclic heterocyclyl or fused bicyclic heteroaryl, each of which is optionally substituted with one or more R 3 ; R 7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR 5 -alkyl, each of which is optionally substituted with one or more R 4 ; R 3 is oxo, -OH, -O-alkyl, or a pharmaceutically acceptable
  • R 6 is 8- to 10-membered fused bicyclic heteroaryl, each of which is optionally substituted with one or more R 3 .
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(O)(C 1 -C 6 alkyl), -C(O)O(C 1 -C 6 alkyl), or -C(O)NR 5 (C 1 -C 6 alkyl), each of which is optionally substituted with one or more R 4 .
  • R 7 is C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R 4 .
  • R 7 is C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more R 4 .
  • R 7 is C 1 -C 3 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R 4 .
  • R 7 is C1-C3 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more R 4 .
  • R 7 is C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more R 4 .
  • R 7 is -CF 3 , isopropyl, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more R 4 .
  • R 7 is -CF 3 , cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more R 4 .
  • R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, -(C1-C6 alkylene)-(3- to 6-membered cycloalkyl), -(C1-C6 alkylene)-(C1-C6 alkoxy), 3- to 6-membered heterocyclyl, or -(C 1 -C 6 alkylene)-(3- to 6-membered heterocyclyl).
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2)p-cyclopropyl, -(CH2)p-cyclobutyl, -(CH2)p-cyclopentyl, or -(CH2)p-cyclohexyl; wherein p is 1, 2, or 3.
  • R 3 is -O-(C1-C6 alkylene)-N(R 5 )2, -N(R 5 )2, -N(R 5 )(C1-C6 alkylene-OH), -C(O)N(R 5 ) 2 , -C(O)N(R 5 )(C 1 -C 6 alkylene-OH), -C(O)(C 1 -C 6 alkyl), -C(O)O(C1-C6 alkyl), or -S(O)m(C1-C6 alkyl).
  • R 3 is -NH 2 , -N(C 1 -C 3 alkyl) 2 , -NHCH 2 CH 2 OH, -N(C 1 -C 3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH 2 CH(CH 2 OH) 2 , -NHCH 2 CH 2 OCH 2 CH 2 OH, -NHCH 2 CH 2 OCH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH(C 1 -C 3 alkyl), -NHCH 2 CH 2 N(C 1 -C 3 alkyl) 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alky
  • R 3 is -NHCH 2 CH 2 OH or –N(CH 3 )CH 2 CH 2 OH.
  • R 4 is halogen, -CN, -N(R 5 ) 2 , -OH, -O-(C 1 -C 6 alkylene)- OH, -S(O) m (C 1 -C 6 alkyl), -C(O)(C 1 -C 6 alkyl), -C(O)-(3- to 6-membered cycloalkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl.
  • the compound has the structure of formula (VIIIA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 is cyclobutyl or -(C1-C4 alkylene)-(C1-C3 alkoxy); R 2 is –NH 2 , CN, or -NHC(O)alkyl; R 6 is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R 3 ; R 3 is oxo, -OH, -O-alkylene-OH, -O-alkylene-N(R 5 )2, -N(R 5 )2, - N(R 5 )(alkylene-OH), -N(R 5 )(alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R 5 )2,
  • R 2 is –NH2.
  • R 6 is 5- to 6-membered heterocyclyl or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more R 3 .
  • R 6 is 5- to 6-membered heteroaryl optionally substituted with one or more R 3 .
  • R 6 is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more R 3 .
  • R 3 is -O-(C 1 -C 6 alkylene)-N(R 5 ) 2 , -N(R 5 ) 2 , -N(R 5 )(C 1 -C 6 alkylene-OH), -C(O)N(R 5 )2, -C(O)N(R 5 )(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C 1 -C 6 alkyl), or -S(O) m (C 1 -C 6 alkyl).
  • R 3 is -(C1-C3 alkyl)OH, -NH2, -N(C1-C3 alkyl)2, -NHCH 2 CH 2 OH, -N(C 1 -C 3 alkyl)CH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 , -NHCH 2 CH(CH 2 OH) 2 , -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH 2 CH 2 NH 2 , -N(C 1 -C 3 alkyl)CH 2 CH 2 NH 2 , -NHCH 2 CH 2 NH(C 1 -C 3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl),
  • R 3 is -NHCH 2 CH 2 OH or –N(CH 3 )CH 2 CH 2 OH.
  • R 4 is halogen, -CN, -N(R 5 ) 2 , -OH, -O-(C 1 -C 6 alkylene)- OH, -S(O) m (C 1 -C 6 alkyl), -C(O)(C 1 -C 6 alkyl), -C(O)-(3- to 6-membered cycloalkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl.
  • n is 1.
  • the compound has the structure of formula (IXA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 is cyclobutyl or -(C1-C4 alkylene)-(C1-C3 alkoxy); R 2 is –NH2, CN, or -NHC(O)alkyl;
  • R 1 is cyclobutyl.
  • R 3 is - NH(C 1 -C 4 alkylene)-OH (e.g., -NH(C 2 -C 4 alkylene)-OH). In some embodiments of Formula (IXA), R 3 is C1-C3 alkyl (e.g., methyl or ethyl). [00242] In some embodiments, of Formula (IXA), R 7 is –CF 3 , isopropyl, cyclopropyl, or cyclobutyl. In some embodiments, of Formula (IXA), R 7 is isopropyl. In some embodiments of Formula (VII), R7 is , , each of which is optionally substituted with one or more R 4 .
  • each R 4 is independently selected from methyl or ethyl.
  • X is –CH.
  • Examples of compounds having formulas (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), (VIIIA), and (IXA) are described in U.S. Patent Application Publication Nos.2015/0072998, 2017/0165241, 2017/0173028, 2018/0118756, WO2018/218251, and WO2020/106998, all of which are incorporated by reference in their entirety.
  • the 15-PGDH inhibitor can include a compound selected from the group consisting of: , , , , , ,
  • R 7 and R 8 are same or different and are each independently selected from the group consisting of H, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl, and at least one of R 7 or R 8 is not H;
  • R 9 , R 10 , R 11 , R 12 , R 13 , and R 15 are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 aryl, heterocycloalkenyl containing from 5-7 ring atoms, (wherein from 1-3 of the ring atoms is independently selected
  • Examples of 15-PGDH inhibitors having formulas (IB), (IBa), (IBb), (IBc), (IBd), (IBe), (IIB), (IIBa), (IIBb), (IIBc), (IIBd), (IBe), or (IIBf) can include the following compounds:
  • 15-PGDH inhibitors include compounds described in WO2022/032230A1, WO2021/236779A1, WO2020/106998A1, WO2018/218251A1, WO2018/145080A1, WO2016/168472A1, WO2015/065716A1, WO2013/158649A1, WO2024/233550A1, U.S. Patent Application Publication No.2024/0294519A1, U.S. Patent Application Publication No.2024/0374579A1, and U.S. Patent Application Publication No. 2024/0409557 all of which are herein incorporated by reference in its entirety.
  • the 15-PGDH inhibitor can be a 5,6-fused and 6,6-fused bicyclic alcohol or ether described in U.S. Patent Application Publication No.2024/0409557.
  • a 5,6- fused and 6,6-fused bicyclic alcohol or ether can be a compound of Formula (A): or pharmaceutically acceptable salts thereof; m is 0 or 1; X is N or CH; Y is N or CR 3 ; Z is N or CR 5 ; b is N or CR 4 ; R 1a is H, deuterium, C 1-6 alkyl, or C 1-6 haloalkyl; wherein, when R 1a is C1-6 alkyl or C1-6 haloalkyl, then R 1a may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, -N(R b ) 2 , C 1-3 alkyl, or C1-3 alkoxy; R 1b is
  • the small molecule 15-PGDH inhibitor can be selected that can ia) at 2.5 ⁇ M concentration, stimulate a Vaco503 reporter cell line expressing a 15- PGDH luciferase fusion construct to a luciferase output level of greater than 70 (using a scale on which a value of 100 indicates a doubling of reporter output over baseline); iia) at 2.5 ⁇ M concentration stimulate a V9m reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 75; iiia) at 7.5 ⁇ M concentration stimulate a LS174T reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 70; and iva) at 7.5 ⁇ M concentration, does not activate a negative control V9m cell line expressing TK-renilla luciferase reporter to a level greater than
  • the small molecule 15-PGDH inhibitor can ib) at 2.5 ⁇ M concentration, stimulate a Vaco503 reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output; iib) at 2.5 ⁇ M concentration stimulate a V9m reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output; iiib) at 7.5 ⁇ M concentration stimulate a LS174T reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output; ivb) at 7.5 ⁇ M concentration, does not activate a negative control V9m cell line expressing TK-renilla luciferase reporter to a luciferase level greater than 20% above background; and vb) inhibits the enzymatic activity of recombinant 15-PGDH protein at an IC 50 of less than 1
  • the small molecule 15-PGDH inhibitor can inhibit the enzymatic activity of recombinant 15-PGDH at an IC 50 of less than 1 ⁇ M, or preferably at an IC50 of less than 250 nM, or more preferably at an IC50 of less than 50 nM, or more preferably at an IC 50 of less than 10 nM, or more preferably at an IC 50 of less than 5 nM at a recombinant 15-PGDH concentration of about 5 nM to about 10 nM.
  • 15-PGDH inhibitors can be used in the methods described herein.
  • 15-PGDH inhibitors can include known 15-PGDH inhibitors including, for example, tetrazole compounds of formulas (I) and (II), 2-alkylideneaminooxyacetamide compounds of formula (I), heterocyclic compounds of formulas (VI) and (VII), and pyrazole compounds of formula (III) described in U.S. Patent Application Publication No.2006/0034786 and U.S. Patent No.7,705,041; benzylidene-1,3- thiazolidine compounds of formula (I) described in U.S.
  • Patent Application Publication No.2007/0071699 phenylfurylmethylthiazolidine-2,4-dione and phenylthienylmethylthiazolidine-2,4-dione compounds described in U.S. Patent Application Publication No.2007/0078175; thiazolidenedione derivatives described in U.S. Patent Application Publication No.2011/0269954; phenylfuran, phenylthiophene, or phenylpyrrazole compounds described in U.S. Patent No.7,294,641, 5-(3,5-disubstituted phenylazo)-2-hydroxybenzene-acetic acids and salts and lactones described in U.S.
  • PubMed PMID 21650226; Duveau DY et al. Structure-activity relationship studies and biological characterization of human NAD(+)- dependent 15-hydroxyprostaglandin dehydrogenase inhibitors. Bioorg Med Chem Lett. 2014;24(2):630-5. doi: 10.1016/j.bmcl.2013.11.081. PubMed PMID: 24360556; PMCID: PMC3970110; Duveau DY et al. Discovery of two small molecule inhibitors, ML387 and ML388, of human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase. Probe Reports from the NIH Molecular Libraries Program.
  • the 15-PGDH inhibitor can include an inhibitory nucleic acid, e.g., antisense DNA or RNA, morpholino oligomer, small interfering RNA (siRNA), microRNA (miRNA), or short hairpin RNA (shRNA).
  • an inhibitory nucleic acid e.g., antisense DNA or RNA, morpholino oligomer, small interfering RNA (siRNA), microRNA (miRNA), or short hairpin RNA (shRNA).
  • the inhibitory RNA targets a sequence that is identical or substantially identical (e.g., at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical) to a target sequence in a 15-PGDH polynucleotide (e.g., a portion comprising at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 contiguous nucleotides, e.g., from 20-500, 20-250, 20-100, 50-500, or 50-250 contiguous nucleotides of a 15-PGDH-encoding polynucleotide sequence (e.g., the human HPGD gene, Gene ID: 3248, including
  • the methods described herein comprise treating a subject with diseases or disorders characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species within the nervous system using an shRNA or siRNA.
  • a shRNA is an artificial RNA molecule with a hairpin turn that can be used to silence target gene expression via the siRNA it produces in cells. See, e.g., Fire et.
  • a method of treating a subject comprises administering to the subject a therapeutically effective amount of a modified RNA or a vector comprising a polynucleotide that encodes an shRNA or siRNA capable of hybridizing to a portion of a 15-PGDH mRNA (e.g., a portion of the human 15-PGDH-encoding polynucleotide sequence set forth in any of GenBank Accession Nos. NM_000860.6.
  • the vector further comprises appropriate expression control elements known in the art, including, e.g., promoters (e.g., inducible promoters or tissue specific promoters), enhancers, and transcription terminators.
  • promoters e.g., inducible promoters or tissue specific promoters
  • enhancers e.g., promoters, enhancers, and transcription terminators.
  • the 15-PGDH inhibitor is a 15-PGDH-specific microRNA (miRNA or miR).
  • miRNA is a small non-coding RNA molecule that functions in RNA silencing and post-transcriptional regulation of gene expression. miRNAs base pair with complementary sequences within the mRNA transcript.
  • the mRNA transcript may be silenced by one or more of the mechanisms, such as cleavage of the mRNA strand, destabilization of the mRNA through shortening of its poly(A) tail, and decrease in the translation efficiency of the mRNA transcript into proteins by ribosomes.
  • the 15-PGDH inhibitor may be a morpholino oligomer, an antisense oligonucleotide, e.g., an RNase H-dependent antisense oligonucleotide (ASO), or combinations thereof.
  • ASOs are single-stranded, chemically modified oligonucleotides that bind to complementary sequences in target mRNAs and reduce gene expression both by RNase H-mediated cleavage of the target RNA and by inhibition of translation by steric blockade of ribosomes.
  • the oligonucleotide is capable of hybridizing to a portion of a 15-PGDH mRNA (e.g., a portion of a human 15-PGDH-encoding polynucleotide sequence as set forth in any of GenBank Accession Nos.
  • the oligonucleotide has a length of about 10-30 nucleotides (e.g., 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or 30 nucleotides). In some embodiments, the oligonucleotide has 100% complementarity to the portion of the mRNA transcript it binds.
  • the DNA oligonucleotide has less than 100% complementarity (e.g., about 95%, about 90%, about 85%, about 80%, about 75%, or about 70% complementarity) to the portion of the mRNA transcript it binds, but can still form a stable RNA:DNA duplex for the RNase H to cleave the mRNA transcript.
  • Suitable antisense molecules, siRNA, miRNA, and shRNA can be produced by standard methods of oligonucleotide synthesis or by ordering such molecules from a contract research organization or supplier by providing the polynucleotide sequence being targeted.
  • Inhibitory nucleic acids can also include morpholino oligomers (DNA bases attached to a backbone of methylenemorpholine rings linked through phosphordiamidate groups), which block access to short (approximately 25 bases) specific sequences of the base- pairing surfaces of ribonucleic acid and are used to knock down gene function. Also included are RNA aptamers, which are short, synthetic oligonucleotide sequences that bind to proteins (see, e.g., Li et al., Nuc. Acids Res. (2006), 34:6416-24). Both are notable for both high affinity and specificity for the targeted molecule, and have the additional advantage of being smaller than antibodies (usually less than 6 kD).
  • RNA aptamers with a desired specificity are generally selected from a combinatorial library, and can be modified to reduce vulnerability to ribonucleases, using methods known in the art.
  • the 15-PGDH inhibitor is an anti-15-PGDH antibody or an antigen-binding fragment thereof.
  • the antibody is a blocking antibody (e.g., an antibody that binds to a target and directly interferes with the target's function, e.g., 15-PGDH enzyme activity).
  • the antibody is a neutralizing antibody (e.g., an antibody that binds to a target and negates the downstream cellular effects of the target).
  • the antibody binds to human 15-PGDH.
  • the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is an antigen-binding fragment, such as a F(ab′)2, Fab′, Fab, scFv, and the like. The term “antibody or antigen-binding fragment” can also encompass multi-specific and hybrid antibodies, with dual or multiple antigen or epitope specificities.
  • an anti-15-PGDH antibody comprises a heavy chain sequence or a portion thereof, and/or a light chain sequence or a portion thereof, of an antibody sequence disclosed herein.
  • an anti-15-PGDH antibody comprises one or more complementarity determining regions (CDRs) of an anti-15-PGDH antibody as disclosed herein.
  • an anti-15-PGDH antibody is a nanobody, or single-domain antibody (sdAb), comprising a single monomeric variable antibody domain, e.g., a single VHH domain.
  • sdAb single-domain antibody
  • antibodies are prepared by immunizing an animal or animals (such as mice, rabbits, or rats) with an antigen for the induction of an antibody response.
  • the antigen is administered in conjugation with an adjuvant (e.g., Freund's adjuvant).
  • an adjuvant e.g., Freund's adjuvant
  • one or more subsequent booster injections of the antigen can be administered to improve antibody production.
  • antigen-specific B cells are harvested, e.g., from the spleen and/or lymphoid tissue. For generating monoclonal antibodies, the B cells are fused with myeloma cells, which are subsequently screened for antigen specificity.
  • genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody.
  • Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells.
  • phage or yeast display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992); Lou et al. m PEDS 23:311 (2010); and Chao et al., Nature Protocols, 1:755-768 (2006)).
  • antibodies and antibody sequences may be isolated and/or identified using a yeast-based antibody presentation system, such as that disclosed in, e.g., Xu et al., Protein Eng Des Sel, 2013, 26:663-670; WO 2009/036379; WO 2010/105256; and WO 2012/009568. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby, Immunology (3rd ed.1997)). Techniques for the production of single chain antibodies or recombinant antibodies (U.S. Pat. Nos.4,946,778, 4,816,567) can also be adapted to produce antibodies.
  • Antibodies can be produced using any number of expression systems, including prokaryotic and eukaryotic expression systems.
  • the expression system is a mammalian cell, such as a hybridoma, or a CHO cell. Many such systems are widely available from commercial suppliers.
  • the VH and VL regions may be expressed using a single vector, e.g., in a di-cistronic expression unit, or be under the control of different promoters. In other embodiments, the VH and VL region may be expressed using separate vectors.
  • an anti-15-PGDH antibody comprises one or more CDR, heavy chain, and/or light chain sequences that are affinity matured.
  • chimeric antibodies methods of making chimeric antibodies are known in the art.
  • chimeric antibodies can be made in which the antigen binding region (heavy chain variable region and light chain variable region) from one species, such as a mouse, is fused to the effector region (constant domain) of another species, such as a human.
  • “class switched” chimeric antibodies can be made in which the effector region of an antibody is substituted with an effector region of a different immunoglobulin class or subclass.
  • an anti-15-PGDH antibody comprises one or more CDR, heavy chain, and/or light chain sequences that are humanized.
  • humanized antibodies methods of making humanized antibodies are known in the art. See, e.g., U.S. Pat. No. 8,095,890.
  • a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human.
  • human antibodies can be generated.
  • transgenic animals e.g., mice
  • mice can be produced that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production.
  • JH antibody heavy-chain joining region
  • antibody fragments such as a Fab, a Fab′, a F(ab′)2, a scFv, nanobody, or a diabody
  • Various techniques have been developed for the production of antibody fragments, such as proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., J. Biochem. Biophys. Meth., 24:107-117 (1992); and Brennan et al., Science, 229:81 (1985)) and the use of recombinant host cells to produce the fragments.
  • antibody fragments can be isolated from antibody phage libraries.
  • Fab′-SH fragments can be directly recovered from E. coli cells and chemically coupled to form F(ab′)2 fragments (see, e.g., Carter et al., BioTechnology, 10:163-167 (1992)).
  • F(ab′)2 fragments can be isolated directly from recombinant host cell culture.
  • Other techniques for the production of antibody fragments will be apparent to those skilled in the art. [00273] Methods for measuring binding affinity and binding kinetics are known in the art.
  • the nucleic acid molecules may be used in a TALEN (transcription activator-like effector nuclease technology), zinc-finger nuclease or CRISPR- Cas system to target a nucleic acid sequence for genetic screening, targeted transcriptional regulation, targeted knock-in, and targeted genome editing, including base editing, epigenetic editing, and introducing double strand breaks (DSBs) for homologous recombination- mediated insertion of a nucleotide sequence.
  • TALEN transcription activator-like effector nuclease technology
  • zinc-finger nuclease or CRISPR- Cas system to target a nucleic acid sequence for genetic screening, targeted transcriptional regulation, targeted knock-in, and targeted genome editing, including base editing, epigenetic editing, and introducing double strand breaks (DSBs) for homologous recombination- mediated insertion of a nucleotide sequence.
  • Genome editing can refer to the targeted modification of a DNA sequence, including but not limited to, adding, removing, replacing, or modifying existing DNA sequences, and inducing chromosomal rearrangements or modifying transcription regulation elements (e.g., methylation/demethylation of a promoter sequence of a gene) to alter gene expression.
  • inhibiting 15-PGDH expression comprises inserting a silencer sequence near a polynucleotide sequence encoding 15-PGDH.
  • upregulating PGE2 synthesis comprises inserting an enhancer sequence near a polynucleotide sequence encoding PGE2.
  • CRISPR-Cas system requires a guide system that can locate Cas protein to the target DNA site in the genome.
  • the guide system comprises a crispr RNA (crRNA) with a 17-20 nucleotide sequence that is complementary to a target DNA site and a trans-activating crRNA (tracrRNA) scaffold recognized by the Cas protein (e.g., Cas9).
  • the 17-20 nucleotide sequence complementary to a target DNA site is referred to as a spacer while the 17-20 nucleotide target DNA sequence is referred to a protospacer.
  • crRNAs and tracrRNAs exist as two separate RNA molecules in nature, single guide RNA (sgRNA or gRNA) can be engineered to combine and fuse crRNA and tracrRNA elements into one single RNA molecule.
  • the CRISPR guide system comprises two or more RNAs, e.g., crRNA and tracrRNA.
  • the CRISPR guide system comprises a sgRNA comprising a spacer sequence for genomic targeting and a scaffold sequence for Cas protein binding.
  • the guide system naturally comprises a sgRNA.
  • Cas12a/Cpf1 utilizes a guide system lacking tracrRNA and comprising only a crRNA containing a spacer sequence and a scaffold for Cas12a/Cpf1 binding. While the spacer sequence can be varied depending on a target site in the genome, the scaffold sequence for Cas protein binding can be identical for all gRNAs.
  • CRISPR-Cas systems described herein can comprise different CRISPR enzymes.
  • the CRISPR-Cas system can comprise Cas9, Cas12a/Cpf1, Cas12b/C2c1, Cas12c/C2c3, Cas12d/CasY, Cas12e/CasX, Cas12g, Cas12h, or Cas12i.
  • Non- limiting examples of Cas enzymes include, but are not limited to, Cas1, CasiB, Cas2, Cas3, Cas4, Cas5, Cas5d, Cas5t, Cas5h, Cas5a, Cas6, Cas7, Cas8, Cas8a, Cas8b, Cas8c, Cas9 (also known as Csn1 or Csx12), Cas10, Cas10d, Cas12a/Cpf1, Cas12b/C2c1, Cas12c/C2c3, Cas12d/CasY, Cas12e/CasX, Cas12f/Cas14/C2c10, Cas12g, Cas12h, Cas12i, Cas12k/C2c5, Cas13a/C2c2, Cas13b, Cas13c, Cas13d, C2c4, C2c8, C2c9, Csy1, Csy2, Csy3, Csy4, Cse1, Cs
  • Type II Cas effector proteins Type V Cas effector proteins
  • Type VI Cas effector proteins CARF, DinG, homologues thereof, or modified or engineered versions thereof such as dCas9 (endonuclease-dead Cas9) and nCas9 (Cas9 nickase that has inactive DNA cleavage domain).
  • compositions, methods, devices, and systems, described herein may use the Cas9 nuclease from Streptococcus pyogenes, of which amino acid sequences and structures are well known to those skilled in the art.
  • Binding of a Cas protein to its target DNA sequence i.e. target dsDNA
  • PAM protospacer adjacent motif
  • Cas proteins from different bacterial species recognize different PAM sequences and make cuts 3-4 nucleotides upstream (e.g., Cas9) or 18-23 nucleotides downstream (e.g., Cas12a/Cpf1) of the PAM sequence.
  • Cas9 from Streptococcus pyogene recognizes the PAM sequence 5′-NGG-3′ (wherein “N” can be any nucleotide) and cleaves 3 nucleotide upstream of the PAM sequence.
  • Cas9 from Staphylococcus aureus recognizes the PAM sequence 5′-NNGRRN-3′ (wherein “N” can be any nucleotide) and cleaves 4 nucleotide upstream of the PAM sequence.
  • N can be any nucleotide
  • the PAM sequence is essential for Cas-mediated cleavage, in some instances, the gRNA sequence does not comprise a PAM sequence.
  • nucleic acid molecules comprising a target sequence comprising a spacer that is complementary to a sequence at a target site in the genome.
  • a spacer, as described herein can comprise about 10 to about 25 nucleotides in length.
  • a spacer sequence that is complementary to a target site sequence in the genome can be about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 27, 28, 30, or more nucleotides in length.
  • a target site, as described herein can comprise a sequence of about 20 nucleotides immediately upstream or 5′ of the first nucleotide of the PAM.
  • guide system nucleic acid molecules wherein at least 1, at least 2, or at least 3 consecutive nucleotides at the 5′ terminus of the guide system nucleic acid molecules are 100% identical to the 3′ terminus of the target sequence in a genome.
  • guide system nucleic acid molecules exhibiting enhanced editing efficiency of a target sequence when guide system nucleic acid molecules are contacted with the target sequence in a complex with a CRISPR-Cas system (e.g., CRISPR- Cas9, CRISPR-Cas12a/Cpf1, etc.).
  • gRNA guide RNA
  • gRNA can exhibit enhanced editing efficiency of a target sequence when in complex with a CRISPR- Cas system compared to a gRNA comprising additional one or more 5′ terminal G nucleotides, wherein the additional one or more 5′ terminal G nucleotides are not present in the protospacer sequence or not complementary to one or more nucleotides at the 3′ terminus of the target sequence in a genome.
  • the term “codon” generally refers to three consecutive nucleotides, which may or may not encode an amino acid.
  • the efficiency of editing can refer to the ability of a guide system nucleic acid molecule directed effector protein (e.g., CRISPR-Cas protein) to modify a target DNA sequence.
  • modification of a target sequence can include introducing a double stranded break, modifying a nucleobase, inducing chromosomal rearrangements, and modifying methylation/demethylation of a promoter sequence of a gene.
  • a target sequence may be located in a gene or in a promoter region in a genome.
  • An effector protein may be a gRNA directed nuclease, e.g., Cas protein such as Cas9 or any other Cas protein described herein.
  • the editing efficiency can be measured by using any methods well known to one skilled in the art.
  • the efficiency of genome editing or editing efficiency can be measured by using tracking of indels by decomposition (TIDE) analysis, surveyor nuclease assay, junction PCR, droplet digital PCR (ddPCR), denaturing high- performance liquid chromatography (DHPLC), PCR single-stranded conformational polymorphism (SSCP), high-resolution melting (HRM), restriction enzyme digestion- suppressed PCR (RE-PCR), engineered nuclease-induced translocations (ENIT), restriction enzyme digestion, Sanger DNA sequencing, deep sequencing such as next generation sequencing (NGS), or any combination thereof.
  • TIDE indels by decomposition
  • ddPCR droplet digital PCR
  • DPLC denaturing high- performance liquid chromatography
  • SSCP PCR single-stranded conformational polymorphism
  • HRM high-resolution melting
  • RE-PCR restriction enzyme digestion- suppressed PCR
  • ENIT engine
  • the efficiency of genome editing e.g., generating a double-strand break
  • TIDE analysis a three-step method whereby the region targeted by the nuclease (e.g., Cas9) is PCR-amplified from DNA isolated from cells transfected with CRISPR-Cas system and gRNAs. Amplicons of 500-1500 bp generated around the target site are subject to conventional Sanger DNA sequencing followed by analysis using the web-based TIDE software.
  • the editing efficiency e.g., the efficiency of generating a DNA break in the intended target site, is at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.
  • guide system nucleic acid molecules that exhibit reduced off-target editing (e.g., editing of a non-target sequence) when guide system nucleic acid molecules are contacted with the target sequence in a complex with a CRISPR-Cas system (e.g., CRISPR-Cas9, CRISPR-Cas12a/Cpf1, etc.).
  • off-target editing e.g., editing of a non-target sequence
  • CRISPR-Cas system e.g., CRISPR-Cas9, CRISPR-Cas12a/Cpf1, etc.
  • gRNA provided herein can exhibit reduced off-target editing when in complex with a CRISPR-Cas system compared to a gRNA comprising additional one or more 5′ terminal G nucleotides, wherein the additional one or more 5′ terminal G nucleotides are not present in the protospacer sequence or not complementary to one or more nucleotides at the 3′ terminus of the target sequence in a genome.
  • the off-target editing can be reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.
  • the scaffold region of the guide system nucleic acid molecule recognized by the Cas protein may form a secondary structure such as a stem, a hairpin, and/or a loop.
  • Stems or hairpins, described herein can be about 3-10 nucleotides in length.
  • Loops can be about 6-20 nucleotides in length.
  • Stems may comprise one or more bulges of 1-10 nucleotides in length.
  • guide system nucleic acid molecules comprising a target sequence comprising one or more mismatched nucleotide
  • the spacer sequence may comprise one or more nucleotides that are not complementary to the target site sequence in the genome.
  • Spacers described herein may harbor various number of mismatches, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches.
  • a spacer comprises at most 1, 2, 3, 4, or 5 mismatches.
  • a spacer does not comprise any mismatch as compared to a protospacer sequence at the target site, i.e., the spacer hybridizes with the target sequence at 100%.
  • Spacers described herein may comprise at least 1 to at least 5 mismatched nucleotides.
  • the spacer may comprise at least 1, at least 2, at least 3, at least 4, or at least 5 mismatched nucleotides.
  • the spacer may comprise at most 3, at most 4, at most 5, at most 6, or at most 7 mismatched nucleotides.
  • the one or more mismatched nucleotides may be located at the 5′ terminus of the spacer sequence.
  • the one or more mismatched nucleotides may be located at the 3′ terminus of the spacer sequence.
  • the one or more mismatched nucleotides may be internally located in the spacer sequence.
  • a sequence extension can be on the 5′ or 3′ terminus or can be added internally.
  • the 5′ terminus of the gRNA Cas12a/Cpf1 e.g., crRNA
  • the 5′ terminus of the gRNA Cas12a/Cpf1 can be extended by 2- 59 nucleotides.
  • Extending the 5′ terminus of the Cas12a/Cpf1 gRNA, which comprises a scaffold sequence for Cas12a/Cpf1 binding on the 5′ terminus and a target sequence on the 3′ terminus can increase the editing efficiency and delivery of Cas12a/Cpf1 in vitro and in vivo.
  • a gRNA of Cas9 comprising an internal extension of 2-10 nucleotides to extend the stem region of the stem loop structure can increases gene knockout efficiency in CRISPR-Cas9-mediated genome editing.
  • a gRNA may comprise two or more of crRNA sequences and tracrRNA sequence and bind two or more Cas proteins and a target DNA sites at two or more distinct regions in the genome.
  • the gRNAs described herein may comprise a 5′ sequence extension.
  • the gRNAs described herein may comprise a 3′ sequence extension.
  • the gRNAs described herein may comprise an internal sequence extension.
  • the sequence extension can comprise about at least 1 to at least 70 nucleotides.
  • the sequence extension can comprise at least 1, at least 5, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, or at least 70 nucleotides.
  • G guanine
  • a nucleotide analog comprises an alteration in a phosphate backbone, a sugar, and/or nucleobases.
  • Non-limiting examples of nucleotide analog include 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5- iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2- aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 0(6)-methylguanine, 2-thiocytidine, 2′-fluororibose, ribose, 2′-deoxyribose, arabinose, hexose, phosphorothioate linkages, 5′-N-phosphoramidite link
  • gRNAs comprising a 5′ terminal G analog that can exhibit enhanced editing efficiency of a target sequence when in complex with a CRISPR-Cas system compared to a gRNA lacking 5′ terminal G analog.
  • nucleic acid molecules comprising 10 to 100 nucleotides in length.
  • the synthesized nucleic acid molecules comprises 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nucleotides in length.
  • the synthesized nucleic acid molecules comprises 10 to 20 nucleotides, 10 to 30 nucleotides, 10 to 40 nucleotides, 10 to 50 nucleotides, 10 to 60 nucleotides, 10 to 70 nucleotides, 10 to 80 nucleotides, 10 to 90 nucleotides, 10 to 100 nucleotides, 20 to 30 nucleotides, 20 to 40 nucleotides, 20 to 50 nucleotides, 20 to 60 nucleotides, 20 to 70 nucleotides, 20 to 80 nucleotides, 20 to 90 nucleotides, 20 to 100 nucleotides, 30 to 40 nucleotides, 30 to 50 nucleotides, 30 to 60 nucleotides, 30 to 70 nucleotides, 30 to 80 nucleotides, 30 to 90 nucleotides, 30 to 100 nucleotides, 40 to 50 nucleotides, 40 to 60 nucleotides, 30 to 70 nucleotides, 30
  • the synthesized nucleic acid molecules comprises at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, or at least 90 nucleotides in length. In some embodiments, the synthesized nucleic acid molecules comprises at most 20, at most 30, at most 40, at most 50, at most 60, at most 70, at most 80, at most 90, or at most 100 nucleotides in length. In some embodiments, the synthesized nucleic acid molecules comprises at least 20 nucleotides in length. In some embodiments, the synthesized nucleic acid molecules comprises at least 80 nucleotides in length. In some embodiments, the synthesized nucleic acid molecules comprises at most 30 nucleotides in length.
  • the synthesized nucleic acid molecules can comprise one or more modifications.
  • the synthesized nucleic acid molecules can comprise synthetic nucleotide, synthetic nucleotide analog, nucleotide derivatives, and/or modified nucleotides.
  • the one or more modification can increase stability of the synthesized nucleic acid molecules.
  • the one or more modification can enhance biological activity of the synthesized nucleic acid molecules.
  • a modification of internucleotide linkage using phosphorothioate (PS) bond substitutes can be introduced to inhibit exonuclease-mediated degradation of nucleic acid molecules.
  • PS phosphorothioate
  • the one or more modifications can be made at any location of the synthesized nucleic acid molecule.
  • the synthesized nucleic acid molecule can comprise natural nucleosides (e.g., adenosine, guanosine, cytidine, and uridine), nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5- iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2- aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-ox
  • nucleic acid molecule comprising a chemical modification.
  • Chemical modifications as described herein may comprise one or more 5′ modifications selected from the group consisting of 5′ triphosphate, 5′ diphosphate, 5′ monophosphate, and 5′ hydroxyl.
  • the chemical modification comprises one or more ribose modifications selected from the group consisting of 2′-O-methylation (2′OMe), 2′-O- methoxy-ethyl (2′-MOE), 2′-fluoro (2′F), 2-deoxy-2′-thio, and 2′-azido.
  • the chemical modification comprises one or more internucleotide linkage modifications selected from the group consisting of phosphorothioate, methylphosphonate, phosphonocarboxylate phosphonothiocarboxylate, boranophosphonate, alkylphosphonate, and alkylphosphonate.
  • Chemical modifications can further comprise modified nucleotides comprising one or more heterocyclic modifications selected from the group consisting of 2,6- Diaminopurine, 2-Aminopurine, inosine, 2-aminoadenosine, N6-methyladenosine, N6,2′-O- dimethyladenosine, N1-methyladenosine, 2-amino-6-chloropurineriboside, 5-methylcytidine, 5-hydroxymethylcytidine, 8-oxo-7,8-dihydroguanosine, pseudouridine, N4-acetylcytidine, 5- bromo-uridine, 5-methyluridine, and 5-nitroindole.
  • heterocyclic modifications selected from the group consisting of 2,6- Diaminopurine, 2-Aminopurine, inosine, 2-aminoadenosine, N6-methyladenosine, N6,2′-O- dimethyladenosine, N1-methyladeno
  • the chemical modification comprises, but is not limited to, modified nucleotides comprising one or more 5′ cap modifications selected from the group consisting of GpppG, 7-methylguanylate (m7GpppG), m2,2,7GpppG, and m7-3′-OGpppG (ARCA).
  • the chemical modification comprises modified nucleotides comprising one or more 5′ cap modifications selected from the group consisting of an attachment chemistry (e.g., biotin), a dye, a cell targeting moiety, an active chemistry, and an amino modifier.
  • the attachment chemistry can comprise biotin.
  • the dye comprises fluorescein.
  • the cell targeting moiety comprises digoxigenin.
  • the active chemistry comprises azides, acrydite, thiols, or alkynes.
  • the amino modifier comprises aminoallyl.
  • the 15-PGDH inhibitor can provide regulated degradation of 15-PGDH by incorporating a degron into the amino acid sequence of 15- PGDH that allows recruitment to the endogenous protein turnover machinery. Mechanisms for targeted protein degradation include, but are not limited to, recruitment to an E3 ligase for ubiquitination and subsequent proteasomal degradation, direct recruitment to the proteasome, and recruitment to the lysosome.
  • methods for inducible protein degradation by a degron includes, but is not limited to, ligand induced degradation (LID) using a SMASH tag, ligand induced degradation using Shield-1, ligand induced degradation using auxin, ligand induced degradation using rapamycin, peptidic degrons (e.g., IKZF3 based degrons), and proteolysis- targeting chimeras (PROTACs).
  • LID ligand induced degradation
  • Shield-1 ligand induced degradation using auxin
  • ligand induced degradation using rapamycin peptidic degrons (e.g., IKZF3 based degrons)
  • PROTACs proteolysis- targeting chimeras
  • a degron tag that is held in an inactive conformation but is induced to adopt a conformation capable of recognition by the proteasome upon binding of a specific molecule, such as but not limited to, a Shield-1 molecule.
  • a specific molecule such as but not limited to, a Shield-1 molecule.
  • the inducible degron element is selected from the group consisting of a ligand inducible degron element such as a small molecule-assisted shutoff (SMASH) degron element, Shield-1 responsive degron element, auxin responsive degron element, and rapamycin responsive degron element; a peptidic degron element; and a peptidic proteolysis targeting chimera (PROTAC) element.
  • SMASH small molecule-assisted shutoff
  • PROTAC peptidic proteolysis targeting chimera
  • the ligand inducible degron element is a small molecule-assisted shutoff (SMASH) degron element and the exogenous factor for controlling immunogenicity is asunaprevir.
  • SMASH small molecule-assisted shutoff
  • a peptide tag is used that confers small molecule-mediated recruitment to an E3 ligase.
  • the peptide tag comprises the lymphoid-restricted transcription factor IKZF3 that is recruited to the E3 ligase receptor (CRBN) in an immunomodulatory drug (IMiD) dependent manner, as described in Koduri et al., Proc Natl Acad Sci, 2019, 116(7), 2539-2544, which is herein incorporated by reference in its entirety.
  • the degron is capable of targeting immunosuppressive factors for degradation (e.g., through a ubiquitination pathway), inducing protein degradation, or degrading proteins.
  • the 15-PGDH inhibitors and/or 15-PGDH substrates described herein can be used to treat, prevent, or reduce the symptoms or severity of any neural injury, neurodegeneration, neurodegenerative and/or neuropsychiatric conditions, diseases, and/or disorders characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species within the nervous system of a subject in need thereof.
  • a subject having the neural injury, neurodegeneration, neurodegenerative and/or neuropsychiatric conditions, diseases, and/or disorders characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species within the nervous system of a subject in need thereof can have or be at risk of memory loss, cognitive decline, axonal degeneration, neuronal cell death, glia cell damage, and/or blood brain barrier permeability, and the 15-PGDH inhibitor can be administered to the subject at an amount effective to decrease structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species within the nervous system of a subject in need thereof.
  • Subjects amenable to treatment by 15-PGDH inhibitors and/or 15-PGDH substrates as disclosed herein include subjects having structural deterioration of the blood- brain barrier and/or increased generation of reactive oxygen species within the nervous system and at risk of a neurodegenerative condition, disease, or disorder but not showing symptoms (for example asymptomatic subjects), as well as subjects presently showing symptoms.
  • the present methods can be administered prophylactically to the general population characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species within the nervous system without any assessment of the risk of the subject patient.
  • Subjects can be further screened for their likelihood of having or developing a neurodegenerative condition, disease, or disorder based on a number of biochemical and genetic markers in addition to structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system. For example, one can also diagnose a subject with increased risk of developing Alzheimer's Disease using genetic markers for Alzheimer's Disease. Genetic abnormality in a few families has been traced to chromosome 21 (St.
  • One genetic marker is, for example mutations in the APP gene, particularly mutations at position 717 and positions 670 and 671 referred to as the Hardy and Swedish mutations respectively (see Hardy, TINS, supra).
  • Other markers of risk are mutations in the presenilin genes, PS1 and PS2, and ApoE4, family history of Alzheimer's Disease, hypercholesterolemia or atherosclerosis. Subjects with APP, PS1 or PS2 mutations are highly likely to develop Alzheimer's disease. ApoE is a susceptibility gene, and subjects with the e4 isoform of ApoE (ApoE4 isoform) have an increased risk of developing Alzheimer's disease.
  • Alzheimer disease susceptibility genes include, for example ACE, CHRNB2, CST3, ESR1, GAPDH, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF and be used to identify subjects with increased risk of developing Alzheimer's disease (Bertram et al, Nat. Genet.2007 January; 39(1):17-23), as well as variances in the alpha-T catenin (VR22) gene (Bertram et al, J Med. Genet.2007 January; 44(1):e63) and Insulin-degrading enzyme (IDE) and Kim et al, J Biol. Chem.2007; 282:7825-32).
  • Neurodegenerative conditions, disease, or disorders associated with cognitive decline or memory loss can be diagnosed using standard practice and the progression can be monitored over an extended period of time.
  • One such method includes at least one of the following; (i) a memory assessment, (ii) an extensive neuropsychological exam, (iii) an examination by a geriatric neurologist and (iv) MRI imaging of the brain.
  • Disease progression can be documented by changes in these parameters over time.
  • changes in the parameters of at least one of these assessments can be used to assess the efficacy of the 15-PGDH inhibitors and/or 15-PGDH substrates in the subject over time.
  • Other methods to diagnose a patient at risk of or having a neurodegenerative condition, disease or disorder includes measurement of blood-brain barrier permeability and/or generation of reactive oxygen species within the nervous system and 15-PGDH activity and/or expression in the neurotissue, such as brain tissue, wherein increased blood-brain barrier permeability and/or increased generation of reactive oxygen species within the nervous system of the subject and 15-PGDH activity and/or expression compared to a control (e.g., normal or healthy neurotissue) is indicative of the subject having or at increased risk of the neurodegenerative condition, disease, or disorder.
  • a control e.g., normal or healthy neurotissue
  • direct detection of BBB breakdown can be assessed using MRI and injection of contrasting agent. Improvements in the resolution of MRIs and in the use of special contrasting agents can be used to detect BBB permeability.
  • subjects are administered a contrasting agent immediately prior to brain imaging, such as MRI imaging.
  • MRI imaging In cases of intact BBB, the contrasting agents are confined to brain blood vessels whereas, in subjects with a disrupted BBB, the contrasting agent is "sprayed out" into the brain tissue, which can be visualized.
  • the brain locations, the size of BBB breakdown and extent of BBB compromise, such as extent of vascular leak in subjects can be directly and quantitatively assessed as measurable parameters of BBB permeability.
  • such methods can be used to assess any improvements in these parameters resulting from treatment of the subject with an agent that inhibits 15-PGDH activity.
  • Direct visualization of BBB breakdown and its associated vascular leak into the brain is useful in the methods as disclosed herein for monitoring the beneficial effects of treating a subject with BBB permeability with a 15-PGDH inhibitor and/or 15-PGDH substrate.
  • An improvement in at least one measurable parameter of BBB permeability, such as location, size of BBB breakdown and extent of vascular leak in subjects administered a 15-PGDH inhibitor and/or 15-PGDH substrate indicates a positive outcome from administration of an inhibitor of 15- PGDH.
  • Parameters of BBB permeability can be monitored by direct visualization and quantified by MRI-associated image analysis and are useful in the methods as disclosed herein.
  • the 15-PGDH inhibitors and/or 15-PGDH substrates described herein are useful in preventing and treating neurodegenerative conditions, diseases and disorders, such as those characterized by structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system, aberrant 15-PGDH activity, and risk of memory loss, cognitive decline, axonal degeneration, neuronal cell death, or glia cell damage.
  • neurodegenerative conditions, diseases, or disorders can include subarachnoid hemorrhage, schizophrenia, depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury and/or a visual symptom associated therewith, post-traumatic stress disorder, Parkinson’s disease, Parkinson Plus syndromes, Lewy Body Dementia, multiple system atrophy, corticobasal neurodegeneration, progressive supranuclear palsy, Alexander’s disease, Alzheimer’s disease, Alzheimer's disease related dementias, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington’s disease, stroke, brain radiation therapy, chronic stress, abuse or cellular toxicity of a neuro-active drug, retinal degeneration, spinal cord injury, peripheral nerve injury, idiopathic peripheral neuropathy, cognitive decline and/or general frailty associated with normal aging and/or chemotherapy, chemotherapy induced neuropathy, concussive injury, peripheral nerve crush injury, peripheral neuropathy, diabetic neuropathy, post-traumatic headache, multiple
  • Additional examples of neurodegenerative diseases or disorders associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system include, for example, polyglutamine repeat disorders such as Spinocerebellar ataxias (e.g., types 1, 2, 3, 6, 7 and 17), Machado-Joseph disease, Spinal and Bulbar muscular atrophy (SBMA or Kennedy's disease), Dentatorubral Pallidoluysian Atrophy (DRPLA) and other neurological conditions arising from polyglutamine expansions, or disease arising from non-coding DNA repeat expansions such as Fragile X syndrome, Fragile XE mental retardation, Friedreich ataxia, myotonic dystrophy, Spinocerebellar ataxias (types 8, 10 and 12) or other neurodegenerative diseases such as spinal muscular atrophy (Werdnig-Hoffman disease, Kugelberg-Welander disease), and spongiform encephalopathies.
  • polyglutamine repeat disorders such
  • Additional neurodegenerative diseases associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system for which agents inhibiting 15-PGDH can be useful include, for example, age-related memory impairment, agyrophilic grain dementia, Parkinsonism-dementia complex of Guam, auto-immune conditions (eg Guillain-Barre syndrome, Lupus), Biswanger's disease, brain and spinal tumors (including neurofibromatosis), cerebral amyloid angiopathies (Journal of Alzheimer's Disease vol 3, 65-73 (2001)), cerebral palsy, chronic fatigue syndrome, corticobasal degeneration, conditions due to developmental dysfunction of the CNS parenchyma, conditions due to developmental dysfunction of the cerebrovasculature, dementia--multi infarct, dementia--subcortical, dementia with Lewy bodies, dementia of human immunodeficiency virus (HIV), dementia lacking distinct histology, Dementia Pugilistica, diffies neurodegenerative diseases
  • Additional neurodegenerative diseases associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system for which 15-PGDH inhibitors and/or 15-PGDH substrates are useful include other dementias not listed above, such as but without limitation, other mixed dementia, frontotemporal dementia, progressive supranuclear palsy (PSP), Parkinson's Disease with associated dementia, corticobasal degeneration, multiple system atrophy, HIV-induced dementia, white matter disease-associated dementias, mild cognitive impairment (MCI).
  • the 15-PGDH inhibitors and/or 15-PGDH substrates described herein are useful in preventing and treating blood brain barrier (BBB) permeability in a subject.
  • BBB blood brain barrier
  • diseases and disorders where BBB permeability occurs include, for example, multiple sclerosis, cerebral amyloid angiopathy, diabetic retinopathy, prion disorders, amyotrophic lateral sclerosis (ALS), Stiff-person Syndrome, Spinocerebellar Ataxias, Friedreich Ataxia, Ataxia Telangiectasia, Bulbospinal Atrophy (Kennedy Syndrome), Spinal Muscular Atrophy, Neuronal storage diseases (lipofuscinoses), Mitochondrial encephalomyopathies, Leukodystrophies, Neural sequelae of spinal shock/blunt trauma, Hypertensive Cerebrovascular disease, such as Lacunar Infarcts, Slit hemorrhages, Hypertensive encephalopathy.
  • ALS amyotrophic lateral sclerosis
  • Stiff-person Syndrome Spinocerebellar Ataxias
  • Friedreich Ataxia Friedreich Ataxia
  • Ataxia Telangiectasia Bulbospinal At
  • the 15-PGDH inhibitor and/or 15-PGDH substrate can be administered to a subject with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system associated with or caused by administration of a drug or therapeutic agent to the subject.
  • the drug or therapeutic agent can be one that interacts with brain-located cellular receptors (membranous and cytosolic) or one that interacts with physiological pathways in the brain (action on a transporter), or a drug targeted to an organ other than the brain that interacts with brain- located cellular receptors or impacts/interferes physiological pathways of the brain.
  • the drug is for use in treating a brain-related pathology; the brain-related pathology may include depression, anxiety, stress, panic disorder, pain, epilepsy, dementia, suicidal ideation, Alzheimer's disease, Parkinson's disease.
  • the drug may include a selective- serotonin reuptake inhibitor (SSRI), a selective norepinephrine reuptake inhibitor (SNRI), a selective dopamine reuptake inhibitor (SDRI), serotonin receptor agonist/antagonists (interacting with the ‘5-HT’ receptor family), dopamine receptor agonist/antagonists (interacting with the ‘DT’ receptor family), adrenergic receptor agonist/antagonists (interacting with the ‘alpha’ and ‘beta’ receptor families, including beta-2-adrenergic receptor agonists), GABA receptor agonist/antagonists (interacting with the ‘GABAA’ and ‘GABAB’ receptor families), acetylcholine receptor agonist/antagonists (interacting with the ‘muscarinic’ and ‘nicotinic’ receptor families), glutamate receptor agonists/antagonists (e.g., NMDA receptor agonist/antagonists), opioid receptor agonist/antagonists (interacting with the ‘delta’, ‘kappa’
  • the drug can result in a change in homeostasis to neurotransmitter-related physiological pathways.
  • the drug can be intended for use in or is used in treating a neuropsychiatric condition.
  • the condition can be, for example, depression, anxiety, panic disorder, suicidal ideation or stress.
  • the drug can be any drug tested for use in or used to treat a neuropsychiatric condition but is preferably a neurotransmitter reuptake inhibitor such as an SSRI, SNRI, or SDRI or a neurotransmitter receptor agonist or antagonist (includes partial agonists/antagonists), especially a serotonin or dopamine receptor.
  • the 15-PGDH inhibitors and/or 15-PGDH substrates described herein can be provided in a pharmaceutical composition.
  • a pharmaceutical composition containing the 15-PGDH inhibitors and/or 15-PGDH substrates described herein as an active ingredient may be manufactured by mixing the derivative with a pharmaceutically acceptable carrier(s) or an excipient(s) or diluting the 15-PGDH inhibitors and/or 15-PGDH substrates with a diluent in accordance with conventional methods.
  • the pharmaceutical composition may further contain fillers, anti-cohesives, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives and the like.
  • the pharmaceutical composition may be formulated into a suitable formulation in accordance with the methods known to those skilled in the art so that it can provide an immediate, controlled or sustained release of the 15-PGDH inhibitors and/or 15-PGDH substrates after being administered into a mammal.
  • the pharmaceutical composition may be formulated into a parenteral or oral dosage form.
  • the solid dosage form for oral administration may be manufactured by adding excipient, if necessary, together with binder, disintegrants, lubricants, coloring agents, and/or flavoring agents, to the 15-PGDH inhibitors and shaping the resulting mixture into the form of tablets, sugar-coated pills, granules, powder or capsules.
  • the additives that can be added in the composition may be ordinary ones in the art.
  • examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicate and the like.
  • exemplary binders include water, ethanol, propanol, sweet syrup, sucrose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphonate and polypyrrolidone.
  • examples of the disintegrant include dry starch, sodium arginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic monoglyceride and lactose.
  • purified talc, stearates, sodium borate, and polyethylene glycol may be used as a lubricant; and sucrose, bitter orange peel, citric acid, tartaric acid, may be used as a flavoring agent.
  • the pharmaceutical composition can be made into aerosol formulations (e.g., they can be nebulized) to be administered via inhalation.
  • the 15-PGDH inhibitors and/or 15-PGDH substrates described herein may be combined with flavoring agents, buffers, stabilizing agents, and the like and incorporated into oral liquid dosage forms such as solutions, syrups or elixirs in accordance with conventional methods.
  • One example of the buffers may be sodium citrate.
  • the stabilizing agents include tragacanth, acacia and gelatin.
  • the 15-PGDH inhibitors and/or 15-PGDH substrates described herein may be incorporated into an injection dosage form, for example, for a subcutaneous, intramuscular or intravenous route by adding thereto pH adjusters, buffers, stabilizing agents, relaxants, topical anesthetics.
  • the pH adjusters and the buffers include sodium citrate, sodium acetate and sodium phosphate.
  • the stabilizing agents include sodium pyrosulfite, EDTA, thioglycolic acid and thiolactic acid.
  • the topical anesthetics may be procaine HCl, lidocaine HCl and the like.
  • the relaxants may be sodium chloride, glucose and the like.
  • the 15-PGDH inhibitors and/or 15-PGDH substrates described herein may be incorporated into suppositories in accordance with conventional methods by adding thereto pharmaceutically acceptable carriers that are known in the art, for example, polyethylene glycol, lanolin, cacao butter or fatty acid triglycerides, if necessary, together with surfactants such as Tween.
  • the pharmaceutical composition may be formulated into various dosage forms as discussed above and then administered through various routes including an oral, inhalational, transdermal, subcutaneous, intravenous or intramuscular route.
  • the dosage can be a pharmaceutically or therapeutically effective amount.
  • Therapeutically effective dosages of 15-PDGH inhibitor is one that reduces activity and/or expression of 15-PGDH and structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species within the nervous system and generates the maximum protective effect in preventing a neurodegenerative disease or disorder, or reduces a symptom of a neurodegenerative disease or disorder.
  • an optimum dosage of the 15-PGDH inhibitor and/or 15- PGDH substrate is one generating the maximum beneficial effect on damaged tissue.
  • An effective dosage causes at least a statistically or clinically significant attenuation of at least one marker, symptom, or histological evidence characteristic of neurodegenerative condition, disease, or disorder.
  • Markers, symptoms and histological evidence characteristic of neurodegenerative condition, disease, or disorder include memory loss, confusion, disturbances in axonal transport, demyelination, induction of metalloproteinases (MMPs), activation of glial cells, infiltration of lymphocytes, edema and immunological reactions that lead to tissue damage and further vascular injury. Stabilization of symptoms or diminution of tissue damage, under conditions wherein control patients or animals experience a worsening of symptoms or tissue damage, is one indicator of efficacy of a suppressive treatment. [00315] Therapeutically effective dosage amounts of the 15-PGDH inhibitor and/or 15- PGDH substrate may be present in varying amounts in various embodiments.
  • a therapeutically effective amount of the 15-PGDH inhibitor may be an amount ranging from about 10-1000 mg (e.g., about 20 mg-1,000 mg, 30 mg-1,000 mg, 40 mg-1,000 mg, 50 mg-1,000 mg, 60 mg-1,000 mg, 70 mg-1,000 mg, 80 mg-1,000 mg, 90 mg- 1,000 mg, about 10-900 mg, 10-800 mg, 10-700 mg, 10-600 mg, 10-500 mg, 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 200-1000 mg, 200-900 mg, 200-800 mg, 200-700 mg, 200-600 mg, 200-500 mg, 200-400 mg, 300-1000 mg, 300-900 mg, 300-800 mg, 300-700 mg, 300-600 mg, 300-500 mg, 400 mg-1,000 mg, 500 mg-1,000 mg, 100 mg-900 mg, 200 mg-800 mg, 300 mg-700 mg, 300-600 mg, 300-500 mg, 400 mg-1,000 mg, 500 mg-
  • the 15-PGDH inhibitor is present in an amount of or greater than about 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg. In some embodiments, the 15-PGDH inhibitor is present in an amount of or less than about 1000 mg, 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, 500 mg, 450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, or 100 mg.
  • a therapeutically effective dosage amount may be, for example, about 0.001 mg/kg weight to 500 mg/kg weight, e.g., from about 0.001 mg/kg weight to 400 mg/kg weight, from about 0.001 mg/kg weight to 300 mg/kg weight, from about 0.001 mg/kg weight to 200 mg/kg weight, from about 0.001 mg/kg weight to 100 mg/kg weight, from about 0.001 mg/kg weight to 90 mg/kg weight, from about 0.001 mg/kg weight to 80 mg/kg weight, from about 0.001 mg/kg weight to 70 mg/kg weight, from about 0.001 mg/kg weight to 60 mg/kg weight, from about 0.001 mg/kg weight to 50 mg/kg weight, from about 0.001 mg/kg weight to 40 mg/kg weight, from about 0.001 mg/kg weight to 30 mg/kg weight, from about 0.001 mg/kg weight to 25 mg/kg weight, from about 0.001 mg/kg weight to 20 mg/kg weight, from about 0.00 0.001 mg/kg weight to
  • a therapeutically effective dosage amount may be, for example, about 0.0001 mg/kg weight to 0.1 mg/kg weight, e.g. from about 0.0001 mg/kg weight to 0.09 mg/kg weight, from about 0.0001 mg/kg weight to 0.08 mg/kg weight, from about 0.0001 mg/kg weight to 0.07 mg/kg weight, from about 0.0001 mg/kg weight to 0.06 mg/kg weight, from about 0.0001 mg/kg weight to 0.05 mg/kg weight, from about 0.0001 mg/kg weight to about 0.04 mg/kg weight, from about 0.0001 mg/kg weight to 0.03 mg/kg weight, from about 0.0001 mg/kg weight to 0.02 mg/kg weight, from about 0.0001 mg/kg weight to 0.019 mg/kg weight, from about 0.0001 mg/kg weight to 0.018 mg/kg weight, from about 0.0001 mg/kg weight to 0.017 mg/kg weight, from about 0.0001 mg/kg weight to 0.016 mg/kg weight, from
  • the therapeutically effective dose may be 0.0001 mg/kg weight, 0.0002 mg/kg weight, 0.0003 mg/kg weight, 0.0004 mg/kg weight, 0.0005 mg/kg weight, 0.0006 mg/kg weight, 0.0007 mg/kg weight, 0.0008 mg/kg weight, 0.0009 mg/kg weight, 0.001 mg/kg weight, 0.002 mg/kg weight, 0.003 mg/kg weight, 0.004 mg/kg weight, 0.005 mg/kg weight, 0.006 mg/kg weight, 0.007 mg/kg weight, 0.008 mg/kg weight, 0.009 mg/kg weight, 0.01 mg/kg weight, 0.02 mg/kg weight, 0.03 mg/kg weight, 0.04 mg/kg weight, 0.05 mg/kg weight, 0.06 mg/kg weight, 0.07 mg/kg weight, 0.08 mg/kg weight, 0.09 mg/kg weight, or 0.1 mg/kg weight.
  • a therapeutically effective dosage may be a dosage of 10 ⁇ g/kg/day, 50 ⁇ g/kg/day, 100 ⁇ g/kg/day, 250 ⁇ g/kg/day, 500 ⁇ g/kg/day, 1000 ⁇ g/kg/day or more.
  • the amount of the 15-PGDH inhibitor or pharmaceutical salt thereof is sufficient to provide a dosage to a patient of between 0.01 ⁇ g/kg and 10 ⁇ g/kg; 0.1 ⁇ g/kg and 5 ⁇ g/kg; 0.1 ⁇ g/kg and 1000 ⁇ g/kg; 0.1 ⁇ g/kg and 900 ⁇ g/kg; 0.1 ⁇ g/kg and 900 ⁇ g/kg; 0.1 ⁇ g/kg and 800 ⁇ g/kg; 0.1 ⁇ g/kg and 700 ⁇ g/kg; 0.1 ⁇ g/kg and 600 ⁇ g/kg; 0.1 ⁇ g/kg and 500 ⁇ g/kg; or 0.1 ⁇ g/kg and 400 ⁇ g/kg.
  • Particular doses or amounts to be administered in accordance with the present invention may vary, for example, depending on the nature and/or extent of the desired outcome, on particulars of route and/or timing of administration, and/or on one or more characteristics (e.g., weight, age, personal history, genetic characteristic, lifestyle parameter, severity of cardiac defect and/or level of risk of cardiac defect, etc., or combinations thereof). Such doses or amounts can be determined by those of ordinary skill. In some embodiments, an appropriate dose or amount is determined in accordance with standard clinical techniques.
  • an appropriate dose or amount is a dose or amount sufficient to reduce a disease severity index score by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100% or more.
  • an appropriate dose or amount is a dose or amount sufficient to reduce a disease severity index score by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100%.
  • an appropriate dose or amount is determined through use of one or more in vitro or in vivo assays to help identify desirable or optimal dosage ranges or amounts to be administered.
  • Various embodiments may include differing dosing regimen.
  • the 15-PGDH inhibitor and/or 15-PGDH substrate can be administered via continuous infusion.
  • the continuous infusion is intravenous.
  • the continuous infusion is subcutaneous.
  • the 15-PGDH inhibitor can be administered bimonthly, monthly, twice monthly, triweekly, biweekly, weekly, twice weekly, thrice weekly, daily, twice daily, or on another clinically desirable dosing schedule.
  • the composition can be administered in the form of aqueous, alcoholic, aqueous-alcoholic or oily solutions or suspensions, or of a dispersion of the lotion or serum type, of emulsions that have a liquid or semi-liquid consistency or are pasty, obtained by dispersion of a fatty phase in an aqueous phase (O/W) or vice versa (W/O) or multiple emulsions, of a free or compacted powder to be used as it is or to be incorporated into a physiologically acceptable medium, or else of microcapsules or microparticles, or of vesicular dispersions of ionic and/or nonionic type.
  • aqueous, alcoholic, aqueous-alcoholic or oily solutions or suspensions or of a dispersion of the lotion or serum type, of emulsions that have a liquid or semi-liquid consistency or are pasty, obtained by dispersion of a fatty phase in an aqueous phase (O/W) or vice versa
  • It may thus be in the form of a salve, a tincture, milks, a cream, an ointment, a powder, a patch, an impregnated pad, a solution, an emulsion or a vesicular dispersion, a lotion, aqueous or anhydrous gels, a spray, a suspension, a shampoo, an aerosol or a foam. It may be anhydrous or aqueous. It may also comprise solid preparations constituting soaps or cleansing cakes.
  • compositions including the 15-PGDH inhibitor described herein can additionally contain, for example, at least one 15-PGHD substrate chosen from prostaglandins, in particular prostaglandin PGE 1 , PGE 2 , their salts, their esters, their analogues and their derivatives, in particular those described in WO 98/33497, WO 95/11003, JP 97-100091, JP 96-134242, in particular agonists of the prostaglandin receptors.
  • at least one 15-PGHD substrate chosen from prostaglandins, in particular prostaglandin PGE 1 , PGE 2 , their salts, their esters, their analogues and their derivatives, in particular those described in WO 98/33497, WO 95/11003, JP 97-100091, JP 96-134242, in particular agonists of the prostaglandin receptors.
  • the composition can include at least one 15-PGDH inhibitor as defined above and at least one prostaglandin or one prostaglandin derivative such as for example the prostaglandins of series 2 including in particular PGF 2 ⁇ and PGE 2 in saline form or in the form of precursors, in particular of the esters (example isopropyl esters), their derivatives such as 16,16-dimethyl PGE 2 , 17-phenyl PGE 2 and 16,16-dimethyl PGF 2 ⁇ 17- phenyl PGF2 ⁇ , prostaglandins of series 1 such as 11-deoxyprostaglandin E1, 1- deoxyprostaglandin E1 in saline or ester form, is their analogues, in particular latanoprost, travoprost, fluprostenol, unoprostone, bimatoprost, cloprostenol, viprostol, butaprost, misoprostol, their salts or their esters, in particular of the est
  • TBI Alzheimer’s Disease
  • BBB traumatic brain injury
  • 15-PGDH is a short chain dehydrogenase/reductase that catalyzes nicotinamide adenine dinucleotide (NAD + )-dependent oxidative degradation of various substrates throughout the body, including prostaglandin E2 (PGE2), PGF2 ⁇ , resolvin D1 (RvD1), lipoxin A4 (LXA4), and 15-hydroxyeicosatetranenoic acid (15-HETE).
  • PGE2 prostaglandin E2
  • PGF2 ⁇ PGF2 ⁇
  • RvD1 resolvin D1
  • LXA4 lipoxin A4
  • 15-HETE 15-hydroxyeicosatetranenoic acid
  • mice overexpress the K670N/M671L (Swedish), I716V (Florida), and V717I (London) mutations in human amyloid precursor protein (APP) isoform 695, as well as M146L and L286V mutations in human presenilin 1 (PS1) and were generated as described previously.
  • APP amyloid precursor protein
  • PS1 human presenilin 1
  • mice Male and female 5xFAD (C57BL/6J background, Stock No: 034848, Jackson Laboratory) were bred with Hpgd -/- mice (C57BL/6J background) to generate Tg-WT Hpgd +/+ , Tg-WT Hpgd +/- , Tg-5xFAD Hpgd +/+ , and Tg-5xFAD Hpgd +/- mice. Genotypes of the animals were blinded until they were euthanized. For TBI genetic studies, Hpgd -/- mice were also backcrossed for 14 generations onto an FVB background for generation of complete knockout animals for studies with TBI.
  • mice were randomly assigned to the treatment groups until we have similar number in each treatment groups.
  • mice had unrestricted access to food and water, and they were randomly allocated to various experimental groups. Hpgd -/- mice, the kind gift of Dr. Beverly Koller in whose laboratory the mice were derived, were backcrossed for 12 generations onto a C57BL/6J background for studies involving crosses to 5xFAD mice. In the AD rat study, six-month-old male TgF344-AD rats and WT littermates were used.
  • Human subjects [00328] Experiments with human brain samples were approved by Institutional Review Board (IRB): Northwestern ADRC IRB Number STU00023196 and Case Western Reserve University IRB Number 03-00-26. Human subjects or their representative provided written informed consent. Sex and age information of samples related to Fig.1A.
  • (+)-SW033291 compound was custom synthesized by WuXi AppTec. The compound dissolved in two parts pre-warmed ethanol at 10 mg/ml concentration by incubation at 37°C for at least 15 minutes with vortexing every 5 minutes. One part of Kolliphor EL was added, followed by further dilution with 17 parts of 5% D-Glucose water. The final working concentration of (+)-SW033291 compound was 1 mg/ml in 10% ethanol, 5.0% Kolliphor EL, and 4.25% d-glucose water. Behavioral analysis [00330] The Morris water maze (MWM) test was conducted in a 128-cm diameter tank filled with 22-23°C water.
  • the Congo Red kit (Sigma- Aldrich, HT60) was used according to the manufacturer’s instruction. Briefly, sections were mounted on slides and dried overnight at room temperature. Tissues were quickly rinsed with tap water 3 times and then incubated with hematoxylin solution for 10 mins.
  • sections were incubated in 50% formamide and 2x SSC at 65°C for 2 hours to denature DNA, followed by 5 minute washing with 2xSSC.
  • sections were incubated in 2M HCl at 37°C for 30 minutes for additional denaturation.
  • sections were rinsed in 0.1M borate buffer followed by PBS washing.
  • For blocking sections were incubated in 5% BSA and 5% normal horse serum in 0.1% T-PBS for 1 hour at room temperature.
  • Anti-BrdU antibody was used at 1:1,000 in 5% BSA and 5% normal horse serum in T-PBS and sections were incubated at 4°C overnight.
  • sections of 40 ⁇ m thickness were prepared, rinsed in PBS containing 0.3% Triton X-100, and blocked with 5% normal goat serum. They were then rinsed with PBS and left to incubate overnight at 4°C with rabbit anti-4-HNE (1:500, HNE11S, Alpha diagnostic International) or rabbit anti-3-NT (1:500, AB5411, Millipore Sigma). The following day, sections were washed with PBS and then incubated for two hours at room temperature with either goat anti-rabbit Alexa 594 or 488 (Invitrogen). After another rinse in PBS, sections were mounted using an antifade aqueous media (Vectashield® Plus with DAPI, Vector Laboratories).
  • Protocol for multiplex fluorescent detection (ACD, #323110) of probe for mouse 15-PGDH (Hpgd, #456681), mouse CD206 (Mrc1, #437511), mouse Tmem119 (Tmem119, #472901) was performed according to manufacturer specifications. Fluorescent reagents were employed as per protocol from Akoya BiosciencesTM for the Fluorescein green (#FP1487991KT) and Texas red (#FP1495001KT) to detect Tmem119, CD206, and 15-PGDH, respectively. All sections were counterstained with Akoya Spectral DAPI mounting medium. Slides were stored at 4°C in the dark until high magnification perivascular imaging could be performed.
  • mice were anesthetized and euthanized by transcardial perfusion with a fixative solution (1/4 strength Karnovsky’s fixative) at a flow rate of 10 ml/min for 10 min.
  • the brains were carefully removed and then sliced into thin slices (4 mm x 4 mm x 2 mm). Tissues were fixed with 2.5% glutaraldehyde, 2% paraformaldehyde in 0.1 M HEPES buffer, pH 7.4 for 2h at room temperature.
  • specimens were thoroughly rinsed in 0.1 M phosphate buffer, pH7.4, and then postfixed for 2 h in an unbuffered 1:1 mixture of 2% osmium tetroxide and 3% potassium ferricyanide. After rinsing with distilled water, specimens were soaked overnight in an acidified solution of 0.25% uranyl acetate. After another rinse in distilled water, specimens were dehydrated in ascending concentrations of ethanol, passed through propylene oxide, and embedded in EMbed 812 resin mixture (Electron Microscopy Sciences, PA). For genetic study in AD and TBI studies, free-floating sections were used.
  • Thin sections (70 nm) were cut on an RMC MT6000-XL ultramicrotome and mounted on Gilder square 300 mesh nickel grids (Electron Microscopy Sciences, PA). Thin sections were sequentially stained with acidified uranyl acetate followed by a modification of Sato’s triple lead stain and examined in a FEI Tecnai Spirit (T12) with a Gatan US40004k x 4k CCD.
  • Microglia and non-microglia isolation for western blot Each mouse was perfused with DPBS for 5 min at 15.5rpm and whole brain tissue was collected in DPBS and processed using the MACS Adult Brain dissociation kit (Miltenyi Biotec, 130-107-677) to generate a single cell suspension. Each sample was digested using a combination of enzymatic and mechanical dissociation after being finely sliced with a scalpel. For enzymatic dissociation, enzyme mixes 1 and 2 (provided in the kit) were used for mechanical dissociation.
  • CD11b positive cells labeled by microbead-CD11b antibodies
  • the CD11b positive cell population was collected by removing the column from the magnetic stand and placing the plunger into the column to flush out the cells. After centrifugation, cells were lysed in in RIPA buffer (Sigma-Aldrich, R0278) containing protease and phosphatase inhibitor cocktail (Thermo Scientific, #1861284) for subsequent western blot analysis.
  • mice were euthanized 30 minutes after the last dose of vehicle or (+)-SW033291 injection and brain tissues were excised. Then, tissues were further rinsed in ice-cold PBS only, and snap-frozen in liquid nitrogen. Frozen samples were pulverized over liquid nitrogen.
  • the powder was transferred to an Eppendorf tube with 500 ⁇ L of cold lysis buffer (50 mM Tris-HCl, pH 7.5, 0.1 mM DTT, 0.1 mM EDTA) and then homogenized using Kimble Kontes Pellet Pestle Cordless Motor (Fisher, K749540-0000) with Kimble Kontes blue pellet pestles (Fisher, K749521-1590) for ⁇ 30s on ice.
  • the suspension was centrifuged for 10 min at 12,000rpm.
  • the enzyme activity was measured by transfer of tritium from a tritiated PGE2 substrate to glutamate by coupling 15-PGDH to glutamate dehydrogenase in a 1 hour reaction with 1mM NAD+, 5 mM NH4Cl, 1 mM ⁇ - keto-glutarate (Sigma#75890), and 16 U of bovine liver glutamic dehydrogenase (Sigma, cat. #G-2501), as described previously.
  • the activity was normalized to protein concentration measured by BCA assay (Thermo Scientific, cat. #23225) and expressed as CPM/Hour/mg protein.
  • the head is secured in a cushioned holder without any restraints, while the body is entirely protected by a metal tube.
  • Microglia and non-microglia isolation for 15-PGDH activity assays [00337] Whole brain tissue was collected in DPBS with calcium, magnesium, glucose, and pyruvate (Thermo Fisher Scientific, 14287080) and processed using the MACS Adult Brain dissociation kit (Miltenyi Biotec, 130-107-677) to generate a single cell suspension. Each sample was digested using a combination of enzymatic and mechanical dissociation after being finely sliced with a scalpel. For enzymatic dissociation, enzyme mixes 1 and 2 (provided in the kit) were used for mechanical dissociation.
  • Protocol for multiplex fluorescent detection (ACD, #323110) of probe for mouse 15-PGDH (Hpgd, #456681), mouse CD11b (Itgam, #311491) was performed according to manufacturer specifications. Fluorescent reagents of Opal 570 (Akoya Biosciences, #FP1488001KT) and Opal 650 (Akoya Biosciences, #FP1495001KT) were used to detect 15-PGDH and CD11b mRNA, respectively. Next, brain sections were blocked in 5% normal donkey serum (NDS) and 5% bovine serum albumin (BSA) in PBS with 0.25% Triton-X (PBS-T) for 1 hour.
  • NDS normal donkey serum
  • BSA bovine serum albumin
  • tissues were incubated with anti-CD31 antibody (BD #550274) in 1:50 dilution in 1% NHS, 1% BSA, in PBS with 0.25% Triton-X for 1hr. After 3 times of PBS wash, tissues were incubated with Donkey anti-rat 488 antibody (1:500, #A21208, Invitrogen). Then, tissues were washed with PBS three times and stained with DAPI (Thermo Scientific, D3571).0.1% Sudan Black B (Sigma-Aldrich, #199694) in 70% ethanol was applied to the sections to reduce autofluorescence signals. After rising with PBS, slides were cover slipped with Vectashield antifade mounting medium (Vector Laboratories, H-1000-10).
  • Fluorescence images were acquired using a z-stack approach with a 0.5 ⁇ m interval, spanning a total depth of 2 ⁇ m, across five optical sections. Orthogonal projection was performed for visualization and analysis. Cell detection and quantification was performed using QuPath. Nuclei were identified based on DAPI staining, and the proximity of each detected cell to the nearest CD31+ endothelial cell to determine the distance to the closest blood vessel. Quantification of immunohistochemistry [00339] Images were acquired with Axiolmager.M2 with monochromatic digital camera (Zeiss Ax- ioCam MRm Rev.3) and Zeiss Axio Scan.Z1.
  • ImageJ version 1.42 software National Institutes of Health, Bethesda, MD was used to analyze the integrated density of silver staining with the plugin of the color deconvolution method, as previously described. BrdU-labelled cells were counted manually using AxioImager.M2 and normalized by the total area of hippocampus. The percentage of Congo Red-positive area was analyzed by measuring total percent area in ImageJ. 4-HNE and 3-NT staining images were captured on LSM 880, and the mean fluorescence intensities and number of colocalized cells were quantified using Fiji Image J.
  • mice were carefully removed from the skull to include the entire brain, cerebellum, and the proximal brainstem, and placed in fresh 10% neutral buffered formalin (NBF) and stored at 4°C for 24 hours.
  • NBF neutral buffered formalin
  • the fixed brains were then rinsed in PBS and placed in an adult mouse Zivic instrument device (Pittsburgh, PA) (coronal 1 mm divisions) (BSMAA001-1) and sectioned to provide seven to eight 2 mm thick sections ranging from immediately posterior to the olfactory lobe to the proximal brain stem.
  • the 2 mm sections were then placed serially on three glass slides to preserve left-right orientation and anterior to posterior order and coated with a thin layer of 2% Sea Plaque Agarose (Lonza, #50104) to maintain optimal flat sections.
  • the composite slabs of brain sections were wrapped in Histowrap®, placed in routine depth processing cassettes, returned to fresh cold 10% NBF, and stored for up to 2 days at 4°C.
  • the fixed tissue slabs were processed for paraffin embedding (FFPE) using an 8-hour standard schedule at the shared Tissue Resource Core within the Case Comprehensive Cancer Center. Paraffin blocks were sectioned at 5 ⁇ m for initial hematoxylin and eosin staining.
  • the paraffin tissue block containing optimal hippocampus morphology was used for further sectioning at 5 ⁇ m for mRNA in situ hybridization.
  • Quantification of in situ hybridization [00341] Whole section scans were acquired with Keyence BZ-X810, which is an inverted fluorescence phase contrast microscope with 2/3 inch, 2.83-million-pixel monochrome CCD (colorized with LC filter). Each field of view was stitched together with BZ-H4XD/Advanced Observation Module. QuPath version 0.3.2 software with the built in Cell detection method was used to identify DAPI positive nuclei, and the QuPath built in Subcellular detection method was used to quantify 15-PGDH, CD206, and TMEM119 positive cells.
  • Proteins were heated at 95°C in either 2x or 4x Laemmli Sample Buffer (Bio-Rad Laboratories, Inc., #1610737 or #1610747) with beta-mercaptoethanol (Bio-Rad Laboratories, Inc., #1610710) for 5 min, and then resolved in 4%–20% Criterion TGX Stain- Free gels (Bio-Rad Laboratories, Inc., #5678095).
  • Proteins were transferred onto 0.2 mm polyvinylidene fluoride (Bio-Rad Laboratories, Inc., #1704157) or nitrocellulose membranes (Bio-Rad Laboratories, Inc., #1704271) with the Trans-Blot Turbo system (Bio-Rad Laboratories, Inc.). Membranes were blocked with 5% nonfat dry milk (Research Products International, #M17200) in tris-buffered saline-tween 20 (TBS-T) for 1 hour at room temperature, and then incubated with primary antibodies at 4°C overnight.
  • TBS-T tris-buffered saline-tween 20
  • mice anti-15-PGDH Markowitz laboratory MM1, 1:1,000
  • mouse anti-GFAP Thermo Fisher, MA5-12023, 1:1,000
  • rabbit anti-IBA1 Wako, #019-19741, 1:1,000
  • rabbit anti-APP Sigma Aldrich, #A8717, 1:5,000
  • mouse anti-GAPDH EMD Millipore Corp, MAB 374, 1:5,000.
  • RNA concentrations, 260/230 ratio, and 260/280 ratio were determined by UV visible absorption spectra, using Nanodrop 2000 (Thermo Scientific, USA).
  • First-strand cDNA was synthesized from total RNA (500ng) using iScript cDNA Synthesis Kit (Bio-Rad Laboratories Inc., #1708891), according to the manufacturer’s instruction.
  • Quantitative PCR was performed in triplicate using Fast Taqman Master Mix (Thermo Fisher Scientific, #444964) on the QuantStudio 6 Pro real-time PCR systems (Applied Biosystems).
  • Taqman probes were used to examine the relative expression of human HPGD gene (Thermo Fisher Scientific, #Hs00168359_m1) and mouse Hpgd (Thermo Fisher Scientific, #Mm00515121_m1) gene. Fold change of gene expression was calculated by the comparative CT quantification method. Mouse gene expression was normalized to expression of Gapdh (Thermo Fisher Scientific, #Mm99999915_g1) and human gene expression was normalized to the geometric mean of three housekeeping genes, ACTB (Thermo Fisher Scientific, #Hs01060665_g1), LDHA (Thermo Fisher Scientific, #Hs01378790_g1), and POLR1B (Thermo Fisher Scientific, #Hs00219263_m1).
  • ACTB Thermo Fisher Scientific, #Hs01060665_g1
  • LDHA Thermo Fisher Scientific, #Hs01378790_g1
  • POLR1B Thermo Fisher Scientific, #Hs002192
  • the single cell transcriptomic profiles of the HPF region are divided into two main parts: (1) the hippocampal region, including fields CA1, CA2, CA3, and dentate gyrus; and (2) the retrohippocampal region, including lateral entorhinal area, medial entorhinal area, parasubiculum, postsubiculum, presubiculum, subiculum, prosubiculum, and the immune/vascular region that includes endothelial cells, smooth muscle cells and pericytes, vascular/leptomeningeal cells, and microglia/perivascular macrophages (Micro-PVM).
  • the hippocampal region including fields CA1, CA2, CA3, and dentate gyrus
  • retrohippocampal region including lateral entorhinal area, medial entorhinal area, parasubiculum, postsubiculum, presubiculum, subiculum, prosubiculum, and the immune/vascular region that includes endothelial cells, smooth muscle cells and pericytes, vascular/leptomen
  • CTX In the cortex (CTX), the following areas were profiled for single cell transcriptomics: frontal pole, primary motor, secondary motor, primary somatosensory (SSp), and supplemental somatosensory.
  • SSp primary somatosensory
  • SSp single cell transcriptomic profiles with 23 different cell subpopulations that mainly included astrocytes, glutamatergic neurons (L2/3 IT, L4/5 IT, Car3, and L6b), vascular/leptomeningeal cells (VLMC), and microglia/perivascular macrophages (Micro-PVM).
  • the Seurat pipeline v4 was employed to study the single cell transcriptomic profile. The preprocessing was performed by removing low-quality cells or empty droplets and dying cells.
  • Expression profiles were normalized using sctransform (SCT) and subsequently scaled to the expression of each gene, so that the mean expression across cells was 0 and variance across cells was 1.
  • SCT sctransform
  • the SCT computes Pearson residuals from regularized negative binomial regression, where sequencing depth is utilized as a covariate in a generalized linear model to remove the influence of technical characteristics while preserving biological heterogeneity.
  • principal component analysis was performed on the top 2000 highly variable genes and the top 10 principal components were inputted to visualization methodologies, including uniform manifold approximation and projection (UMAP) and t-distributed stochastic neighbor embedding (TSNE). Differentially expressed genes have been computed over log2SCT normalized profiles.
  • UMAP uniform manifold approximation and projection
  • TSNE stochastic neighbor embedding
  • a ⁇ peptide preparation [00345] The one milligram of A ⁇ 1-42 peptide (Anygen, Cat. No. AGP-8338) was dissolved in 1 mL of 1,1,1,3,3,3,-hexafluoro-2-propanol (HFIP; Sigma, Cat. No.105228) and incubated at room temperature in the dark for three days with daily vertexing. The solution was then aliquoted into 20 tubes (50 ⁇ g per tube), dried using a SpeedVac, sealed, and stored at ⁇ 80°C until further use.
  • HFIP 1,1,1,3,3,3,3,-hexafluoro-2-propanol
  • a ⁇ oligomers were prepared by dissolving the A ⁇ peptide stock in 11.07 ⁇ L of anhydrous dimethyl sulfoxide and subsequently diluting it with ice-cold 1 ⁇ phosphate-buffered saline to a final concentration of 0.1 mM. The solution was then incubated at 4°C in the dark for 24 hours.
  • ROS measurement [00346] BV2 cells (1.5 ⁇ 104 cells/well) were seeded in a 24-well plate using DMEM supplemented with 10% FBS and 1% Antibiotics/antimycotic.
  • 15-PGDH substrates PGE 2 , PGF 2 ⁇ , RvD1, RvD2, LXA 4 , 15-HETE
  • the culture medium was then replaced with 500 ⁇ L of phenol red-free medium containing 5.7 ⁇ M CM-H2DCFDA, followed by treatment with A ⁇ oligomers (5 ⁇ M).
  • ROS levels were immediately measured using the Incucyte live-cell imaging system (IncuCyte S3, Sartorius, Germany).
  • (+)-SW033291 pharmacokinetics [00347] Studies to evaluate (+)-SW033291 pharmacokinetics were approved and conducted under the oversight of the UT Soiled IACUC. Twenty-one female CD-1 mice were dosed IP with 10 mg/kg (+)-SW033291. For plasma measurements, whole blood was collected, and plasma was processed from whole blood by centrifugation of the ACD anticoagulant-treated blood for 10 minutes at 9600 x g in a microcentrifuge. For measurement of brain levels, brain tissues were collected, rinsed to remove surface adhering blood, weighed, and snap frozen in liquid nitrogen.
  • brain tissue was homogenized in a 3-fold volume of PBS so that the total volume of homogenate in mL was 4 times the weight of tissue in g.
  • Samples were stored at -80°C until analysis.
  • plasma or brain homogenate was diluted with 2 parts methanol containing 0.15% formic acid, 3mM ammonium acetate (final conc.2mM), and 37.5ng/ml internal standard (IS, final conc. 25ng/ml, n-benzylbenzamide, Sigma Aldrich, 02914LH).
  • (+)-SW033291 was detected with the mass spectrometer in multiple reaction monitoring (MRM) mode with compound transition 413.1 to 339.2 and n-benzylbenzamide internal standard transition 212.1 to 91.1.
  • concentration of (+)-SW033291 in each time-point sample was quantified using Sciex Analyst software.
  • a value of 3-fold above the signal obtained from blank plasma or tissue homogenate was designated as the limit of detection (LOD).
  • LOD limit of quantitation
  • LOQ limit of quantitation
  • Brain concentrations were adjusted to remove the amount of compound present in murine brain vasculature (30 ⁇ l/g brain tissue) according to literature values and measured plasma concentrations.
  • TBI is a major risk factor for AD, and these conditions also display various common pathological features.
  • RNA-fluorescence in situ hybridization RNA-FISH
  • Fig.1F RNA-fluorescence in situ hybridization
  • RNA-sequencing sc- RNAseq
  • sc- RNAseq public single-cell RNA-sequencing
  • the next highest Hpgd-expressing population comprised a rare subset of Layer L2/3 glutamatergic cortical neurons, with only 9% of these neurons showing expression (average expression level of 0.1 log2(SCT) (Fig.6B-E).
  • 15-PGDH enrichment was similarly observed in the hippocampal myeloid cell (micro-PVM) cluster (Fig.6F and G).
  • Bead fractionation of murine cortical cells into CD11b + and CD11b- populations confirmed an approximately 200-fold enrichment of 15-PGDH enzyme activity in the CD11b + myeloid cell population (Fig.7A).
  • Dual RNA-FISH confirmed 15-PGDH colocalization with both microglia (Hpgd + red and Tmem119 + green, double positive) and PVMs (Hpgd + red and Mrc1 + green, double positive) in both 5xFAD and WT mice (Fig.1I and J).
  • 5xFAD mice exhibited a two-fold increase in both 15-PGDH-expressing microglia and PVMs within both the cortical and hippocampal regions, as compared to WT littermates (Fig.1I and J).
  • our findings demonstrate that 15-PGDH is predominantly enriched in brain myeloid cells tightly associated with the BBB, with 15-PGDH level and cellular prevalence markedly elevated in AD mouse brain.
  • 15-PGDH inhibition prevents cognitive impairment in AD without reducing amyloid pathology
  • both pharmacologic and genetic inhibition of 15-PGDH robustly prevented BBB structural degradation in 5xFAD mice (Fig.2I and J).
  • the glial limitans barrier formed through astrocytic endfeet interactions with endothelial cells, normally prevents infiltration of blood-derived components into brain tissue and represents a region of functional compromise associated with astrocytic endfeet swelling.
  • IgG immunoglobulin
  • pharmacologic 15- PGDH inhibition fully rescued this neurodegeneration and attenuated axonal degeneration in the dorsal fornix, a major hippocampal output tract (Fig.3A and Fig.10E).
  • Genetic 15- PGDH haploinsufficiency similarly restored survival of adult-born neurons in 5xFAD mice to WT levels (Fig.3B), showing that even partial 15-PGDH suppression suffices for neuroprotection.
  • 15-PGDH inhibition attenuates astrocyte reactivity and microglial oxidative stress in AD
  • 15-PGDH inhibition attenuates astrocyte reactivity and microglial oxidative stress in AD
  • GFAP a marker of astrocyte reactivity
  • IBA1 a marker of microglia activation
  • lipid peroxidation is known to rapidly accumulate within hours of TBI, thereby driving the acute phase of pathology, and also to persist chronically and increase the risk of developing other forms of aging related neurodegeneration, such as AD. Consistent with our previous reports in this model, we detected no changes in IBA1 or GFAP expression after TBI (Fig.13E-G). [00369] To validate target specificity, we further performed TBI studies in Hpgd +/+ and Hpgd -/- mice (Fig.4H). Genetic ablation of 15-PGDH mirrored pharmacologic inhibition, conferring complete protection against axonal neurodegeneration (Fig.4I), BBB damage (Fig.4J), and oxidative stress (Fig.4K and Fig.13H).
  • This Example identifies 15-PGDH as a novel therapeutic target for AD and TBI, demonstrating that its inhibition preserves BBB integrity and cognitive function.
  • 15-PGDH was observed elevated 15-PGDH in aging, TBI, and AD in both human and mouse brains, with prominent localization to brain myeloid cells, including microglia and PVMs at the BBB.
  • Genetic or pharmacologic inhibition of 15-PGDH in mouse models of AD and TBI mitigated perivascular inflammation, protected BBB integrity, and prevented downstream neuroinflammation, oxidative stress, and neurodegeneration.
  • 15-PGDH inhibition is critically positioned to therapeutically interrupt the self-amplifying pathogenic cycle created as ROS generation and BBB degradation reciprocally drive and reinforce one another.
  • 15-PGDH acts to catalyze the degradation of a diverse array of bioactive molecules with context-dependent pro- or anti-inflammatory effects.
  • Our attempts to define global eicosanoid profile changes after 15-PGDH inhibition were confounded by the rapid induction and lability of these signaling molecules.
  • 15-PGDH inhibition represents a paradigm-shifting therapeutic strategy for AD, TBI, and potentially other neurodegenerative conditions marked by BBB dysfunction.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A method of treating diseases or disorders characterized by structural deterioration of the blood-brain barrier or increased generation of reactive oxygen species within the nervous system of a subject in need thereof includes administering to the subject an amount of a 15-PGDH inhibitor and/or 15-PGDH substrate.

Description

COMPOSITIONS AND METHODS OF TREATING DISEASES AND DISORDERS CHARACTERIZED BY BLOOD-BRAIN BARRIER DETERIORATION OR REACTIVE OXYGEN SPECIES GENERATION RELATED APPLICATION [0001] This application claims priority from U.S. Provisional Application Nos.63/665,460, filed June 28, 2024 and 63/774,295, filed March 19, 2025, the subject matter of which are incorporated herein by reference in their entirety. GOVERNMENT FUNDING [0002] This invention was made with government support under AG073323, GM142002, CA197442, AG083111, DA044123, AG073684, and AG071512 awarded by the National Institutes of Health; and W81XWH-22-1-0129 awarded by the Department of Defense, and I01BX005976-01A1 awarded by the Department of Veterans Affairs. The government has certain rights in the invention. BACKGROUND [0003] A prominent and early feature of Alzheimer’s Disease (AD) is deterioration in blood-brain barrier (BBB) structure and function, which impairs neurovascular coupling and increases permeability of blood-borne substances and peripheral immune cells into the brain parenchyma, triggering perivascular inflammation. These events induce oxidative stress and lead to neurodegeneration and cognitive impairment. Importantly, BBB dysfunction occurs in the earliest pathological stages of AD and has been proposed as an early biomarker for the disease. Aging further contributes to BBB deterioration, especially in the hippocampus, a region essential for learning and memory that is particularly vulnerable in AD. [0004] In addition to aging, another major risk factor for AD is traumatic brain injury (TBI), defined as any injury resulting from an external force that disrupts normal brain function. Common causes of TBI include falls, motor vehicle accidents, explosions, interpersonal violence, and sports injuries. Although the mechanistic links between TBI and AD remain unclear, TBI-induced vascular dysfunction at the BBB has been proposed as a contributing factor. Given the central role of BBB deterioration in declining brain health associated with aging, TBI, and AD, protecting the BBB represents a new direction that merits therapeutic exploration. SUMMARY [0005] Embodiments described herein relate to compositions and methods of treating diseases or disorders characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species within the nervous system of a subject in need thereof. We found that 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that catabolizes eicosanoids and other anti-inflammatory mediators, is enriched in blood brain barrier (BBB)-associated myeloid cells and becomes markedly elevated in human and mouse models of Alzheimer’s disease (AD), traumatic brain injury (TBI), and aging. Pathological increase in 15-PGDH correlates with pronounced oxidative stress, neuroinflammation, and neurodegeneration, alongside profound BBB structural degeneration characterized by astrocytic endfeet swelling and functional impairment. Pharmacologic inhibition or genetic reduction of 15-PGDH in AD and TBI models strikingly mitigates cognitive decline, oxidative damage, suppresses neuroinflammation, and restores BBB integrity. Most notably, inhibiting 15-PGDH not only blocks damage to the brain by blocking microglial generation of reactive oxygen in 15-PGDH positive microglial cells and halts neurodegeneration but also preserves cognitive function at levels indistinguishable from healthy controls. Remarkably, these neuroprotective effects in AD are achieved without affecting amyloid pathology, underscoring a non-canonical mechanism for treating AD. Thus, our findings position 15-PGDH inhibition as a novel and broad-spectrum strategy to treat oxidative stress, neuroinflammation, and neurodegeneration, alongside profound BBB structural degeneration, associated with pathological increases in 15-PGDH. [0006] In some embodiments, a method of treating diseases or disorders characterized by structural deterioration of the blood-brain barrier in a subject in need thereof can include administering to the subject an amount of a 15-PGDH inhibitor and/or 15-PGDH substrate effective to prevent the onset of deterioration and/or the progression of further deterioration of the blood-brain barrier and/or prevent the neurodegeneration associated with blood-brain barrier deterioration and/or prevent the impaired neuronal function associated with blood- brain barrier deterioration and/or restore the integrity and/or structure and/or function of the blood-brain barrier. [0007] In other embodiments, a method of treating diseases or disorders characterized by increased generation of reactive oxygen species within the nervous system, and particularly, central nervous system, of a subject in need thereof can include administering to the subject an amount of a 15-PGDH inhibitor and/or 15-PGDH substrate effective to prevent and/or decrease reactive oxygen species generation and/or neurodegeneration and/or impaired neuronal function associated with reactive oxygen species. [0008] In some embodiments, the subject has memory loss and/or cognitive decline and the 15-PGDH inhibitor and/or 15-PGDH substrate is administered at an amount effective to improve memory and/or cognition. [0009] In some embodiments, the 15-PGDH inhibitor and/or 15-PGDH substrate is administered to the subject at an amount effective to block aberrantly increased 15-PGDH enzymatic activity and prevent perivascular inflammation. [0010] In some embodiments, the subject is asymptomatic for Alzheimer’s dementia, has preclinical Alzheimer’s disease, or prodromal Alzheimer’s disease. [0011] In some embodiments, the 15-PGDH inhibitor and/or 15-PGDH substrate is administered to the subject at an amount effective to decrease 4-hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or more. [0012] In some embodiments, the 15-PGDH inhibitor is a small molecule that binds to 15-PGDH protein. [0013] In some embodiments, the 15-PGDH inhibitor can inhibit enzymatic activity of recombinant 15-PGDH at an IC50 of less than 1 µM, or preferably at an IC50 of less than 250 nM, or more preferably at an IC50 of less than 50 nM, or more preferably at an IC50 of less than 10 nM, or more preferably at an IC50 of less than 5 nM at a recombinant 15-PGDH concentration of about 5 nM to about 10 nM. [0014] In some embodiments, the 15-PGDH inhibitor has the following formula (V): (V) or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein n is 0-2 X6 is independently is N or CRc R1, R6, R7, and Rc are the same or different each independently hydrogen or a substituted or unsubstituted group selected from C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, -Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C2-C24 alkylamido substituted with a hydroxyl, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5- C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, and phosphate esters, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof, and wherein R6 and R7 may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl; and U1 is N, C-R2, or C-NR3R4, wherein R2 is selected from the group consisting of a H, a lower alkyl group, O, (CH2)n1OR’ (wherein n1=1, 2, or 3), CF3, CH2-CH2X, O-CH2- CH2X, CH2-CH2-CH2X, O-CH2-CH2X, X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, O(CO)R’, COOR’ (wherein R’ is H or a lower alkyl group), and wherein R1 and R2 may be linked to form a cyclic or polycyclic ring, wherein R3 and R4 are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH2)n1OR’ (wherein n1=1, 2, or 3), CF3, CH2-CH2X, CH2-CH2-CH2X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, COOR’ (wherein R’ is H or a lower alkyl group), and R3 or R4 may be absent. [0015] In some embodiments, the 15-PGDH inhibitor is a molecule or generates a molecule that binds to 15-PGDH mRNA to promote degradation 15-PGDH mRNA and/or inhibit expression of 15-PGDH. For example, the molecule can include an RNA interference (RNAi) molecule, preferably at least one of a small interfering RNA (siRNA) or microRNA (miRNA). [0016] In other embodiments, the 15-PGDH inhibitor can include an agent or method of gene editing that inactivates or alters the HPGD gene that encodes 15-PGDH. For example, the 15-PGDH inhibitor can include at least one nuclease that can remove, cut, or alter a target nucleic acid sequence of the HPGD gene. [0017] In other embodiments, the 15-PGDH inhibitor is an agent that promotes the degradation of 15-PGDH protein. For example, the agent can include at least one of a small molecule-assisted shutoff (SMASh) system, a Shield-1-inducible degron, an auxin inducible degron, an IMid-inducible degron, a peptidic degron, a proteolysis targeting chimera, or an antibody for targeted 15-PGDH degradation. [0018] In some embodiments, the 15-PGDH substrate can include at least one of PGE2, PGF2α, RvD1, LXA4, or 15-HETE. [0019] In some embodiments, the method can include measuring at least one biomarker of reactive oxygen species generation in the brain of the subject and comparing the at least one biomarker of reactive oxygen species generation to a control to determine the efficacy of the 15-PGDH inhibitor and/or PGDH substrate in treating neurodegeneration and/or impaired neuronal function in the subject. For example, the method can include measuring 4-hydroxy- 2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels of the subject following administration of the 15-PGDH inhibitor and/or 15-PGDH substrate and comparing the measured 4-hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels to a control, wherein a decrease in 4-hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels is indicative of efficacy of the 15-PGDH inhibitor and/or PGDH substrate in treating neurodegeneration and/or impaired neuronal function in the subject. [0020] In some embodiments, the control is the 4-hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels of the subject prior to administration of the 15-PGDH inhibitor and/or 15-PGDH substrate. [0021] In other embodiments, the method can include measuring blood-brain barrier (BBB) permeability of the subject following administration of the 15-PGDH inhibitor and/or 15-PGDH substrate and comparing the measured BBB permeability to a control, wherein a decrease in BBB permeability is indicative of efficacy of the 15-PGDH inhibitor and/or PGDH substrate in treating neurodegeneration and/or impaired neuronal function in the subject. [0022] In some embodiments, the control is the BBB permeability of the subject prior to administration of the 15-PGDH inhibitor and/or 15-PGDH substrate. BRIEF DESCRIPTION OF THE DRAWINGS [0023] Figs.1(A-J) illustrate brain 15-PGDH increases in human and mouse AD, TBI, and aging, and is enriched in brain myeloid cells. (A) qPCR data from human cortex reveals that 15-PGDH mRNA (HPGD expression) is increased in subjects with Alzheimer’s disease (AD), compared to control subjects without dementia. HPGD was normalized to the geometric mean of ACTB, POLR1B, and LDHA (* p<0.05, unpaired t-test). (B) Mouse whole brain qPCR data reveals that 15-PGDH mRNA (Hpgd expression) is increased in symptomatic (6 months old) 5xFAD mice, compared to WT littermates. Hpgd was normalized to Actb (** p<0.01, unpaired t-test). (C) Mouse 15-PGDH enzymatic activity is increased in symptomatic (6 and 12 months old) 5xFAD mice, compared to WT littermates (5xFAD versus WT genotype effect p<0.001, 6 versus 12-month time effect p=0.0533, *** p<0.001, two-way ANOVA and Tukey’s post hoc analysis). (D) Human brain RNA seq data from Seo et al. (ERP015139) reveals that 15-PGDH mRNA (HPGD expression) is increased in subjects with chronic traumatic encephalopathy (CTE), compared to control subjects (* p<0.05, unpaired t-test). Data are shown from both superior parietal cortex and posterior visual cortex. (E) Mouse hippocampal 15-PGDH enzymatic activity is increased 3 weeks after TBI, relative to sham-injury (**** p<0.0001, unpaired t-test). (F) Fluorescent in situ hybridization (FISH) for Hpgd mRNA (red) in mouse brain shows more 15-PGDH positive cells in the cortex and hippocampus of symptomatic (6 months old) 5xFAD mice, compared to WT littermates (* p<0.05, *** p<0.001, unpaired t-test; 2-7 brain sections/mouse). (G) CD11b+ myeloid cells show increased 15-PGDH protein expression in the brains of 6- month-old 5xFAD mice, compared to WT littermates (Interaction** p<0.01, ****p<0.0001, two-way ANOVA). (H) Single cell RNA sequencing data analyzed from Yao et al. reveals that Hpgd expressing myeloid cells are composed of Mrc1 positive PVMs and Tmem119 positive microglia. A heatmap of cortical myeloid cells depicting expression (log2(SCT)) of 15-PGDH mRNA (Hpgd), Mrc1 (perivascular macrophages), Lyve1 (perivascular macrophages), Aif1 (microglia and macrophages), and Tmem119 (microglia) is shown. (I) RNA FISH in mouse brain shows an increase in Hpgd-expressing microglia [double positive for 15-PGDH mRNA, Hpgd, (red) and Tmem119 mRNA (green)], in symptomatic 5xFAD mice (6 months old), compared to WT littermates, in cortex and hippocampus (** p<0.01, unpaired t-test; 4-8 brain sections/mouse). (J) RNA FISH shows an increase in Hpgd-expressing PVMs [double positive for 15-PGDH mRNA, Hpgd (red) and Mrc1 mRNA (green)] in symptomatic 5xFAD mice (6 months old), compared to WT littermates, in cortex and hippocampus (* p<0.05, ** p<0.01, unpaired t-test; 2-7 brain sections/mouse). Expanded view of boxed region shown at lower right. In all graphs (A-J), datapoints indicate values of individual human subjects or individual mice. [0024] Figs.2(A-L) illustrate 15-PGDH inhibition protects 5xFAD mice from cognitive impairment and BBB deterioration without reducing amyloid pathology. (A) Schematic diagram of experimental procedure for evaluating the protective efficacy of pharmacologic inhibition of 15-PGDH. Mice were intraperitoneally (IP) injected with (+)-SW033291 twice daily (5 mg/kg x 2 = 10 mg/kg/day) from 2 to 6 months of age. At 5 months of age, a bolus of bromodeoxyuridine (BrdU, 150 mg/kg) was administered to label newborn hippocampal neurons. Morris water maze (MWM) testing of cognition was conducted one week before brain tissue was harvested for analysis at 6 months of age. Males (shown as filled circles or filled squares in subsequent panels) and females (shown as open circles or open squares in subsequent panels) of all four combinations of 5xFAD genotype and treatment groups were housed under normal conditions. (B) Treatment with (+)-SW033291 for 4 months markedly reduced brain 15-PGDH activity in both 5xFAD mice and WT littermates, as compared to vehicle-treated mice (Interaction p<0.0001, ** p<0.01, **** p<0.0001, two-way ANOVA and Tukey’s post hoc analysis).15-PGDH activity was also higher in vehicle-treated 5xFAD mice than vehicle-treated WT littermates, consistent with the results shown in Fig.1C. (C) (+) SW033291 fully prevents cognitive deficits in 5xFAD mice in the MWM test. In vehicle- treated animals, 5xFAD mice performed significantly worse than WT littermates, as shown by a significantly longer latency time to first cross the platform area. However, in 5xFAD mice treated with (+)-SW033291, performance (latency time) was preserved at the normal WT littermate vehicle levels. Performance was identical between WT mice treated with either vehicle or (+)-SW033291 (Interaction p<0.05, ** p<0.01, *** p<0.001, two-way ANOVA and Tukey’s post hoc analysis). (D) Schematic diagram of experimental procedure for evaluating the protective efficacy of genetic haploinsufficiency of 15-PGDH (Hpgd+/-) in 5xFAD mice. Tg-WT and Tg-5xFAD refer to 5xFAD genotypes, respectively designating absence or presence of the 5xFAD transgene, and Hpgd+/+ and Hpgd+/- denote Hpgd genotype. Mice were injected with a bolus of BrdU (150 mg/kg) 1 month before sacrifice to label newborn hippocampal neurons. MWM testing of cognition was conducted one week before brain tissue was harvested for analysis at nine months of age. Males (shown as filled circles or filled squares in subsequent panels) and females (shown as open circles or open squares in subsequent panels) of all four combinations of 5xFAD and 15-PGDH genotypes were housed under normal conditions. (E) Hpgd haploinsufficiency fully blocks the increase in 15-PGDH enzyme activity in symptomatic 5xFAD mice. Brain 15-PGDH enzyme activity is highly elevated in Tg-5xFAD Hpgd+/+ mice compared to control Tg-WT Hpgd+/+ mice and is preserved at control levels in Tg-5xFAD Hpgd+/- mice, with no difference detected between Tg-WT Hpgd+/+ and Tg-5xFAD Hpgd+/- mice (** p<0.01, one-way ANOVA and Tukey’s post hoc analysis). (F) Hpgd haploinsufficiency prevents cognitive impairment in 5xFAD mice in the MWM. In the MWM probe test of memory, Tg-5xFAD Hpgd+/+ mice performed significantly worse than control Tg-WT Hpgd+/+ mice, as shown by significantly longer latency to first cross the platform area. Tg-5xFAD Hpgd+/- mice were protected from memory deficits, as evidenced by latency to first cross the platform area in the memory test being significantly lower than Tg-5xFAD Hpgd+/+ mice and not significantly different from Tg-WT Hpgd+/+ mice (Interaction p<0.05, * p<0.05, **** p<0.0001, two-way ANOVA and Tukey’s post hoc analysis). (G) Aβ 4G8 staining shows that (+)-SW033291-mediated inhibition of 15-PGDH does not affect amyloid deposition in 5xFAD mice hippocampus (** p<0.001, one- way ANOVA and Tukey’s post hoc analysis, scale bar = 50 µm, 3-4 images / mouse). (H) Aβ 4G8 staining shows that genetic inhibition of 15-PGDH does not affect amyloid deposition in Tg-5xFAD mice hippocampus (** p<0.01, one-way ANOVA and Tukey’s post hoc analysis, scale bar = 50µm, n = 3-4 images / mouse). (I) Transmission electron microscopy (TEM) shows structural damage of the BBB, as measured by the percentage of brain capillaries affected by astrocyte endfeet swelling in 5xFAD mice as compared to WT littermates. This damage was completely prevented by (+)-SW033291 treatment (**** p<0.0001, one-way ANOVA and Tukey’s post hoc analysis, scale bar = 2 µm). Representative pictures are shown on the top (each graphed data point represents the average value from one mouse, with 50 images / mouse). (J) TEM shows structural damage of the BBB, as measured by the percentage of brain capillaries affected by astrocyte endfeet swelling in Tg-5xFAD Hpgd+/+ mice as compared to control Tg-WT Hpgd+/+ mice. Hpgd haploinsufficiency completely prevented this BBB damage (Tg-5xFAD Hpgd+/- versus Tg- 5xFAD Hpgd+/+ comparison) (**** p<0.0001, one-way ANOVA and Tukey’s post hoc analysis, scale bar = 2 µm). Representative pictures are shown on the top (each graphed data point represents the average value from one mouse, with 50 images/mouse). (K) IgG staining shows functional impairment and increased permeability of the BBB as evidenced by IgG infiltration into the brain parenchyma in 5xFAD mice, compared to WT littermates. (+)- SW033291 treatment protects 5xFAD mice from this functional impairment of the BBB. (* p<0.05, *** p<0.001, one-way ANOVA and Tukey’s post hoc analysis, scale bar = 50 µm; 2-3 brain sections/mouse). (L) IgG staining shows functional impairment and increased permeability of the BBB as evidenced by IgG infiltration into the brain parenchyma in Tg- 5xFAD Hpgd+/+ mice, compared to control Tg-WT Hpgd+/+ mice. Hpgd haploinsufficiency protects Tg-5xFAD Hpgd+/- mice from this impairment (Tg-5xFAD Hpgd+/+ compared to Tg- 5xFAD Hpgd+/-) (* p<0.05, ** p<0.01, one-way ANOVA and Tukey’s post hoc analysis, scale bar = 50 µm; 2-3 brain sections/mouse). In all graphs (A-L), data points indicate values of individual mice. [0025] Figs.3(A-J) illustrate 15-PGDH inhibition protects 5xFAD mice from decreased survival of newborn hippocampal neurons, neuroinflammation, and oxidative stress. (A) 6- month-old symptomatic 5xFAD mice have impaired survival of BrdU-labeled newborn hippocampal neurons (black arrows), compared to WT littermates, as assessed 28 days post- BrdU injection. (+)-SW033291 treatment preserves normal survival of newborn hippocampal neurons in 5xFAD mice (genotype p<0.001, treatment p<0.0001, ** p<0.01, **** p<0.0001, two-way ANOVA and Tukey’s post hoc analysis, scale bar = 20 µm). Each graphed dot represents the average value of BrdU-labelled cells from an individual mouse as determined from 5-6 sections spaced at least 400 µm apart across the hippocampus. (B) Tg- 5xFAD Hpgd+/+ mice have impaired survival of BrdU-labeled newborn hippocampal neurons (black arrows), versus Tg-WT Hpgd+/+ littermates, as assessed 28 days post-BrdU injection. Genetic reduction of 15-PGDH in Tg-5xFAD Hpgd+/- mice restores newborn hippocampal neuron survival. (Interaction p<0.05, genotype (Tg-WT vs Tg-5xFAD) p<0.0001, genotype (Hpgd+/+ vs Hpgd+/-) p<0.0001, *** p<0.001, **** p<0.0001, two-way ANOVA and Tukey’s post hoc analysis, scale bar = 20 µm). Each dot represents the average value of BrdU-labelled cells from an individual mouse determined from 5-6 sections each spaced at least 400µm apart across the hippocampus. (C) 5xFAD mice show increased hippocampal GFAP expression, which is significantly reduced by treatment with (+)-SW033291 (Interaction p<0.001, ** p<0.01, **** p<0.0001, two-way ANOVA and Tukey’s post hoc analysis). (D) Tg-5xFAD Hpgd+/+ mice show increased whole brain GFAP expression compared to Tg-WT Hpgd+/+ mice, which is significantly prevented in Tg-5xFAD Hpgd+/- mice (** p<0.01, *** p<0.001, one-way ANOVA and Tukey’s post hoc analysis). (E) 4- HNE staining analysis of brain cortex and its quantification shows increased 4-HNE in 5xFAD mice, relative to WT littermates, which is significantly prevented by (+)-SW033291 treatment (*** p<0.001, **** p<0.0001, one-way ANOVA and Tukey’s post hoc analysis; 2- 3 brain sections/mouse). (F) 4-HNE staining analysis of brain cortex and its quantification shows increased 4-HNE in Tg-5xFAD Hpgd+/+ mice compared to Tg-WT Hpgd+/+ mice, which is fully prevented in Tg-5xFAD Hpgd+/- mice (**** p<0.0001, one-way ANOVA and Tukey’s post hoc analysis; 2-3 brain sections/mouse). (G) 3-NT staining analysis of brain cortex and its quantification shows increased 3-NT in 5xFAD mice, relative to WT littermates, which is significantly prevented by (+)-SW033291 treatment (*** p<0.001, **** p<0.0001, one-way ANOVA and Tukey’s post hoc analysis; 2-3 brain sections/mouse). (H) 3-NT staining analysis of brain cortex and its quantification shows increased 3-NT in Tg- 5xFAD Hpgd+/+ mice compared to Tg-WT Hpgd+/+ mice, which is completely prevented in Tg-5xFAD Hpgd+/- mice (*** p<0.001, one-way ANOVA and Tukey’s post hoc analysis; 2-3 brain sections / mouse). (I) Pretreatment with prostanoid substrates of 15-PGDH, either 5µM PGE2 or 5µM PGF2α, suppressed ROS induction assayed 30 minutes after 5µM Aβ oligomer treatment (* p<0.05, ** p<0.01, one-way ANOVA and Tukey’s post hoc analysis). (J) Pretreatment with 15-PGDH substrates, RvD1, LXA4, 15-HETE suppressed ROS induction assayed 30 minutes after 5µM Aβ oligomer treatment (*** p<0.001, **** p<0.0001, one- way ANOVA and Tukey’s post hoc analysis). In all graphs (A-J), data points indicate the value for an individual mouse or replicate of tested cells. [0026] Figs.4(A-K) illustrate 15-PGDH inhibition protects mice from TBI-induced cognitive impairment, oxidative stress, neurodegeneration, and BBB damage. (A) Schematic diagram of experimental procedure for evaluating the protective efficacy of (+)-SW033921- mediated 15-PGDH inhibition in TBI. 8-week-old mice were administered multimodal TBI on day 0, and 24 hours later started on a 21-day regimen of twice daily (+)-SW03391 (5mg/kg x 2 = 10 mg/kg/day). Morris water maze testing was conducted between days 14 and 18, and brain tissue was harvested for analysis on day 21. (B) Post-TBI administration of (+)-SW033291, initiated 24 hours after injury and continued for two weeks, inhibited brain 15-PGDH activity (**** p<0.0001, unpaired t-test). (C) Vehicle-treated TBI-injured mice show significantly worse memory than sham-injury mice, as evidenced by significantly greater latency time to cross the platform area in the MWM probe test of memory. Treatment of TBI mice with (+)-SW033921 completely prevented post-TBI memory impairment (Interaction p<0.01, **** p<0.0001, two-way ANOVA and Tukey’s post hoc analysis). (D) Vehicle-treated TBI-injured mice showed significantly worse memory than sham-injury mice, as shown by a significantly lower number of platform area crossings on the MWM probe test of memory. Treatment of TBI mice with (+)-SW033921 prevented post-TBI memory impairment. (Interaction p<0.05, ** p<0.01, two-way ANOVA and Tukey’s post hoc analysis). (E) TBI induces axonal degeneration, which was reversed by 15-PGDH pharmacologic inhibition with (+)-SW03329. Axonal degeneration was visualized and quantified by silver staining analysis, using percent positive area. (** p<0.01, one-way ANOVA and Tukey’s post hoc analysis, scale bar = 5µm). (Each dot represents average value from one mouse as determined from 6 images/mouse). (F) TEM analysis and its quantification shows that TBI-induced structural BBB damage, as evidenced by swelling of astrocyte endfeet, was blocked by 15-PGDH pharmacologic inhibition with (+)-SW033291 (**** p<0.0001, one-way ANOVA and Tukey’s post hoc analysis). (G) 3-NT staining and its quantification show that TBI-induced oxidative stress, as evidenced by increased 3-NT, was blocked by 15-PGDH pharmacologic inhibition with (+)-SW033291 (*** p<0.001, **** p<0.0001, one-way ANOVA and Tukey’s post hoc analysis; 2-3 brain sections/mouse). (H) Schematic diagram of experimental procedure for evaluating the protective efficacy of genetic 15-PGDH inhibition in TBI. Control 8-week-old Hpgd+/+ (WT) and Hpgd-/- (KO) mice were subjected to multimodal TBI. Brain tissue was harvested for analysis 3 weeks after TBI. (I) TBI induces axonal degeneration, which was reversed by biallelic Hpgd gene deletion (Hpgd-/-). Axonal degeneration was visualized and quantified by silver staining analysis, using percent positive area. (** p<0.01, *** p<0.001, one-way ANOVA and Tukey’s post hoc analysis, scale bar = 5µm). (Each dot represents average value from one mouse as determined from 6 images / mouse). (J) Electron microscopy analysis and its quantification shows that TBI-induced structural BBB damage, as evidenced by swelling of astrocyte endfeet, was blocked by biallelic Hpgd gene deletion (Hpgd-/-) (**** p<0.0001, one-way ANOVA and Tukey’s post hoc analysis). (K) 3-NT staining and its quantification shows that TBI-induced oxidative stress, as evidenced by increased 3-NT, was blocked by biallelic Hpgd gene deletion (Hpgd-/-) (**** p<0.0001, one-way ANOVA and Tukey’s post hoc analysis; 2-3 brain sections / mouse). In all graphs (A-K), data points indicate values of individual mice. [0027] Figs.5(A-E) illustrate Brain 15-PGDH is elevated in human and rodent Alzheimer’s disease. (A) RNA sequencing data from the Allen brain atlas shows higher 15- PGDH mRNA (HPGD expression, 203913_s_at (ID_Ref)) in the hippocampus of human Alzheimer’s disease (AD) subjects, compared to no dementia matched control subjects (* p<0.05, unpaired t-test). (B) 15-PGDH whole brain enzymatic activity is increased in symptomatic TgF344-AD rats (6 months old), compared to WT littermates (* p<0.05, unpaired t-test). (C) Human frontal cortex microarray data from Lu et al. (GDS5204) (9) reveals that 15-PGDH mRNA (HPGD expression) is positively correlated with aging in frontal cortex (r=0.3751, p=0.0157). (D) Mouse whole brain qPCR data reveals that 15- PGDH mRNA (Hpgd expression) is increased in aged mice (22-24 months old), compared to young mice (5-7 months old). Hpgd was normalized by Actb (* p<0.05, unpaired t-test). (E) Mouse whole brain 15-PGDH enzymatic activity is increased in aged mice (22-24 months old), relative to young mice (5-7 months old) (* p<0.05, unpaired t-test). In all graphs (A-E), data points indicate values of individual human subjects or mice. [0028] Figs.6(A-G) illustrate Brain 15-PGDH expression is enriched in PVMs and microglia. (A) UMAP depiction of single cell RNA sequencing data reanalyzed from Yao et al. reveals 15-PGDH mRNA (Hpgd expression) is most highly enriched in a brain PVM plus microglia cell cluster (bold arrow), along with lesser enrichment in a minority neuronal subpopulation (thin arrow). Increased Hpgd expression level is indicated by increased dot size and color intensity. (B) Single cell RNA sequencing data shows that 48% of the PVM/microglia population express Hpgd, and only 9% of neurons (labeled L2/3 IT Cortex Hpgd) express Hpgd (**** p<0.0001, Fisher’s exact test, SE for binominal probability: 0.038 (Microglia/PVM) and 0.003 (L2/3 IT CTX). (C) The mean level of Hpgd in PVM/microglia is 0.64 log2(SCT) (Log2(sctransform normalized units)), while the mean level in L2/3 IT Cortex neurons is 0.1 log2(SCT) (**** p<0.0001, two-sample t-test). (D) Distribution of Hpgd positive cells in the cortex shows that the PVM/microglia population has the highest percentage of Hpgd positive cells, followed by L2/3 IT CTX neurons. (E) The mean log2(SCT) expression level of Hpgd in each cluster of the cortex shows that the PVM/microglia population has the highest mean expression of Hpgd, followed by L2/3 IT neurons. (F) Distribution of Hpgd positive cells in the hippocampus shows that the PVM/microglia population has the highest percentage of Hpgd-positive cells, followed by neurons in CA3 and IG-FC (induseum griseum, IG, and fasciolo cinerea, FC; small brain regions in the hippocampus). (G) The mean log2(SCT) expression level of Hpgd in each cluster of the hippocampus shows that the PVM/microglia population has the highest mean expression of Hpgd, followed by neurons in CA3 and IG-FC. [0029] Figs.7(A-C) illustrate 15-PGDH expressing myeloid cells are proximal to blood vessels. (A) Mouse brain 15-PGDH enzymatic activity in WT mice (6 months old) is enriched ~200-fold in CD11b (+) myeloid cells, compared to CD11b (-) non-myeloid cells (* p<0.05, paired t-test). Data points indicate values of individual mice. (B) RNA FISH for Hpgd and Itgam combined with CD31 immunofluorescence (IF) in mouse brain shows 15- PGDH positive brain myeloid cells (Hpgd+ Itgam+ cells) close to blood vessel (CD31) in cortex and hippocampus of 6-month-old WT mouse. Histogram shows the number of Hpgd and Itgam double positive cells in each distance category from the nearest CD31 marked cell. A total of 12 images per brain section (6 from the cortex, 6 from the hippocampus) were analyzed. Two brain sections from each mouse were used, with a total of 6 WT mice included in the study. (C) Western blot of 15-PGDH protein in CD11b (+) myeloid cells and CD11b (-) non-myeloid cells from WT and 5xFAD mice, quantified in Fig.1G. [0030] Figs.8(A-J) illustrate Pharmacokinetics of (+)-SW033291 in the plasma and the brain; 15-PGDH inhibition protects 5xFAD mice from cognitive impairment, with similar swim speed in Morris water maze (MWM) across all groups. (A) Brain pharmacokinetic data of (+)-SW033291 shows the compound’s uptake and presence in the brain for up to 6 hours after 10 mg/kg intraperitoneal injection (n=3 per time point). (B) Plasma pharmacokinetic data of (+)-SW033291 shows the compound’s continued presence in the plasma 6 hours after 10 mg/kg intraperitoneal injection (n=3 per time point). (C) (+)-SW033291 fully prevents cognitive deficits in 5XFAD mice in the MWM, in which vehicle-treated 5xFAD mice performed significantly worse than vehicle-treated WT littermates, as evidenced by significantly fewer platform area crossings. This was preserved at normal WT littermate vehicle levels in 5xFAD mice treated with (+)-SW033291 (Treatment (vehicle vs. (+)- SW033291) p<0.01, * p<0.05, two-way ANOVA and Tukey’s post hoc analysis). (D) Time to find the platform (escape latency) was similar across all groups on every day of MWM training (learning), and all groups learned where the platform was located over three days, with improved learning on successive days (Time from day 1 to 2 to 3, p<0.0001, repeated measures two-way ANOVA and Tukey’s post hoc analysis). Learning data is the average of 4 successive trials performed daily. Memory data represents performance and recall on a single memory challenge trial. (E) Swim speed on probe test day of the MWM test was similar across all groups of WT, 5XFAD, (+) SW033291-treated, and vehicle-treated mice (Two-way ANOVA and Tukey’s post hoc analysis; no significant difference observed). (F) Swim speed was significantly slower in 5xFAD mice compared to WT littermates on day 1 of the training phase, but not on days 2 or 3. (+)-SW033291-treated 5xFAD mice showed no difference in swim speed compared to vehicle-treated 5xFAD mice over training days (Time p<0.05, group p<0.05**, p<0.01, repeated measures two-way ANOVA with Greenhouse- Geisser correction and Tukey’s post hoc analysis). (G) Hpgd haploinsufficiency reverses cognitive impairment in 5xFAD mice in the MWM. In the MWM probe test of memory, Tg- 5xFAD Hpgd+/+ mice performed significantly worse than control Tg-WT Hpgd+/+ mice, as evidenced by significantly fewer platform area crossings. Hpgd haploinsufficient Tg-5xFAD Hpgd+/- mice were protected from memory deficit, as evidenced by a normal level of platform area crossings. (Genotype (Hpgd+/+ vs Hpgd+/-) p<0.01, genotype (Tg-WT vs Tg-5xFAD) p<0.01*, p<0.05, two-way ANOVA and Tukey’s post hoc analysis;). (H) Tg-5xFAD Hpgd+/+ mice displayed learning deficit during the training phase, as evidenced by longer time to find the platform (escape latency) than the other groups on days 2 and 3 of training, which was significantly protected by Hpgd haploinsufficiency in Tg-5xFAD Hpgd+/+ mice. Tg-5xFAD Hpgd+/- mice performed comparably to Tg-WT Hpgd+/+ and Tg-WT Hpgd+/- mice (Time x group Interaction p<0.001, ** p<0.01, **** p<0.0001, repeated measures two-way ANOVA and Tukey’s post hoc analysis). (I) On probe test day of the MWM test, Tg-5xFAD mice showed significant difference in swim speed versus Tg-WT mice (Genotype (Tg-WT vs Tg- 5xFAD) p<0.05, two-way ANOVA and Tukey’s post hoc analysis; no difference between other groups were observed, including no difference in swim speed as a function of haploinsuffiency of Hpgd). (J) During training, swim speed showed no significant differences between any of the four genotypes of mice across all three days (Tg-WT Hpgd+/+, Tg-WT Hpgd+/-, Tg-5xFAD Hpgd+/+, Tg-5xFAD Hpgd+/-), (Time x group interaction p<0.05, * p<0.05, repeated measures two-way ANOVA). In all graphs (C-J) except A and B, data points indicate values of individual mice. [0031] Figs.9(A-F) illustrate body weight gain and Aβ accumulation are not altered in 5xFAD mice after pharmacologic or genetic 15-PGDH inhibition. (A) Body weight gain over four months of treatment with either vehicle or (+)-SW033291 shows no difference detected across all groups of 5xFAD mice and WT littermates (Two-way ANOVA and Tukey’s post hoc analysis). (B) There is no significant difference in body weight between Tg-5xFAD Hpgd+/+ and Tg-5xFAD Hpgd+/- mice. When grouped, Tg-5xFAD Hpgd+/+ and Tg-5xFAD Hpgd+/- mice weighed significantly less compared to Tg-WT Hpgd+/+ and Tg-WT Hpgd+/- mice (Genotype (Tg-WT vs Tg-5xFAD) p<0.01, two-way ANOVA and Tukey’s post hoc analysis). Males are shown as filled circles or filled squares and females are shown as open circles or open squares, here and in all subsequent panels. (C) Aβ 4G8 staining shows that (+)-SW033291-mediated inhibition of 15-PGDH does not affect amyloid deposition in 5xFAD mice cortex (similar to findings in the hippocampus of Fig.2G) (*** p<0.0001, one- way ANOVA and Tukey’s post hoc analysis, scale bar = 50 µm, 3-4 images/mouse). (D) Aβ 4G8 staining shows that genetic inhibition of 15-PGDH does not affect amyloid deposition in Tg-5xFAD mice cortex (similar to findings in the hippocampus of Fig.2H) (* p<0.05, one- way ANOVA and Tukey’s post hoc analysis, scale bar = 50µm, n = 3-4 images/mouse). (E) Representative picture of Congo red staining and its whole brain quantification show that (+)-SW033291 does not affect amyloid plaque deposition in 5xFAD mice (Genotype p<0.0001, **** p<0.0001, two-way ANOVA and Tukey’s post hoc analysis, scale bar = 50µm, 3-4 images/mouse). (F) Representative picture of Congo red staining and its whole brain quantification show that genetic reduction of 15-PGDH does not affect amyloid plaque deposition in Tg-5xFAD mice (Genotype (Tg-WT vs Tg-5xFAD) p<0.0001, **** p<0.0001, two-way ANOVA and Tukey’s post hoc analysis, scale bar = 50µm, 3-4 images / mouse). In all graphs of panels (A-F), data points indicate values of individual mice. [0032] Figs.10(A-E) illustrate pharmacologic or genetic 15-PGDH inhibition increases survival of newborn hippocampal neurons. (A) Genetic inhibition of 15-PGDH (Hpgd-/-) increases survival of BrdU-labeled newborn hippocampal neurons (black arrows) in male and female adult mice, assayed 15 days post-BrdU injection (Genotype p<0.0001, **** p<0.0001, two-way ANOVA and Tukey’s post hoc analysis). No difference was detected between males and females. (B) (+)-SW033291 inhibition of 15-PGDH increases survival of BrdU-labeled newborn hippocampal neurons (black arrows) in adult wild type (Hpgd+/+) mice. Hpgd-/- mice show increased survival of BrdU-labeled new hippocampal neurons (versus control Hpgd+/+), but do not show any additional response to (+)-SW033291 treatment, confirming that (+)-SW033291 potentiates the net magnitude of hippocampal neurogenesis by an on-target effect of inhibiting 15-PGDH. BrdU-labeled cells were quantified 28 days post-BrdU injection. (Interaction p<0.0001, **** p<0.0001, two-way ANOVA and Tukey’s post hoc analysis). (C) 15-PGDH inhibition with (+)-SW033291 does not alter the rate of generation of newborn neurons in the adult WT hippocampal dentate gyrus, as assessed by quantifying BrdU-labeled cells (black arrows) at 1-hour post-BrdU injection (unpaired t-test). (D) P7C3-A20 treatment increases survival of BrdU-labeled newborn hippocampal neurons in both wild type (Hpgd+/+) and 15-PGDH KO (Hpgd-/-), confirming that an alternative proneurogenic compound can enhance survival of postnatally born hippocampal neurons in 15-PGDH KO (Hpgd-/-) mice. BrdU-labeled cells were quantified 28 days post-BrdU injection. (Interaction p<0.0001, **** p<0.0001, two-way ANOVA and Tukey’s post hoc analysis). (E) 5xFAD mouse brains display axonal degeneration in the dorsal fornix, which was reversed by 15-PGDH pharmacologic inhibition with (+)-SW033291. Axonal degeneration was visualized and quantified by silver staining analysis, using percent positive area. (Interaction p<0.05, * p<0.05, **** p<0.0001, two-way ANOVA and Tukey’s post hoc analysis, scale bar = 5µm, 3 brain sections / mouse). In all graphs (A-E), data points indicate values of individual mice. [0033] Figs.11(A-D) illustrate astrocyte and microglial reactivity after pharmacologic or genetic 15-PGDH inhibition. (A) Western blot of GFAP protein, quantified in Fig.3C, with each lane on the gel representing an individual mouse. (A to B) 5xFAD mice also show characteristic over-expression of APP and induction of IBA1, neither of which are prevented by treatment with (+)-SW033291 (Genotype p<0.0001, ** p<0.01, two-way ANOVA and Tukey’s post hoc analysis). (C) Western blot of GFAP protein, quantified in Fig.3D, with each lane on the gel representing an individual mouse. (C to D) Tg-5xFAD Hpgd+/+ mice also show overexpression of APP and IBA1, as compared to control Tg-WT Hpgd+/+ mice, and neither of these are prevented in Tg-5xFAD Hpgd+/- mice. (* p<0.05, one-way ANOVA and Tukey’s post hoc analysis). In all graphs (A-D), data points indicate values of individual mice. [0034] Figs.12(A-C) illustrate Aβ oligomer-induced generation of reactive oxygen species (ROS) in BV2 microglia cells is suppressed by treatment with 15-PGDH substrates. (A) 30 minutes of treatment with Aβ oligomer induces dose dependent ROS production by BV2 cells (left). Confluency of the cells did not change in response to treatment of Aβ oligomer (right, * p<0.05, ** p<0.01, one-way ANOVA and Tukey’s post hoc analysis). (B) Treating BV2 cells with Aβ oligomer for 30 minutes, or with Aβ oligomer preceded by 24 hrs exposure to 15-PGDH substrates PGE2 or PGF2a, did not affect confluency of cells (One-way ANOVA). (C) Treating BV2 cells with Aβ oligomer for 30 minutes, or with Aβ oligomer preceded by 24 hrs exposure to 15-PGDH substrate RvD1, LXA4, or 15-HETE, did not affect confluency of cells (One-way ANOVA). In all graphs (A-C), data points indicate the value of an individual replicate of the cells. [0035] Figs.13(A-H) illustrate protection of WT mice from TBI-induced cognitive deficits and oxidative stress by pharmacologic or genetic inhibition of 15-PGDH. (A) Average swim speed during the probe test memory phase of the MWM test showed no differences across all groups shown in Figs.4C, 4D (Two-way ANOVA; legend as per panel C). (B) All four groups tested in the MWM in Figs.4C, 4D showed no differences in ability to learn the task over the 4-day learning period (Time p<0.0001, repeated measures two-way ANOVA and Tukey’s post hoc analysis; legend as per panel C). (C) Average swim speed during the learning phase of the MWM test showed no differences across all groups of the same animals shown in Figs.4B, 4C (Time p<0.0001, repeated measures two-way ANOVA with Greenhouse-Geisser correction and Tukey’s post hoc analysis). (D) 4-HNE staining and its quantification show TBI-induced oxidative stress, as evidenced by increased 4-HNE, which was blocked by 15-PGDH pharmacologic inhibition with (+)-SW033291 (**** p<0.0001, one-way ANOVA and Tukey’s post hoc analysis; 2-3 brain sections / mouse). (E to G) Western blot analysis shows no difference in GFAP or IBA1 expression as a function of TBI or (+)-SW033291 treatment (Two-way ANOVA). In each graph, data points indicate values of individual mice. (H) 4-HNE staining and its quantification shows that TBI-induced oxidative stress, as evidenced by increased 4-HNE, was blocked by biallelic Hpgd gene deletion (Hpgd-/-) (**** p<0.0001, one-way ANOVA and Tukey’s post hoc analysis; 2-3 brain sections / mouse). In all graphs (A-H), data points indicate values of individual mice. DETAILED DESCRIPTION Definitions [0036] For convenience, certain terms employed in the specification, examples, and appended claims are collected here. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. [0037] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. [0038] The terms "comprise," "comprising," "include," "including," "have," and "having" are used in the inclusive, open sense, meaning that additional elements may be included. The terms "such as", "e.g.,", as used herein are non-limiting and are for illustrative purposes only. "Including" and "including but not limited to" are used interchangeably. [0039] The verb “comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. The present invention may suitably “comprise”, “consist of”, or “consist essentially of”, the steps, elements, and/or reagents described in the claims. [0040] It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely", "only" and the like in connection with the recitation of claim elements, or the use of a "negative" limitation. [0041] Throughout the description, where compositions are described as having, including, or comprising, specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remains operable. Moreover, two or more steps or actions can be conducted simultaneously. [0042] The term “pharmaceutically acceptable” means suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use within the scope of sound medical judgment. [0043] The term “pharmaceutically acceptable salt” include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. The term “pharmaceutically acceptable salts” also includes those obtained by reacting the active compound functioning as an acid, with an inorganic or organic base to form a salt, for example salts of ethylenediamine, N-methyl- glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, and the like. Non limiting examples of inorganic or metal salts include lithium, sodium, calcium, potassium, magnesium salts and the like. [0044] Additionally, the salts of the compounds described herein, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc. [0045] The term "solvates" means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate. [0046] The compounds and salts described herein can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present application includes all tautomers of the present compounds. A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism. [0047] Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. [0048] Tautomerizations can be catalyzed by: Base: 1. deprotonation; 2. formation of a delocalized anion (e.g., an enolate); 3. protonation at a different position of the anion; Acid: 1. protonation; 2. formation of a delocalized cation; 3. deprotonation at a different position adjacent to the cation. [0049] The terms below, as used herein, have the following meanings, unless indicated otherwise: “Amino” refers to the -NH2 radical. “Cyano” refers to the -CN radical. “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo radical. “Hydroxy” or “hydroxyl” refers to the -OH radical. “Imino” refers to the =NH substituent. “Nitro” refers to the -NO2 radical. “Oxo” refers to the =O substituent. “Thioxo” refers to the =S substituent. [0050] “Alkyl” or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a C1-C6 alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A C1- C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and C1 alkyl (i.e., methyl). A C1- C6 alkyl includes all moieties described above for C1-C5 alkyls but also includes C6 alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and C1-C6 alkyls, but also includes C7, C8, C9 and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls. Non-limiting examples of C1-C12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t- amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted. [0051] “Alkylene” or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms. Non- limiting examples of C1-C12 alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted. [0052] “Alkenyl” or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 12 carbon atoms is a C2-C12 alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl. A C2- C5 alkenyl includes C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls. A C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes C6 alkenyls. A C2- C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C7, C8, C9 and C10 alkenyls. Similarly, a C2-C12 alkenyl includes all the foregoing moieties, but also includes C11 and C12 alkenyls. Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1- propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4- heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6- octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7- nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7- decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5- undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8- dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted. [0053] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of C2-C12 alkenylene include ethene, propene, butene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted. [0054] “Alkynyl” or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 12 carbon atoms is a C2-C12 alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl, an alkynyl group comprising up to 6 carbon atoms is a C2-C6 alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls. A C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes C6 alkynyls. A C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C7, C8, C9 and C10 alkynyls. Similarly, a C2-C12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls. Non-limiting examples of C2-C12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted. [0055] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Non-limiting examples of C2-C12 alkynylene include ethynylene, propargylene and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted. [0056] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl, alkenyl or alknyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted. [0057] “Alkylamino” refers to a radical of the formula -NHRa or -NRaRa where each Ra is, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted. [0058] “Alkylcarbonyl” refers to the –C(=O)Ra moiety, wherein Ra is an alkyl, alkenyl or alkynyl radical as defined above. A non-limiting example of an alkyl carbonyl is the methyl carbonyl (“acetal”) moiety. Alkylcarbonyl groups can also be referred to as “Cw-Cz acyl” where w and z depicts the range of the number of carbon in Ra, as defined above. For example, “C1-C10 acyl” refers to alkylcarbonyl group as defined above, where Ra is C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl radical as defined above. Unless stated otherwise specifically in the specification, an alkyl carbonyl group can be optionally substituted. [0059] “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from phenyl (benzene), aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term “aryl” is meant to include aryl radicals that are optionally substituted. [0060] “Aralkyl” or “arylalkyl” refers to a radical of the formula -Rb-Rc where Rb is an alkylene group as defined above and Rc is one or more aryl radicals as defined above. Aralkyl radicals include, but are not limited to, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted. [0061] “Aralkenyl” or “arylalkenyl” refers to a radical of the formula -Rb-Rc where Rb is an alkenylene group as defined above and Rc is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkenyl group can be optionally substituted. [0062] “Aralkynyl” or “arylalkynyl” refers to a radical of the formula -Rb-Rc where Rb is an alkynylene group as defined above and Rc is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkynyl group can be optionally substituted. [0063] “Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a ring structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl. Cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted. [0064] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted. [0065] “Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted. [0066] “Cycloalkynyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted. [0067] “Cycloalkylalkyl” refers to a radical of the formula -Rb-Rd where Rb is an alkylene, alkenylene, or alkynylene group as defined above and Rd is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group can be optionally substituted. [0068] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted. [0069] “Haloalkenyl” refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted. [0070] “Haloalkynyl” refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropynyl, 1-fluorobutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkynyl group can be optionally substituted. [0071] “Heterocyclyl,” “heterocyclic ring” or “heterocycle” refers to a stable 3- to 20-membered non-aromatic, partially aromatic, or aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclycl or heterocyclic rings include heteroaryls as defined below. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, and spiral ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, aziridinyl, oextanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, pyridine-one, and the like. The point of attachment of the heterocyclyl, heterocyclic ring, or heterocycle to the rest of the molecule by a single bond is through a ring member atom, which can be carbon or nitrogen. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted. [0072] “Heterocyclylalkyl” refers to a radical of the formula -Rb-Re where Rb is an alkylene group as defined above and Re is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group can be optionally substituted. [0073] “Heterocyclylalkenyl” refers to a radical of the formula -Rb-Re where Rb is an alkenylene group as defined above and Re is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkenyl group can be optionally substituted. [0074] “Heterocyclylalkynyl” refers to a radical of the formula -Rb-Re where Rb is an alkynylene group as defined above and Re is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkynyl group can be optionally substituted. [0075] “N-heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a N-heterocyclyl group can be optionally substituted. [0076] “Heteroaryl” refers to a 5- to 20-membered ring system radical one to thirteen carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, as the ring member. For purposes of this invention, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems, wherein at least one ring containing a heteroatom ring member is aromatic. The nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized and the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolopyridine, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted. [0077] “N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group can be optionally substituted. [0078] “Heteroarylalkyl” refers to a radical of the formula -Rb-Rf where Rb is an alkylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group can be optionally substituted. [0079] “Heteroarylalkenyl” refers to a radical of the formula -Rb-Rf where Rb is an alkenylene, chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkenyl group can be optionally substituted. [0080] “Heteroarylalkynyl” refers to a radical of the formula -Rb-Rf where Rb is an alkynylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkynyl group can be optionally substituted. [0081] “Thioalkyl” refers to a radical of the formula -SRa where Ra is an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted. [0082] The term “substituted” used herein means any of the above groups (e.g., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, etc.) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N- oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, -SO2ORg, =NSO2Rg, and -SO2NRgRh. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NRgRh. In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl. “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N- heteroaryl and/or heteroarylalkyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents. [0083] As used herein, the symbol “ ” (hereinafter can be referred to as “a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example, “ ” indicates that the chemical entity “A” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference. For example, the compound , ” infers that the point of attachment bond is the bond by which X is depicted as being attached to the phenyl ring at the ortho position relative to fluorine. [0084] The phrases "parenteral administration" and "administered parenterally" are art-recognized terms, and include modes of administration other than enteral and topical administration, such as injections, and include, without limitation, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra- articular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion. [0085] The term "treating" is art-recognized and includes inhibiting a disease, disorder or condition in a subject, e.g., impeding its progress; and relieving the disease, disorder or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected. [0086] The term "preventing" is art-recognized and includes stopping a disease, disorder or condition from occurring in a subject, which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it. Preventing a condition related to a disease includes stopping the condition from occurring after the disease has been diagnosed but before the condition has been diagnosed. [0087] A "patient," "subject," or "host" to be treated by the subject method may mean either a human or non-human animal, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. [0088] The terms "prophylactic” or “therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). [0089] The terms "therapeutic agent", "drug", "medicament" and "bioactive substance" are art-recognized and include molecules and other agents that are biologically, physiologically, or pharmacologically active substances that act locally or systemically in a patient or subject to treat a disease or condition. The terms include without limitation pharmaceutically acceptable salts thereof and prodrugs. Such agents may be acidic, basic, or salts; they may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; they may be prodrugs in the form of ethers, esters, amides and the like that are biologically activated when administered into a patient or subject. [0090] The phrase "therapeutically effective amount" or “pharmaceutically effective amount” is an art-recognized term. In certain embodiments, the term refers to an amount of a therapeutic agent that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate, reduce or maintain a target of a particular therapeutic regimen. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular compound without necessitating undue experimentation. In certain embodiments, a therapeutically effective amount of a therapeutic agent for in vivo use will likely depend on a number of factors, including: the rate of release of an agent from a polymer matrix, which will depend in part on the chemical and physical characteristics of the polymer; the identity of the agent; the mode and method of administration; and any other materials incorporated in the polymer matrix in addition to the agent. [0091] The term "ED50" is art-recognized. In certain embodiments, ED50 means the dose of a drug, which produces 50% of its maximum response or effect, or alternatively, the dose, which produces a pre-determined response in 50% of test subjects or preparations. The term "LD50" is art-recognized. In certain embodiments, LD50 means the dose of a drug, which is lethal in 50% of test subjects. The term "therapeutic index" is an art-recognized term, which refers to the therapeutic index of a drug, defined as LD50/ED50. [0092] The terms "IC50," or “half maximal inhibitory concentration” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. [0093] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present. [0094] The term "or" as used herein should be understood to mean "and/or", unless the context clearly indicates otherwise. [0095] As used herein, the term "about" or "approximately" refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. In one embodiment, the term "about" or "approximately" refers a range of quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, or ± 1% about a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. [0096] All percentages and ratios used herein, unless otherwise indicated, are by weight. [0097] The terms "healthy" and "normal" are used interchangeably herein to refer to a subject or particular cell or tissue that is devoid (at least to the limit of detection) of a disease condition. [0098] The term “brain injury” includes traumatic injuries and injuries as a result of disease, in particular neurodegenerative diseases and dementias. Thus, “brain injury” includes, but is not limited to mild, moderate, or severe trauma to the brain such as that received in military conflict, sports injury, accidents and falls, and the like, and also includes but is not limited to injury to the brain as a result of any tauopathy or dementia. In a specific embodiment, the brain injury is accompanied by, associated with, or mediated by astrogliosis or astroglial activation. [0099] "Glasgow Coma Scale" or "GCS" as used herein refers to a 15 point scale for estimating and categorizing the outcomes of brain injury on the basis of overall social capability or dependence on others. The test measures the motor response, verbal response and eye opening response with these values: I. Motor Response (6--Obeys commands fully; 5--Localizes to noxious stimuli; 4--Withdraws from noxious stimuli; 3--Abnormal flexion, i.e., decorticate posturing; 2--Extensor response, i.e. decerebrate posturing; and 1--No response); II. Verbal Response (5--Alert and Oriented; 4--Confused, yet coherent, speech; 3-- Inappropriate words and jumbled phrases consisting of words; 2--Incomprehensible sounds; and 1--No sounds); and III. Eye Opening (4--Spontaneous eye opening; 3--Eyes open to speech; 2--Eyes open to pain; and 1--No eye opening). The final score is determined by adding the values of I+II+III. The final score can be categorized into four possible levels for survival, with a lower number indicating a more severe injury and a poorer prognosis: Mild (13-15); Moderate Disability (9-12) (Loss of consciousness greater than 30 minutes; Physical or cognitive impairments which may or may resolve: and Benefit from Rehabilitation); Severe Disability (3-8) (Coma: unconscious state. No meaningful response, no voluntary activities); and Vegetative State (Less Than 3) (Sleep wake cycles; Arousal, but no interaction with environment; No localized response to pain). [00100] Moderate brain injury is defined as a brain injury resulting in a loss of consciousness from 20 minutes to 6 hours and a Glasgow Coma Scale of 9 to 12. Severe brain injury is defined as a brain injury resulting in a loss of consciousness of greater than 6 hours and a Glasgow Coma Scale of 3 to 8. [00101] "Glasgow Outcome Scale" as used herein refers to a global scale for functional outcome that rates patient status into one of five categories: Dead, Vegetative State, Severe Disability, Moderate Disability or Good Recovery. [00102] Primary brain injuries occur during the initial insult and result from displacement of the physical structures of the brain. More specifically, a primary brain injury is the physical damage to parenchyma (tissue, vessels) that occurs during the traumatic event, resulting in shearing and compression of the surrounding brain tissue. Secondary brain injuries occur subsequent to the primary injury and may involve an array of cellular processes. More specifically, a secondary brain injury refers to the changes that evolve over a period of time (from hours to days) after the primary brain injury. It includes an entire cascade of cellular, chemical, tissue, or blood vessel changes in the brain that contribute to further destruction of brain tissue. [00103] An injury to the head can be either closed or open (penetrating). A closed head injury refers to a trauma to the scalp, skull or brain where there is no penetration of the skull by a striking object. An open head injury refers a trauma to the scalp, skull or brain where there is penetration of the skull by a striking object. An injury to the head may be caused by physical shaking of a person, by blunt impact by an external mechanical or other force that results in a closed or open head trauma (e.g., vehicle accident, such as with an automobile, plane, train, etc.; blow to the head, such as with a baseball bat, or from a firearm), a cerebral vascular accident (e.g., stroke), one or more falls (e.g., as in sports or other activities), explosions or blasts (collectively, "blast injuries") and by other types of blunt force trauma. Alternatively, an injury to the head may be caused by the ingestion and/or exposure to a chemical, toxin or a combination of a chemical and toxin. Examples of such chemicals and/or toxins include fires, molds, asbestos, pesticides and insecticides, organic solvents, paints, glues, gases (such as carbon monoxide, hydrogen sulfide, and cyanide), organic metals (such as methyl mercury, tetraethyl lead and organic tin) and/or one or more drugs of abuse. Alternatively, an injury to the head may be caused as a result of a subject suffering from an autoimmune disease, a metabolic disorder, a brain tumor, one or more viruses, meningitis, hydrocephalus, hypoxia or any combinations thereof. In some cases, it is not possible to be certain whether any such event or injury has occurred or taken place. For example, there may be no history on a patient or subject, the subject may be unable to speak, the subject may not be aware of or have full information on what events they were exposed to, etc. Such circumstances are described herein as the subject "may have sustained an injury to the head." In certain embodiments herein, the closed head injury does not include and specifically excludes a cerebral vascular accident, such as stroke. [00104] "Traumatic Brain Injury" or "TBI" as used interchangeably herein refers to a complex injury with a broad spectrum of symptoms and disabilities. TBI is most often an acute event similar to other injuries. TBI can be classified as "mild," "moderate," or "severe." The causes of TBI are diverse and include, for example, physical shaking by a person, a car accident, injuries from firearms, cerebral vascular accidents (e.g., strokes), falls, explosions or blasts and other types of blunt force trauma. Other causes of TBI include the ingestion and/or exposure to one or more chemicals or toxins (such as fires, molds, asbestos, pesticides and insecticides, organic solvents, paints, glues, gases (such as carbon monoxide, hydrogen sulfide, and cyanide), organic metals (such as methyl mercury, tetraethyl lead and organic tin), one or more drugs of abuse or combinations thereof). Alternatively, TBI can occur in subjects suffering from an autoimmune disease, a metabolic disorder, a brain tumor, hypoxia, one or more viruses, meningitis, hydrocephalus or combinations thereof. Young adults and the elderly are the age groups at highest risk for TBI. In certain embodiments herein, traumatic brain injury or TBI does not include and specifically excludes cerebral vascular accidents such as strokes. [00105] "Mild TBI" as used herein refers to a brain injury where loss of consciousness is brief and usually a few seconds or minutes and/or confusion and disorientation is shorter than 1 hour. Mild TBI is also referred to as a concussion, minor head trauma, minor TBI, minor brain injury, and minor head injury. While Mill and CT scans are often normal, the individual with mild TBI may have cognitive problems, such as headache, difficulty thinking, memory problems, attention deficits, mood swings and frustration. [00106] Mild TBI is the most prevalent TBI and is often missed at time of initial injury. Typically, a subject has a Glasgow Coma scale number of between 13-15 (such as 13-15 or 14-15). Fifteen percent (15%) of people with mild TBI have symptoms that last 3 months or more. Mild TBI is defined as the result of the forceful motion of the head or impact causing a brief change in mental status (confusion, disorientation or loss of memory) or loss of consciousness for less than 30 minutes. Common symptoms of mild TBI include fatigue, headaches, visual disturbances, memory loss, poor attention/concentration, sleep disturbances, dizziness/loss of balance, irritability-emotional disturbances, feelings of depression, and seizures. Other symptoms associated with mild TBI include nausea, loss of smell, sensitivity to light and sounds, mood changes, getting lost or confused, and/or slowness in thinking. [00107] "Moderate TBI" as used herein refers to a brain injury where loss of consciousness and/or confusion and disorientation is between 1 and 24 hours and the subject has a Glasgow Coma scale number of between 9-12. The individual with moderate TBI have abnormal brain imaging results. "Severe TBI" as used herein refers to a brain injury where loss of consciousness is more than 24 hours and memory loss after the injury or penetrating skull injury longer than 24 hours and the subject has a Glasgow Coma scale number between 3-8. The deficits range from impairment of higher level cognitive functions to comatose states. Survivors may have limited function of arms or legs, abnormal speech or language, loss of thinking ability or emotional problems. Individuals with severe injuries can be left in long-term unresponsive states. For many people with severe TBI, long-term rehabilitation is often necessary to maximize function and independence. [00108] Common symptoms of moderate to severe TBI include cognitive deficits including difficulties with attention, concentration, distractibility, memory, speed of processing, confusion, perseveration, impulsiveness, language processing, and/or "executive functions", not understanding the spoken word (receptive aphasia), difficulty speaking and being understood (expressive aphasia), slurred speech, speaking very fast or very slow, problems reading, problems writing, difficulties with interpretation of touch, temperature, movement, limb position and fine, discrimination, the integration or patterning of sensory impressions into psychologically meaningful data, partial or total loss of vision, weakness of eye muscles and double vision (diplopia), blurred vision, problems judging distance, involuntary eye movements (nystagmus), intolerance of light (photophobia), hearing, such as decrease or loss of hearing, ringing in the ears (tinnitus), increased sensitivity to sounds, loss or diminished sense of smell (anosmia), loss or diminished sense of taste, the convulsions associated with epilepsy that can be several types and can involve disruption in consciousness, sensory perception, or motor movements, control of bowel and bladder, sleep disorders, loss of stamina, appetite changes, regulation of body temperature, menstrual difficulties, dependent behaviors, emotional ability, lack of motivation, irritability, aggression, depression, disinhibition, or denial/lack of awareness. [00109] The terms "neurodegenerative disease", "neurodegenerative disorder", or "neurodegenerative condition" are used interchangeably herein to refer to a varied assortment of central nervous system diseases, disorders, and conditions characterized by gradual and progressive loss of neural tissue and/or neural tissue function. A neurodegenerative disease is a class of neurological disorder or disease, and where the neurological disease is characterized by a gradual and progressive loss of neural tissue, and/or altered neurological function, typically reduced neurological function as a result of a gradual and progressive loss of neural tissue. [00110] The term "vascular dementia" is also referred to as "multi-infarct dementia" in the art refers to a group of syndromes caused by different mechanisms all resulting in vascular lesions in the brain. The main subtypes of vascular dementia are, for example vascular mild cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct (affecting the thalamus, the anterior cerebral artery, the parietal lobes or the cingulate gyrus), vascular dementia due to hemorrhagic lesions, small vessel disease (including, e.g., vascular dementia due to lacunar lesions and Binswanger disease), and mixed Alzheimer's Disease with vascular dementia. [00111] The term "disease", "disorder", or “condition” is used interchangeably herein, and refers to any alteration in state of the body or of some of the organs, interrupting or disturbing the performance of the functions and/or causing symptoms such as discomfort, dysfunction, distress, or even death to the person afflicted or those in contact with a person. A disease or disorder can also relate to a distemper, ailing, ailment, malady, disorder, sickness, illness, complaint, or affectation. [00112] The terms "blood-brain barrier" or "BBB" are used interchangeably herein, and are used to refer to the permeability barrier that exists in blood vessels as they travel through the brain tissue that severely restricts and closely regulates what is exchanged between the blood and the brain tissue. The blood brain barrier components include the endothelial cells that form the innermost lining of all blood vessels, the tight junctions between adjacent endothelial cells that are the structural correlate of the BBB, the basement membrane of endothelial cells and the expanded foot processes of nearby astrocytes which cover nearly all of the exposed outer surface of the blood vessel. The BBB prevents most substances in the blood from entering brain tissue, including most large molecules such as Ig, antibodies, complement, albumin and drugs and small molecules. [00113] The term "abnormal BBB" is used to refer to a dysfunctional BBB, for example, where the BBB does not allow transit of molecules that normally transit a functional BBB, for example nutrients and sugars such as glucose. An abnormal BBB can also refer to when the BBB is permeable to molecules that a normally functioning BBB would typically exclude, which is typically referred to "BBB permeability" herein. [00114] The terms "BBB permeability" or "permeable BBB" are commonly referred to by persons in the art as "leaky BBB". The terms are used interchangeably herein to refer to impaired BBB integrity and increased vascular permeability. For example, a permeable BBB allows transit of molecules through the BBB that an intact BBB would normally exclude from the brain tissue, for example, Ig molecules, complement proteins, serum albumin and numerous other proteins. An assay to determine the presence of a permeable BBB can be, for example, to assess the presence of extravascular Ig in the brain tissue which is normally be restricted to the lumen of blood vessels when the BBB is functioning normally (i.e., when the BBB is not permeable). Introduction [00115] Embodiments described herein relate to compositions and methods of treating diseases or disorders characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species within the nervous system of a subject in need thereof. We found that 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that catabolizes eicosanoids and other anti-inflammatory mediators, is enriched in blood brain barrier (BBB)-associated myeloid cells and becomes markedly elevated in human and mouse models of Alzheimer’s disease (AD), traumatic brain injury (TBI), and aging. Pathological increase in 15-PGDH correlates with pronounced oxidative stress, neuroinflammation, and neurodegeneration, alongside profound BBB structural degeneration characterized by astrocytic endfeet swelling and functional impairment. Pharmacologic inhibition or genetic reduction of 15-PGDH in AD and TBI models strikingly mitigates cognitive decline, oxidative damage, suppresses neuroinflammation, and restores BBB integrity. Most notably, inhibiting 15-PGDH not only blocks damage to the brain by blocking microglial generation of reactive oxygen in 15-PGDH positive microglial cells and halts neurodegeneration but also preserves cognitive function at levels indistinguishable from healthy controls. Generation of reactive oxygen species by microglial cells can also be blocked with multiple substrates that 15-PGDH enzymatically degrades and limits, including PGE2, PGF2a, 15-HETE, RvD1, and LXA4 (respectively prostaglandin E2, prostaglandin F2 alpha, 15-HETE, resolving D1, and lipoxin A4). Remarkably, these neuroprotective effects in AD are achieved without affecting amyloid pathology, underscoring a non-canonical mechanism for treating AD. Thus, our findings position 15-PGDH inhibition as a novel and broad-spectrum strategy to treat oxidative stress, neuroinflammation, and neurodegeneration, alongside profound BBB structural degeneration, associated with pathological increases in 15-PGDH. Methods of treating diseases or disorders characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species [00116] In some embodiments, the cognitive decline, neuroinflammation, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, diseases and/or disorders characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species within the nervous system can also be associated with enhanced or aberrant 15-PGDH activity in a subject in need thereof. [00117] In some embodiments, a method of treating diseases or disorders characterized by structural deterioration of the blood-brain barrier, including cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, can include administering to the subject an amount of a 15-PGDH inhibitor and/or 15-PGDH substrate effective to prevent the onset of deterioration and/or the progression of further deterioration of the blood-brain barrier and/or prevent the neurodegeneration associated with blood-brain barrier deterioration and/or prevent the impaired neuronal function associated with blood-brain barrier deterioration and/or restore the integrity and/or structure and/or function of the blood-brain barrier. [00118] In other embodiments, a method of treating diseases or disorders characterized by increased generation of reactive oxygen species within the nervous system or central nervous system of a subject in need thereof, including cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, can include administering to the subject an amount of a 15-PGDH inhibitor and/or 15-PGDH substrate effective to prevent and/or decrease reactive oxygen species generation and/or neurodegeneration and/or impaired neuronal function associated with reactive oxygen species. [00119] In some embodiments, the subject has memory loss and/or cognitive decline and the 15-PGDH inhibitor and/or 15-PGDH substrate is administered at amount effective to improve memory and/or cognition. [00120] In some embodiments, the 15-PGDH inhibitor and/or 15-PGDH substrate is administered to the subject at amount effective to block aberrantly increased 15-PGDH enzymatic activity and prevent perivascular inflammation. [00121] Other embodiments described herein relate to a method of treating cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, diseases, and/or disorders characterized by increased generation of reactive oxygen species within the nervous system in a subject in need thereof. [00122] In some embodiments, the 15-PGDH inhibitor and/or 15-PGDH substrate can be administered to the subject at an amount effective to decrease at least one biomarker of reactive oxygen species generation, such as 4-hydroxy-2-nonenal (4-HNE) and/or 3- nitrotyrosine (3-NT) levels, by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or more. [00123] In some embodiments, the method includes measuring at least one biomarker of reactive oxygen species generation in the brain of the subject and administering to the subject an amount of a 15-PGDH inhibitor and/or 15-PGDH substrate effective to decrease reactive oxygen species generation in the brain of the subject. Methods of measuring reactive oxygen species generation in the brain can include, for example, measuring 4-hydroxy-2-nonenal (4- HNE) and/or 3-nitrotyrosine (3-NT) levels as described in Domenico et al., Free Radic. Biol. Med.111, 253–261 (2017); Shin et al., Biomedicines 8, 326 (2020); and Sultana, et al., Neurobiol. Dis.22, 76–87 (2006). [00124] In some embodiments, the method includes measuring at least one biomarker of reactive oxygen species generation, such as 4-hydroxy-2-nonenal (4-HNE) and/or 3- nitrotyrosine (3-NT) levels, in blood of the subject following administration of the 15-PGDH inhibitor and comparing the measured biomarker of reactive oxygen species generation to a control, wherein a decrease in 4-hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels is indicative of efficacy of the 15-PGDH inhibitor and/or PGDH substrate in treating neurodegeneration and/or impaired neuronal function in the subject. The control can be, for example, the 4-hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels of the subject prior to administration of the 15-PGDH inhibitor and/or 15-PGDH substrate. [00125] In some embodiments, the cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, diseases and/or disorders are associated with an increase in reactive oxygen species in neurotissue, such as brain tissue, of at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% relative to normal or healthy neurotissue. In certain embodiments, administration of a 15-PGDH inhibitor and/or 15- PGDH substrate can be used to decrease reactive oxygen species in neurotissue of the subject from about 5% to about 200%, about 5% to about 180%, about 5% to about 160%, about 5% to about 140%, about 5% to about 120%, about 5% to about 100%, about 5% to about 80%, about 5% to about 60%, about 5% to about 40%, about 10% to about 200%, about 10% to about 180%, about 10% to about 160%, about 10% to about 140%, about 10% to about 120%, about 10% to about 100%, about 10% to about 80%, about 10% to about 60%, about 30% to about 200%, about 30% to about 180%, about 30% to about 160%, about 30% to about 140%, about 30% to about 120%, about 30% to about 100%, about 30% to about 80%, about 40% to about 200%, about 40% to about 180%, about 40% to about 160%, about 40% to about 140%, about 40% to about 120%, about 40% to about 100%, about 50% to about 200%, about 50% to about 180%, about 50% to about 160%, about 50% to about 140%, about 50% to about 120%, about 60% to about 200%, about 60% to about 180%, about 60% to about 160%, about 60% to about 140%, about 70% to about 200%, about 70% to about 180%, about 70% to about 160%, about 80% to about 200%, about 80% to about 180%, or about 80% to about 200%. [00126] Still other embodiments described herein relate to a method of treating cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, diseases, and/or disorders characterized by structural deterioration of the blood- brain barrier in a subject in need thereof. [00127] In some embodiments, the 15-PGDH inhibitor and/or 15-PGDH substrate can be administered to the subject at an amount effective to decrease BBB permeability by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or more. [00128] In some embodiments, the method includes measuring BBB permeability of the subject and administering to the subject an amount of a 15-PGDH inhibitor and/or 15-PGDH substrate effective to decrease the measured BBB permeability of the subject. Methods of measuring BBB permeability can include, for example, tracer-based techniques using dyes, fluorescent tracers, or radiolabeled tracers, magnetic resonance imaging (MRI) techniques using dynamic contrast-enhanced MRI imaging and chelated metal contrast agents, PET/SPECT imaging using radiolabeled small molecules, and/or measurement of albumin CSF/serum ratio. [00129] In some embodiments, the method includes measuring BBB permeability of the subject following administration of the 15-PGDH inhibitor and/or 15-PGDH substrate and comparing the measured BBB permeability a control, wherein a decrease in BBB permeability is indicative of efficacy of the 15-PGDH inhibitor and/or PGDH substrate in treating neurodegeneration and/or impaired neuronal function in the subject. The control can be, for example, the BBB permeability of the subject prior to administration of the 15-PGDH inhibitor and/or 15-PGDH substrate. [00130] In some embodiments, the cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, diseases and/or disorders are associated with an increase in BBB permeability of at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% relative to normal or healthy BBB. In certain embodiments, administration of a 15-PGDH inhibitor and/or 15-PGDH substrate can be used to decrease BBB permeability of the subject from about 5% to about 200%, about 5% to about 180%, about 5% to about 160%, about 5% to about 140%, about 5% to about 120%, about 5% to about 100%, about 5% to about 80%, about 5% to about 60%, about 5% to about 40%, about 10% to about 200%, about 10% to about 180%, about 10% to about 160%, about 10% to about 140%, about 10% to about 120%, about 10% to about 100%, about 10% to about 80%, about 10% to about 60%, about 30% to about 200%, about 30% to about 180%, about 30% to about 160%, about 30% to about 140%, about 30% to about 120%, about 30% to about 100%, about 30% to about 80%, about 40% to about 200%, about 40% to about 180%, about 40% to about 160%, about 40% to about 140%, about 40% to about 120%, about 40% to about 100%, about 50% to about 200%, about 50% to about 180%, about 50% to about 160%, about 50% to about 140%, about 50% to about 120%, about 60% to about 200%, about 60% to about 180%, about 60% to about 160%, about 60% to about 140%, about 70% to about 200%, about 70% to about 180%, about 70% to about 160%, about 80% to about 200%, about 80% to about 180%, or about 80% to about 200%. [00131] In some embodiments, the diseases or disorders characterized by structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species include brain injuries. Brain injuries that can be treated include any brain injury that is mediated by structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species. These injuries include but are not limited to traumatic brain injury (TBI), stroke (ischemic and hemorrhagic), spinal cord injury (SCI), brain hemorrhage (for example intracerebral hemorrhage and subarachnoid hemorrhage), chronic traumatic encephalopathy (CTE), Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), multiple sclerosis (MS), amyloid lateral sclerosis (ALS), prodromal chronic traumatic encephalopathy (CTE), and prodromal Alzheimer’s disease (AD). [00132] TBI occurs due to physical trauma to the brain, including closed head injury and penetrating head injury. Typically, TBI occurs due to a fall, vehicle collision, work injury, sports injury, violence, and the like. TBI can result in various physical, cognitive and behavioral symptoms, depending on the area of the brain affected and its severity, symptoms which may be permanent. It is a major cause of death and disability. Current treatment focusses on minimizing the damage caused, and prevention. [00133] CTE, also referred to as traumatic encephalopathy syndrome or dementia pugilisitca, is a neurodegenerative condition caused by repeated head injuries, and tends to get worse over time, resulting in dementia. The cause frequently is repeated injury in contact sports, the military, domestic violence, or repeated banging of the head. Firm diagnosis often is made only at autopsy, and no treatment is available and focusses on maintenance and support only. [00134] Neurodegenerative diseases are those which involve progressive loss of neurons or their function, including death of neurons, and which result in a progressive loss of brain function. Neurodegenerative diseases associated with a tauopathy (a pathological aggregation of Tau protein in neurofibrillary or gliofibrillary tangles in the brain) include Alzheimer's disease, FTD, and the like. CTE also sometimes also is classified as this type of neurodegenerative disease. [00135] In some embodiments, the cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, diseases, and/or disorders characterized by structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species can include at least one of subarachnoid hemorrhage, schizophrenia, depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury and/or a visual symptom associated therewith, post-traumatic stress disorder, Parkinson’s disease, Parkinson Plus syndromes, Lewy Body Dementia, multiple system atrophy, corticobasal neurodegeneration, progressive supranuclear palsy, Alexander’s disease, Alzheimer’s disease, Alzheimer's disease related dementias, prodromal Alzheimer’s disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington’s disease, stroke, brain radiation therapy, chronic stress, abuse or cellular toxicity of a neuro-active drug, retinal degeneration, spinal cord injury, peripheral nerve injury, idiopathic peripheral neuropathy, cognitive decline and/or general frailty associated with normal aging and/or chemotherapy, chemotherapy induced neuropathy, concussive injury, peripheral nerve crush injury, peripheral neuropathy, diabetic neuropathy, post-traumatic headache, multiple sclerosis, retinal degeneration and dystrophy, Leber congenital amaurosis, retinitis pigmentosa, cone-rod dystrophy, microphthalmia, anophthalmia, myopia, and hyperopia, spinal cord injury, traumatic spinal cord injury, peripheral nerve injury, retinal neuronal death related diseases, retinal trauma, Autism, Stargardt disease, Kearns-Sayre syndrome, Pure neurosensory deafness, Hereditary hearing loss with retinal diseases, Hereditary hearing loss with system atrophies of the nervous system, Progressive spinal muscular atrophy, Progressive bulbar palsy, Primary lateral sclerosis, Hereditary forms of progressive muscular atrophy and spastic paraplegia, Frontotemporal dementia, Dementia with Lewy bodies, Corticobasal degeneration, Progressive supranuclear palsy, Prion disorders causing neurodegeneration, Multiple system atrophy, Hereditary spastic paraparesis, Friedreich ataxia, Non-Friedreich ataxia, Spinocerebellar atrophies, Amyloidoses, Metabolic-related neurodegenerative disorders, Toxin-related neurodegenerative disorders, Multiple sclerosis, Charcot Marie Tooth, Diabetic neuropathy, Metabolic neuropathies, Endocrine neuropathies, Creutzfeldt-Jacob Disease, Primary progressive aphasia, Frontotemporal Lobar Degeneration, Cortical blindness, Shy-Drager Syndrome, Diffuse cerebral cortical atrophy of non- Alzheimer type, Lewy-body dementia, Pick disease, Thalamic degeneration, Mesolimbocortical dementia of non-Alzheimer type, Nonhuntingtonian types of chorea and dementia, Cortical-striatal-spinal degeneration, Dementia-Parkinson-amyotrophic lateral sclerosis complex, Cerebrocerebellar degeneration, Cortico-basal ganglionic degeneration, Familial dementia with spastic paraparesis or myoclonus, Tourette syndrome, or viral infection. [00136] In some embodiments, the cognitive decline, neural injuries, neurodegeneration, and/or neurodegenerative and/or neuropsychiatric conditions, diseases and/or disorders characterized by structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species is also associated with an aberrant level (e.g., decrease or increase in the level) of at least one eicosanoid selected from PGE2, 15-keto-PGE2, PGF2α, 6-keto-PGF1α, PGD2, PGJ2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5- HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, 14,15-DHET, or 11,12-DHET in neurotissue of the subject. For example, the neurodegenerative condition, disease, or disorder can be characterized by structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species and an increase or decrease in the level of at least one eicosanoid selected from PGE2, 15-keto-PGE2, PGF2α, 6-keto-PGF1α, PGD2, PGJ2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10- DiHOME, 14,15-DHET, or 11,12-DHET of at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, or more in neurotissue of the subject relative to a normal or healthy subject. [00137] In some embodiments, the 15-PGDH inhibitor and/or 15-PGDH substrate can be administered to the subject to decrease structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species and modulate the level of the aberrant eicosanoid to a normal or healthy level in the neurotissue. For example, the neurodegeneration and/or neurodegenerative condition, disease, or disorder can be associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species and an increase in the level of at least one of 15-keto-PGE2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, or 14,15-DHET in neurotissue (e.g., brain tissue) of the subject, and the 15-PGDH inhibitor and/or 15-PGDH substrate can be administered to the subject at amount effective to decrease structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species and the levels of the at least one of 15-keto-PGE2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, or 14,15-DHET in neurotissue of the subject. In another example, the neurodegeneration and/or neurodegenerative condition, disease, or disorder can be associated with an increase in structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species and a decrease in the levels of at least one of PGJ2, TNE, 15-HETE, or 9,10- DiHOME in neurotissue (e.g., brain tissue) of the subject, and the 15-PGDH inhibitor and/or 15-PGDH substrate can be administered to the subject at amount effective to decrease structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species and increase the levels of the at least one of PGJ2, TNE, 15-HETE, or 9,10-DiHOME in neurotissue (e.g., brain tissue) of the subject. [00138] Other embodiments described herein relate to a method of treating and/or inhibiting memory loss and/or cognitive decline associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species in a subject in need thereof by administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor and/or 15-PGDH substrate. In some embodiments, the memory loss and/or cognitive decline associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species in a subject in need thereof can be caused by and/or associated with neural injuries, neurodegeneration, neurodegenerative and/or neuropsychiatric conditions, diseases, and/or disorders. The therapeutically effective amount of the administered 15-PGDH and/or 15-PGDH substrate can be an amount effective to decrease structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species and ameliorate memory loss and/or cognitive decline and/or improve memory and/or cognition. [00139] In some embodiments, neurodegenerative condition, disease, or disorder can include at least one of Alzheimer's disease, prodromal Alzheimer’s disease, Lewy body dementia, prodromal Lewy body dementia, Vascular dementia, prodromal Vascular dementia, Age-related dementia, Frontotemporal dementia, prodromal Frontotemporal dementia, mixed dementia, prodromal mixed dementia, or traumatic brain injury. [00140] In still other embodiments, the memory loss and/or cognitive decline associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system is also associated with an aberrant level (e.g., decrease or increase in the level) of at least one eicosanoid selected from PGE2, 15-keto-PGE2, PGF2α, 6-keto-PGF1α, PGD2, PGJ2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, 14,15-DHET, or 11,12-DHET in brain tissue of the subject. The 15-PGDH inhibitor can be administered to the subject to lower GFAP levels and modulate the level of the aberrant eicosanoid to a normal or healthy level in the brain tissue. For example, the memory loss and/or cognitive decline can be associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system and an increase in the level of at least one of 15-keto-PGE2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, or 14,15-DHET in brain tissue of the subject, and the 15-PGDH inhibitor can be administered to the subject at amount effective to decrease the structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species within the nervous system and the level of the at least one of 15-keto-PGE2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, or 14,15-DHET in brain tissue of the subject. In another example, the memory loss and/or cognitive decline can be associated with an increase structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system and a decrease in the level of at least one of PGJ2, TNE, 15-HETE, or 9,10-DiHOME in brain tissue of the subject, and the 15-PGDH inhibitor can be administered to the subject at amount effective to decrease the structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species within the nervous system and increase the levels of the at least one of PGJ2, TNE, 15-HETE, or 9,10-DiHOME in e.g., brain tissue of the subject. Small Molecule 15-PGHD inhibitors [00141] In some embodiments, small molecule 15-PGDH inhibitors used to decrease structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species within the nervous system can be identified using assays in which putative inhibitor compounds are applied to cells expressing 15-PGDH and then the functional effects on 15- PGDH activity are determined. Samples or assays comprising 15-PGDH that are treated with a potential inhibitor are compared to control samples without the inhibitor to examine the extent of effect. Control samples (untreated with modulators) are assigned a relative 15- PGDH activity value of 100%. Inhibition of 15-PGDH is achieved when the 15-PGDH activity value relative to the control is about 80%, optionally 50% or 25%, 10%, 5% or 1%. [00142] Small molecules tested as 15-PGDH inhibitors can be any small chemical molecule or compound. The assays are designed to screen large chemical libraries by automating the assay steps and providing compounds from any convenient source to assays, which are typically run in parallel (e.g., in microtiter formats on microtiter plates in robotic assays). [00143] In some embodiments, the 15-PGDH inhibitor can include a compound having the following formula (I): pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein n is 0-2; Y1, Y2, and R1 are the same or different and are independently hydrogen or a substituted or unsubstituted group selected from C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, -Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, and phosphate esters, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof, and wherein Y1 and Y2 may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl; U1 is N, C-R2, or C-NR3R4, wherein R2 is selected from the group consisting of a H, a lower alkyl group, O, (CH2)n1OR’ (wherein n1=1, 2, or 3), CF3, CH2-CH2X, O-CH2- CH2X, CH2-CH2-CH2X, O-CH2-CH2X, X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, O(CO)R’, COOR’ (wherein R’ is H or a lower alkyl group), and wherein R1 and R2 may be linked to form a cyclic or polycyclic ring, wherein R3 and R4 are same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH2)n1OR’ (wherein n1=1, 2, or 3), CF3, CH2-CH2X, CH2-CH2-CH2X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, COOR’ (wherein R’ is H or a lower alkyl group), and R3 or R4 may be absent; X1 and X2 are independently N or C, and wherein when X1 and/or X2 are N, Y1 and/or Y2, respectively, are absent; and Z1 is O, S, CRaRb or NRa, wherein Ra and Rb are independently H or a C1-8 alkyl, which is linear, branched, or cyclic, and which is unsubstituted or substituted. [00144] In other embodiments, the 15-PGDH inhibitor can include a compound having the following formula (II): pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein n is 0-2 X4, X5, X6, and X7 are independently N or CRc; R1, R6, R7, and Rc are the same or different and independently hydrogen or a substituted or unsubstituted group selected from C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, -Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C2-C24 alkylamido substituted with a hydroxyl, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5- C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, and phosphate esters, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof, and wherein R6 and R7 may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl; U1 is N, C-R2, or C-NR3R4, wherein R2 is selected from the group consisting of a H, a lower alkyl group, O, (CH2)n1OR’ (wherein n1=1, 2, or 3), CF3, CH2-CH2X, O-CH2- CH2X, CH2-CH2-CH2X, O-CH2-CH2X, X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, O(CO)R’, COOR’ (wherein R’ is H or a lower alkyl group), and wherein R1 and R2 may be linked to form a cyclic or polycyclic ring, wherein R3 and R4 are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH2)n1OR’ (wherein n1=1, 2, or 3), CF3, CH2-CH2X, CH2-CH2-CH2X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, COOR’ (wherein R’ is H or a lower alkyl group), and R3 or R4 may be absent; and Z1 is O, S, CRaRb or NRa, wherein Ra and Rb are independently H or a C1-8 alkyl, which is linear, branched, or cyclic, and which is unsubstituted or substituted. [00145] In yet other embodiments, the 15-PGDH inhibitor can include a compound having the following formula (III) or (IV): (IV) or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein n is 0-2 X6 is independently N or CRc; R1, R6, R7, and Rc are the same or different and independently hydrogen or a substituted or unsubstituted group selected from C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, -Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C2-C24 alkylamido substituted with a hydroxyl, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5- C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, and phosphate esters, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof, and wherein R6 and R7 may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl; U1 is N, C-R2, or C-NR3R4, wherein R2 is selected from the group consisting of a H, a lower alkyl group, O, (CH2)n1OR’ (wherein n1=1, 2, or 3), CF3, CH2-CH2X, O-CH2- CH2X, CH2-CH2-CH2X, O-CH2-CH2X, X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, O(CO)R’, COOR’ (wherein R’ is H or a lower alkyl group), and wherein R1 and R2 may be linked to form a cyclic or polycyclic ring, wherein R3 and R4 are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH2)n1OR’ (wherein n1=1, 2, or 3), CF3, CH2-CH2X, CH2-CH2-CH2X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, COOR’ (wherein R’ is H or a lower alkyl group), and R3 or R4 may be absent; Z1 is O, S, CRaRb or NRa, wherein Ra and Rb are independently H or a C1-8 alkyl, which is linear, branched, or cyclic, and which is unsubstituted or substituted. [00146] In some embodiments, R1 is selected from the group consisting of branched, linear, or cyclic alkyl, wherein n2=0-6 and X is any of the following: CFyHz (y + z = [00147] In other embodiments, R6 and R7 can each independently be one of the following:
R73 , and R74 are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C1-C6 alkyl), NC(O)(C1-C6 alkyl), O, and S), heteroaryl or heterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C1-C3 alkyl), O, and S), C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl (including C2-C24 alkylcarbonyl (--CO-alkyl) and C6-C20 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C20 aryloxycarbonyl (-(CO)-O-aryl), C2-C24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C20 arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO-), carbamoyl (-(CO)--NH2), C1-C24 alkyl-carbamoyl (-(CO)-NH(C1-C24 alkyl)), arylcarbamoyl (-(CO)-NH- aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano(-CN), isocyano (-N+C- ), cyanato (-O-CN), isocyanato (-O-N+=C-), isothiocyanato (-S-CN), azido (-N=N+=N-), formyl (--(CO)--H), thioformyl (--(CS)--H), amino (--NH2), C1-C24 alkyl amino, C1-C24 alkyl amino substituted with hydroxyl, C5-C20 aryl amino, C2-C24 alkylamido (-NH-(CO)-alkyl), C6-C20 arylamido (-NH-(CO)-aryl), sulfanamido (-SO2N(R)2 where R is independently H, alkyl, aryl or heteroaryl), imino (-CR=NH where R is hydrogen, C1-C24 alkyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, etc.), alkylimino (-CR=N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR=N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO2), nitroso (-NO), sulfo (-SO2-OH), sulfonato (-SO2-O-), C1-C24 alkylsulfanyl (-S-alkyl; also termed "alkylthio"), arylsulfanyl (-S-aryl; also termed "arylthio"), C1-C24 alkylsulfinyl (-(SO)-alkyl), C5-C20 arylsulfinyl (-(SO)-aryl), C1-C24 alkylsulfonyl (-SO2- alkyl), C5-C20 arylsulfonyl (-SO2-aryl), sulfonamide (-SO2-NH2, -SO2NY2 (wherein Y is independently H, aryl or alkyl), phosphono (-P(O)(OH)2), phosphonato (-P(O)(O-)2), phosphinato (-P(O)(O-)), phospho (-PO2), phosphino (--PH2), polyalkyl ethers (-[(CH2)nO]m), phosphates, phosphate esters [-OP(O)(OR)2 where R = H, methyl or other alkyl], groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [00148] In still other embodiments, R6 and R7 can independently be a group that improves aqueous solubility, for example, a phosphate ester (-OPO3H2), a phenyl ring linked to a phosphate ester (-OPO3H2), a phenyl ring substituted with one or more methoxyethoxy groups, or a morpholine, or an aryl or heteroaryl ring substituted with such a group. [00149] In other embodiments, the 15-PGDH inhibitor can include a compound having the following formula (V): pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein n is 0-2 X6 is independently is N or CRc R1, R6, R7, and Rc are the same or different each independently hydrogen or a substituted or unsubstituted group selected from C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, -Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C2-C24 alkylamido substituted with a hydroxyl, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5- C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, and phosphate esters, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof, and wherein R6 and R7 may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl; and U1 is N, C-R2, or C-NR3R4, wherein R2 is selected from the group consisting of a H, a lower alkyl group, O, (CH2)n1OR’ (wherein n1=1, 2, or 3), CF3, CH2-CH2X, O-CH2- CH2X, CH2-CH2-CH2X, O-CH2-CH2X, X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, O(CO)R’, COOR’ (wherein R’ is H or a lower alkyl group), and wherein R1 and R2 may be linked to form a cyclic or polycyclic ring, wherein R3 and R4 are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH2)n1OR’ (wherein n1=1, 2, or 3), CF3, CH2-CH2X, CH2-CH2-CH2X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, COOR’ (wherein R’ is H or a lower alkyl group), and R3 or R4 may be absent. [00150] In some embodiments, R1 is selected from the group consisting of branched, linear, or cyclic alkyl, wherein n2=0-6 and X is any of the following: CFyHz (y + z = [00151] In other embodiments, R6 and R7 can each independently be one of the following: each R8 R9 R10 R11 R12 R13 R14 R15 16 17 18 19 20 21 22 23 24 25 26 27 28 , , , , , , , , R , R , R , R , R , R , R , R , R , R , R , R , R , R29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R51 R52 R53 R54 R55 R56 R57 R58 R59 R60 R61 R62 R63 64 65 66 67 68 69 70 71 72 , , , , , , , , , , , , , R , R , R , R , R , R , R , R , R , R73, and R74, are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C1-C6 alkyl), NC(O)(C1-C6 alkyl), O, and S), heteroaryl or heterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C1-C3 alkyl), O, and S), C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl (including C2-C24 alkylcarbonyl (--CO-alkyl) and C6-C20 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C20 aryloxycarbonyl (-(CO)-O-aryl), C2-C24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C20 arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO-), carbamoyl (-(CO)--NH2), C1-C24 alkyl-carbamoyl (-(CO)-NH(C1-C24 alkyl)), arylcarbamoyl (-(CO)-NH- aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano(-CN), isocyano (-N+C- ), cyanato (-O-CN), isocyanato (-O-N+=C-), isothiocyanato (-S-CN), azido (-N=N+=N-), formyl (--(CO)--H), thioformyl (--(CS)--H), amino (--NH2), C1-C24 alkyl amino, C1-C24 alkyl amino substituted with hydroxyl, C5-C20 aryl amino, C2-C24 alkylamido (-NH-(CO)-alkyl), C6-C20 arylamido (-NH-(CO)-aryl), sulfanamido (-SO2N(R)2 where R is independently H, alkyl, aryl or heteroaryl), imino (-CR=NH where R is hydrogen, C1-C24 alkyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, etc.), alkylimino (-CR=N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR=N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO2), nitroso (-NO), sulfo (-SO2-OH), sulfonato (-SO2-O-), C1-C24 alkylsulfanyl (-S-alkyl; also termed "alkylthio"), arylsulfanyl (-S-aryl; also termed "arylthio"), C1-C24 alkylsulfinyl (-(SO)-alkyl), C5-C20 arylsulfinyl (-(SO)-aryl), C1-C24 alkylsulfonyl (-SO2- alkyl), C5-C20 arylsulfonyl (-SO2-aryl), sulfonamide (-SO2-NH2, -SO2NY2 (wherein Y is independently H, aryl or alkyl), phosphono (-P(O)(OH)2), phosphonato (-P(O)(O-)2), phosphinato (-P(O)(O-)), phospho (-PO2), phosphino (--PH2), polyalkyl ethers (-[(CH2)nO]m), phosphates, phosphate esters [-OP(O)(OR)2 where R = H, methyl or other alkyl], groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof, or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [00152] In still other embodiments, R6 and R7 can independently be a group that improves aqueous solubility, for example, a phosphate ester (-OPO3H2), a phenyl ring linked to a phosphate ester (-OPO3H2), a phenyl ring substituted with one or more methoxyethoxy groups, or a morpholine, or an aryl or heteroaryl ring substituted with such a group. [00153] In other embodiments, the 15-PGDH inhibitor can include a compound having a structure of formula (IA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; R2 is –NH2, CN, or -NHC(O)alkyl; R6 is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R3; R7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR5-alkyl, each of which is optionally substituted with one or more R4; R3 is oxo, -OH, -O-alkylene-OH, -O-alkylene-N(R5)2, -N(R5)2, -N(R5)(alkylene-OH), -N(R5)(alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R5)2, -C(O)N(R5)(alkylene-OH), -C(O)-alkyl, - C(O)O-alkyl, or -S(O)m-alkyl, wherein the cycloalkyl and the heterocyclyl is each optionally substituted with R10; R4 is oxo, halogen, -CN, -N(R5)2, -OH, -O-alkylene-OH, -S(O)m-alkyl, -C(O)- alkyl, -C(O)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R8; each R5 is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene- O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)m-alkyl; or alternatively, two R5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8; R8 is halogen, alkyl, or alkoxy; R9 is H or alkyl, or two R9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S(O)t, or N; R10 is –OH, halogen, alkyl, or alkoxy; X is N or CH; m is 0, 1, or 2; n is 0, 1, or 2; and t is 0, 1, or 2. [00154] In some embodiment, the 15-PGDH inhibitor can include a compound having a structure of formula (IIA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; R2 is –NH2, CN, or -NHC(O)alkyl; R6 is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R3; R7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR5-alkyl, each of which is optionally substituted with one or more R4; R3 is oxo, -OH, -O-alkylene-N(R5)2, -N(R5)2, -N(R5)(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R5)2, -C(O)N(R5)(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or -S(O)m-alkyl; R4 is oxo, halogen, -CN, -N(R5)2, -OH, -O-alkylene-OH, -S(O)m-alkyl, -C(O)- alkyl, -C(O)-cycloalkyl, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R8; each R5 is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene- O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)m-alkyl; or alternatively, two R5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8; R8 is halogen, alkyl, or alkoxy; R9 is H or alkyl, or two R9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S(O)t, or N; X is N or CH; m is 0, 1, or 2; n is 0, 1, or 2; and t is 0, 1, or 2. [00155] In some embodiments, R1 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, -(C1-C6 alkylene)-(3- to 6-membered cycloalkyl), -(C1-C6 alkylene)-(C1-C6 alkoxy), 3- to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl). [00156] In other embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2)p-cyclopropyl, -(CH2)p-cyclobutyl, -(CH2)p-cyclopentyl, or -(CH2)p-cyclohexyl; wherein p is 1, 2, or 3. [00157] In still other embodiments, R2 is –NH2. [00158] In some embodiments, R6 is 5- to 6-membered heterocyclyl or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more R3. [00159] In other embodiments, R6 is 5- to 6-membered heteroaryl optionally substituted with one or more R3. [00160] In still other embodiments, R6 is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more R3. [00161] In some embodiments, R7 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), or -C(O)NR5(C1-C6 alkyl), each of which is optionally substituted with one or more R4. [00162] In other embodiments, R7 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R4. [00163] In still other embodiments, R7 is C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 10-membered heteroaryl each of which is optionally substituted with one or more R4. [00164] In some embodiments, R3 is -O-(C1-C6 alkylene)-N(R5)2, -N(R5)2, -N(R5)(C1-C6 alkylene-OH), -C(O)N(R5)2, -C(O)N(R5)(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), - C(O)O(C1-C6 alkyl), or -S(O)m(C1-C6 alkyl). [00165] In other embodiments, R3 is -(C1-C3 alkyl)OH, -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH(C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl), or -OCH2CH2N(C1-C3 alkyl)2. [00166] In other embodiments, R3 is -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH(C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl), or -OCH2CH2N(C1-C3 alkyl)2. [00167] In still other embodiments, R3 is -NHCH2CH2OH or –N(CH3)CH2CH2OH. [00168] In some embodiments, R4 is halogen, -CN, -N(R5)2, -OH, -O-(C1-C6 alkylene)- OH, -S(O)m(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)-(3- to 6-membered cycloalkyl), C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl. [00169] In some embodiments, n is 1. [00170] In other embodiments, the compound has the structure of formula (IIIA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is 3- to 6-membered cycloalkyl, -(C1-C6 alkylene)-(3- to 6-membered cycloalkyl), 3-to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl); R2 is –NH2, CN, or -NHC(O)alkyl; R6 is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R3; R7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, - C(O)O-alkyl, or -C(O)NR5-alkyl, each of which is optionally substituted with one or more R4; R3 is oxo, –OH, -O-alkylene-N(R5)2, -N(R5)2, -N(R5)(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R5)2, -C(O)N(R5)(alkylene-OH), -C(O)-alkyl, - C(O)O-alkyl, or -S(O)m-alkyl, R4 is oxo, halogen, -CN, -N(R5)2, -OH, -O-alkylene-OH,-S(O)m-alkyl, -C(O)- alkyl, -C(O)-cycloalkyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R8; each R5 is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene- O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)m-alkyl; or alternatively, two R5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8; R8 is halogen, alkyl, or alkoxy; R9 is H or alkyl, or two R9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S(O)t, or N; X is N or CH; m is 0, 1, or 2; and t is 0, 1, or 2. [00171] In some embodiments, R1 is 3- to 5-membered cycloalkyl or -(C1-C6 alkylene)- (3- to 5-membered cycloalkyl). [00172] In other embodiments, R1 is cyclobutyl. [00173] In still other embodiments, R1 is a bicyclic 4- to 6-membered cycloalkyl. [00174] In some embodiments, R7 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), or -C(O)NR5(C1-C6 alkyl), each of which is optionally substituted with one or more R4. [00175] In other embodiments, R7 is C1-C4 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R4. In other embodiments, R7 is C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more R4. [00176] In other embodiments, R7 is C1-C3 alkyl, C1-C3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R4. In other embodiments, R7 is C1-C3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R4. [00177] In other embodiments, R7 is -CF3, isopropyl, cyclopropyl, phenyl, pyridyl, pyrazole, or triazole, each of which is optionally substituted with one or more R4. In other embodiments, R7 is -CF3, cyclopropyl, phenyl, pyridyl, pyrazole, or triazole, each of which is optionally substituted with one or more R4. [00178] In some embodiments, R3 is -O-(C1-C6 alkylene)-N(R5)2, -N(R5)2, -N(R5)(C1-C6 alkylene-OH), -C(O)N(R5)2, -C(O)N(R5)(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), or -S(O)m(C1-C6 alkyl). [00179] In other embodiments, R3 is -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH(C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl), or -OCH2CH2N(C1-C3 alkyl)2. [00180] In still other embodiments, R3 is -NHCH2CH2OH or –N(CH3)CH2CH2OH. [00181] In some embodiments and without being limited by theory, Applicants surprisingly and unexpectedly discovered that substituents at the R7 position could be modified to improve hERG activity, including hERG inhibition (IC50), blockade, and efflux ratio. For example, in some embodiments, certain 6- to 10-membered aryls (e.g., optionally substituted phenyl) and 5-to 10-membered heteroaryls (e.g., optionally substituted pyridyls, pyrazoles, and triazoles) were observed to have beneficial hERG properties. In some embodiments, certain C1-C6 haloalkyls (e.g., -CF3) exhibited improved hERG inhibition (IC50), while also improving half-life and solubility. [00182] In other embodiments, the compound has the structure of formula (IVA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; R2 is –NH2, CN, or -NHC(O)alkyl; R6 is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R3; R7 is C1-C6 haloalkyl, aryl or heteroaryl, each of which is optionally substituted with one or more R4; R3 is oxo, –OH, -O-alkylene-N(R5)2, -N(R5)2, -N(R5)(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R5)2, -C(O)N(R5)(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or -S(O)m-alkyl; each R5 is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene- O-alkylene-NH2, -C(O)-alkyl, -alkylene-COOH, -C(O)O-alkyl, or -S(O)m-alkyl; or alternative, two R5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8; R4 is halogen, alkyl, or alkoxy; X is N or CH; and m is 0, 1, or 2. [00183] In some embodiments, R7 is –CF3, pyridyl, pyrazole, phenyl, or triazole, each of which is optionally substituted with R4. [00184] In other embodiments, R7 is –CF3, pyridyl, fluorophenyl, or a triazole optionally substituted with halogen or methyl. [00186] In still other embodiments, R7 is –CF3. 7 [00187] In still other embodiments, R is . [00189] In some embodiments, R7 is [00190] In other embodiments, R6 is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more R3. [00191] In some embodiments and without being limited by theory, Applicants surprisingly and unexpectedly discovered that 3- to 6-membered cycloalkyls at the R7 position can improve solubility while maintaining PDGH activity. [00192] In other embodiments, the compound has the structure of formula (VA): (VA) or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclyl, or -alkylene-heterocyclyl; R2 is –NH2, CN, or -NHC(O)alkyl; R6 is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R3; R7 is 3- to 6-membered cycloalkyl, optionally substituted with one or more R4; R3 is oxo, –OH, -O-alkylene-N(R5)2, -N(R5)2, -N(R5)(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R5)2, -C(O)N(R5)(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or -S(O)m-alkyl; R4 is halogen, -CN, -NH2, -OH, or C1-C3 alkyl; each R5 is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene- O-alkylene-NH2, -C(O)-alkyl, -alkylene-COOH, -C(O)O-alkyl, or -S(O)m-alkyl; or alternative, two R5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8; R8 is halogen, alkyl, or alkoxy; X is N or CH; m is 0, 1, or 2. [00193] In some embodiments, R7 is cyclopropyl. [00194] In other embodiments, R1 is 3- to 6-membered cycloalkyl, -(C1-C6 alkylene)-(3- to 6-membered cycloalkyl), -(C1-C6 alkylene)-(C1-C6 alkoxy), 3- to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl). [00195] In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2)p-cyclopropyl, -(CH2)p-cyclobutyl, -(CH2)p-cyclopentyl, or -(CH2)p-cyclohexyl; wherein p is 1, 2, or 3. [00196] In some embodiments, R3 is -O-(C1-C6 alkylene)-N(R5)2, -N(R5)2, -N(R5)(C1-C6 alkylene-OH), -C(O)N(R5)2, -C(O)N(R5)(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), or -S(O)m(C1-C6 alkyl). [00197] In some embodiments, R3 is -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH(C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl), or -OCH2CH2N(C1-C3 alkyl)2. [00198] In other embodiments, R3 is -NHCH2CH2OH or –N(CH3)CH2CH2OH. [00199] In some embodiments and without being limited by theory, Applicants surprisingly and unexpectedly discovered that the R6 position can be substituted with certain R3 groups to improve solubility and activity. [00200] In other embodiments, the compound has the structure of formula (VIA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclyl, or -alkylene-heterocyclyl; R2 is –NH2, CN, or -NHC(O)alkyl; R6 is heterocyclyl or heteroaryl, each of which is substituted with one or more R3; R7 is haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, - C(O)O-alkyl, or -C(O)NR5-alkyl, each of which is optionally substituted with one or more R4; R3 is -O-(C1-C6 alkylene)-N(R5)2, -N(R5)2, -N(R5)(C1-C6 alkylene-OH), - C(O)N(R5)2, -C(O)N(R5)(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), or - S(O)m(C1-C6 alkyl); R4 is oxo, halogen, -CN, -N(R5)2, -OH, -O-alkylene-OH, -S(O)m-alkyl, -C(O)- alkyl, -C(O)-cycloalkyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R8; each R5 is independently H, C1-C6 alkyl, -(C1-C6 alkylene)-OH optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene- O-alkylene-NH2, -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), alkylene-COOH, or -S(O)m(C1- C6 alkyl); or alternative, two R5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8; R8 is halogen, alkyl, or alkoxy; X is N or CH; m is 0, 1, or 2. [00201] In some embodiments, R3 is -O-(C1-C6 alkylene)-N(R5)2, -N(R5)2 or -N(R5)(C1- C6 alkylene-OH). [00202] In other embodiments, R5 is H, C1-C6 alkyl, -(C1-C6 alkylene)-OH, or -S(O)2(C1- C3 alkyl). [00203] In some embodiments, R3 is -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH(C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl), or -OCH2CH2N(C1-C3 alkyl)2. [00204] In other embodiments, R3 is -NHCH2CH2OH or –N(CH3)CH2CH2OH. [00205] In still other embodiments, R3 is –NHCH2CH2OH. [00206] In some embodiments, R6 is 5- to 6-membered heterocyclyl or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more R3. [00207] In other embodiments, R6 is 5- to 6-membered heteroaryl optionally substituted with one or more R3. [00208] In some embodiments, R6 is furan, thiophene, pyrrole, thiazole, isothiazole, oxazole, isooxazole, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyridazine, or pyrazine, each optionally substituted with one or more R3. [00209] In other embodiments, R6 is thiazole, imidazole, oxazole, pyridine, or pyrimidine. [00210] In some embodiments, R6 is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more R3. [00211] In other embodiments, R6 is 5- to 6-membered heterocyclyl, optionally substituted with one or more R3, selected from morpholine, pyridine-one, or piperidine. [00212] In some embodiments, R7 is C1-C3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R4. [00213] In other embodiments, R7 is -CF3, cyclopropyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more R4. [00214] In some embodiments, the compound has the structure of formula (VIIA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl; R2 is –NH2, CN, or -NHC(O)alkyl; R6 is fused bicyclic heterocyclyl or fused bicyclic heteroaryl, each of which is optionally substituted with one or more R3; R7 is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR5-alkyl, each of which is optionally substituted with one or more R4; R3 is oxo, -OH, -O-alkylene-N(R5)2, -N(R5)2, -N(R5)(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R5)2, -C(O)-alkyl, -C(O)O-alkyl, or -S(O)m-alkyl; R4 is oxo, halogen, -CN, -N(R5)2, -OH, -O-alkylene-OH, -S(O)m-alkyl, -C(O)- alkyl, -C(O)-cycloalkyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R8; each R5 is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, or -S(O)m-alkyl; or alternatively, two R5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8; R8 is halogen, alkyl, or alkoxy; X is N or CH; and m is 0, 1, or 2. [00215] In some embodiments, R6 is 8- to 10-membered fused bicyclic heteroaryl, each of which is optionally substituted with one or more R3. [00216] In some embodiments, R7 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), or -C(O)NR5(C1-C6 alkyl), each of which is optionally substituted with one or more R4. [00217] In other embodiments, R7 is C1-C4 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R4. In other embodiments, R7 is C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more R4. [00218] In still other embodiments, R7 is C1-C3 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R4. [00219] In other embodiments, R7 is C1-C3 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more R4. In other embodiments, R7 is C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more R4. [00220] In other embodiments, R7 is -CF3, isopropyl, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more R4. In other embodiments, R7 is -CF3, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more R4. [00221] In some embodiments, R1 is C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, -(C1-C6 alkylene)-(3- to 6-membered cycloalkyl), -(C1-C6 alkylene)-(C1-C6 alkoxy), 3- to 6-membered heterocyclyl, or -(C1-C6 alkylene)-(3- to 6-membered heterocyclyl). [00222] In other embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2)p-cyclopropyl, -(CH2)p-cyclobutyl, -(CH2)p-cyclopentyl, or -(CH2)p-cyclohexyl; wherein p is 1, 2, or 3. [00223] In some embodiments, R3 is -O-(C1-C6 alkylene)-N(R5)2, -N(R5)2, -N(R5)(C1-C6 alkylene-OH), -C(O)N(R5)2, -C(O)N(R5)(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), or -S(O)m(C1-C6 alkyl). [00224] In other embodiments, R3 is -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH(C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl), or -OCH2CH2N(C1-C3 alkyl)2. [00225] In some embodiments, R3 is -NHCH2CH2OH or –N(CH3)CH2CH2OH. [00226] In other embodiments, R4 is halogen, -CN, -N(R5)2, -OH, -O-(C1-C6 alkylene)- OH, -S(O)m(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)-(3- to 6-membered cycloalkyl), C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl. [00227] In some embodiments, the compound has the structure of formula (VIIIA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is cyclobutyl or -(C1-C4 alkylene)-(C1-C3 alkoxy); R2 is –NH2, CN, or -NHC(O)alkyl; R6 is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R3; R3 is oxo, -OH, -O-alkylene-OH, -O-alkylene-N(R5)2, -N(R5)2, - N(R5)(alkylene-OH), -N(R5)(alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R5)2, -C(O)N(R5)(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or - S(O)m-alkyl, wherein the cycloalkyl and the heterocyclyl is each optionally substituted with R10; R4 is C1-C3 alkyl; each R5 is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene- O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)m-alkyl; or alternatively, two R5 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8; R8 is halogen, alkyl, or alkoxy; R9 is H or alkyl, or two R9 together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S(O)t, or N; R10 is –OH, halogen, alkyl, or alkoxy; X is N or CH; m is 0, 1, or 2; p is 0 or 1; and t is 0, 1, or 2. [00228] In still other embodiments, R2 is –NH2. [00229] In some embodiments, R6 is 5- to 6-membered heterocyclyl or 5- to 10- membered heteroaryl, each of which is optionally substituted with one or more R3. [00230] In other embodiments, R6 is 5- to 6-membered heteroaryl optionally substituted with one or more R3. [00231] In still other embodiments, R6 is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more R3. [00232] In some embodiments, R3 is -O-(C1-C6 alkylene)-N(R5)2, -N(R5)2, -N(R5)(C1-C6 alkylene-OH), -C(O)N(R5)2, -C(O)N(R5)(C1-C6 alkylene-OH), -C(O)(C1-C6 alkyl), -C(O)O(C1-C6 alkyl), or -S(O)m(C1-C6 alkyl). [00233] In other embodiments, R3 is -(C1-C3 alkyl)OH, -NH2, -N(C1-C3 alkyl)2, -NHCH2CH2OH, -N(C1-C3 alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(C1-C3 alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3 alkyl)CH2CH2NH2, -NHCH2CH2NH(C1-C3 alkyl), -NHCH2CH2N(C1-C3 alkyl)2, -N(C1-C3 alkyl)CH2CH2NH(C1-C3 alkyl), -N(C1-C3 alkyl)CH2CH2N(C1-C3 alkyl)2, -NHSO2CH3, -N(C1-C3 alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(C1-C3 alkyl), or -OCH2CH2N(C1-C3 alkyl)2. [00234] In still other embodiments, R3 is -NHCH2CH2OH or –N(CH3)CH2CH2OH. [00235] In some embodiments, R4 is halogen, -CN, -N(R5)2, -OH, -O-(C1-C6 alkylene)- OH, -S(O)m(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -C(O)-(3- to 6-membered cycloalkyl), C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl. [00236] In some embodiments, n is 1. [00237] In some embodiments, the compound has the structure of formula (IXA): or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1 is cyclobutyl or -(C1-C4 alkylene)-(C1-C3 alkoxy); R2 is –NH2, CN, or -NHC(O)alkyl;
, each of which is optionally substituted with one or more R3; R7 is –CF3, isopropyl, cyclopropyl, cyclobutyl, , , or , each of which is optionally substituted with one or more R4; R3 is -NH2, -NH(C1-C3 alkyl), -NH(C1-C4 alkylene)-OH, or C1-C3 alkyl; R4 is C1-C3 alkyl; and X is N or CH. [00238] In some embodiments of Formula (IXA), R1 is cyclobutyl. In some embodiments of Formula (IXA), R1 -(C1-C4 alkylene)-(C1-C3 alkoxy). In some embodiments of Formula (IXA), the R1 -(C1-C4 alkylene)-(C1-C3 alkoxy) is -(C2-C3 alkylene)-(C1 alkoxy). [00239] In some embodiments of Formula (IXA), R2 is –NH2. . [00241] In some embodiments of Formula (IXA), R3 is -NH2. In some embodiments of Formula (IXA), R3 is -NH(C1-C3 alkyl). In some embodiments of Formula (IXA), R3 is - NH(C1-C4 alkylene)-OH (e.g., -NH(C2-C4 alkylene)-OH). In some embodiments of Formula (IXA), R3 is C1-C3 alkyl (e.g., methyl or ethyl). [00242] In some embodiments, of Formula (IXA), R7 is –CF3, isopropyl, cyclopropyl, or cyclobutyl. In some embodiments, of Formula (IXA), R7 is isopropyl. In some embodiments of Formula (VII), R7 is , , each of which is optionally substituted with one or more R4. In some embodiments, each R4 is independently selected from methyl or ethyl. [00243] In some embodiments of Formula (IXA), X is –CH. [00244] Examples of compounds having formulas (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), (VIIIA), and (IXA) are described in U.S. Patent Application Publication Nos.2015/0072998, 2017/0165241, 2017/0173028, 2018/0118756, WO2018/218251, and WO2020/106998, all of which are incorporated by reference in their entirety. [00245] For example, the 15-PGDH inhibitor can include a compound selected from the group consisting of: , , , ,
, , , ,
,
, ,
, , , ,
, ,
,
, , ,
, ,
or a pharmaceutically acceptable salt thereof, a tautomer thereof, and a solvate thereof. [00246] In other embodiments, the compound can include at least one of the formulas (IB) or (IIB), or a pharmaceutically acceptable salt thereof: (IIB) wherein X1 is N or CR4; X2 is S, S=O, S(=O)2, or C=O; X3 is CR8, the compound forming a polycyclic heteroaryl with 10 ring atoms, or absent, the compound forming a polycyclic heteroaryl with 9 ring atoms; X4 is N, NH, or CR7; X5 is N, C=O, or CR16, and X5 is N if X4 is CR7, or X3 is absent, X4 is NH if X5 is C=O, and X5 is CR16 if X4 is N and X3 is CR8; R1, R2, R3, R4, R9, R10, and R16 are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-7 ring atoms, (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C1-C6 alkyl), NC(O) (C1-C6 alkyl), O, and S), heteroaryl or heterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C1-C3 alkyl), O, and S), C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl (including C2-C24 alkylcarbonyl (--CO-alkyl) and C6-C20 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C20 aryloxycarbonyl (-(CO)-O-aryl), C2-C24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C20 arylcarbonato (-O-(CO)-O-aryl), carboxy (- COOH), carboxylato (-COO-), carbamoyl (-(CO)--NH2), C1-C24 alkyl-carbamoyl (-(CO)-NH(C1-C24 alkyl)), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano(-CN), isocyano (-N+C-), cyanato (-O-CN), isocyanato (- O-N+=C-), isothiocyanato (-S-CN), azido (-N=N+=N-), formyl (--(CO)--H), thioformyl (-- (CS)--H), amino (--NH2), C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido (-NH- (CO)-alkyl), C6-C20 arylamido (-NH-(CO)-aryl), sulfanamido (-SO2N(R)2 where R is independently H, alkyl, aryl or heteroaryl), imino (-CR=NH where R is hydrogen, C1-C24 alkyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, etc.), alkylimino (-CR=N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR=N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO2), nitroso (-NO), sulfo (-SO2-OH), sulfonato (-SO2-O-), C1-C24 alkylsulfanyl (-S-alkyl; also termed "alkylthio"), arylsulfanyl (-S-aryl; also termed "arylthio"), C1-C24 alkylsulfinyl (-(SO)-alkyl), C5-C20 arylsulfinyl (-(SO)-aryl), C1-C24 alkylsulfonyl (-SO2-alkyl), C5-C20 arylsulfonyl (-SO2-aryl), sulfonamide (-SO2-NH2, - SO2NY2 (wherein Y is independently H, aryl or alkyl), phosphono (-P(O)(OH)2), phosphonato (-P(O)(O-)2), phosphinato (-P(O)(O-)), phospho (-PO2), phosphino (--PH2), polyalkyl ethers (-[(CH2)nO]m), phosphates, phosphate esters [-OP(O)(OR)2 where R = H, methyl or other alkyl], groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof; R7 and R8 are same or different and are each independently selected from the group consisting of H, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl, and at least one of R7 or R8 is not H; and wherein the compound is not . [00247] In some embodiments, at least one of R2 or R3 is not H, and at least one of R9 or R10 is not H. [00248] In some embodiments, the 15-PGDH inhibitor can include a compound having at least one of the following formulas: (IBc); (IBd); or (IBe); or a pharmaceutically acceptable salt thereof; wherein X2 is S, S=O, S(=O)2, or C=O; X6 is Cl, Br, or F, and y + z = 3; R1, R2, R3, R5, R6, and R14 are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-7 ring atoms, (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C1-C6 alkyl), NC(O) (C1-C6 alkyl), O, and S), heteroaryl or heterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C1-C3 alkyl), O, and S), C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl (including C2-C24 alkylcarbonyl (--CO-alkyl) and C6-C20 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C20 aryloxycarbonyl (-(CO)-O-aryl), C2-C24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C20 arylcarbonato (-O-(CO)-O-aryl), carboxy (- COOH), carboxylato (-COO-), carbamoyl (-(CO)--NH2), C1-C24 alkyl-carbamoyl (-(CO)-NH(C1-C24 alkyl)), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano(-CN), isocyano (-N+C-), cyanato (-O-CN), isocyanato (-O-N+=C-), isothiocyanato (-S-CN), azido (-N=N+=N-), formyl (--(CO)--H), thioformyl (--(CS)--H), amino (--NH2), C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido (-NH-(CO)-alkyl), C6-C20 arylamido (-NH-(CO)-aryl), sulfanamido (- SO2N(R)2 where R is independently H, alkyl, aryl or heteroaryl), imino (-CR=NH where R is hydrogen, C1-C24 alkyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, etc.), alkylimino (-CR=N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (- CR=N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO2), nitroso (-NO), sulfo (-SO2-OH), sulfonato (-SO2-O-), C1-C24 alkylsulfanyl (-S-alkyl; also termed "alkylthio"), arylsulfanyl (-S-aryl; also termed "arylthio"), C1-C24 alkylsulfinyl (-(SO)-alkyl), C5-C20 arylsulfinyl (-(SO)-aryl), C1-C24 alkylsulfonyl (-SO2-alkyl), C5-C20 arylsulfonyl (-SO2-aryl), sulfonamide (-SO2-NH2, -SO2NY2 (wherein Y is independently H, aryl or alkyl), phosphono (-P(O)(OH)2), phosphonato (-P(O)(O-)2), phosphinato (-P(O)(O-)), phospho (-PO2), phosphino (--PH2), polyalkyl ethers (-[(CH2)nO]m), phosphates, phosphate esters [- OP(O)(OR)2 where R = H, methyl or other alkyl], groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof; wherein R5 and R6 may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl, n1 is 0-4, and each R14 is the same or different. [00249] In other embodiments, the 15-PGDH inhibitor can include a compound having at least one of the following formulas:
pharmaceutically acceptable salt thereof; wherein X7 is S, S=O, S(=O)2, or C=O; R7 and R8 are same or different and are each independently selected from the group consisting of H, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl, and at least one of R7 or R8 is not H; R9, R10, R11, R12, R13, and R15 are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-7 ring atoms, (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C1-C6 alkyl), NC(O) (C1-C6 alkyl), O, and S), heteroaryl or heterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C1-C3 alkyl), O, and S), C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl (including C2-C24 alkylcarbonyl (--CO-alkyl) and C6-C20 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C20 aryloxycarbonyl (-(CO)-O-aryl), C2-C24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C20 arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO-), carbamoyl (-(CO)--NH2), C1-C24 alkyl- carbamoyl (-(CO)-NH(C1-C24 alkyl)), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)- NH2), carbamido (-NH-(CO)-NH2), cyano(-CN), isocyano (-N+C-), cyanato (-O-CN), isocyanato (-O-N+=C-), isothiocyanato (-S-CN), azido (-N=N+=N-), formyl (--(CO)--H), thioformyl (--(CS)--H), amino (--NH2), C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido (-NH-(CO)-alkyl), C6-C20 arylamido (-NH-(CO)-aryl), sulfanamido (- SO2N(R)2 where R is independently H, alkyl, aryl or heteroaryl), imino (-CR=NH where R is hydrogen, C1-C24 alkyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, etc.), alkylimino (-CR=N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (- CR=N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO2), nitroso (-NO), sulfo (-SO2-OH), sulfonato (-SO2-O-), C1-C24 alkylsulfanyl (-S-alkyl; also termed "alkylthio"), arylsulfanyl (-S-aryl; also termed "arylthio"), C1-C24 alkylsulfinyl (-(SO)-alkyl), C5-C20 arylsulfinyl (-(SO)-aryl), C1-C24 alkylsulfonyl (-SO2-alkyl), C5-C20 arylsulfonyl (-SO2-aryl), sulfonamide (-SO2-NH2, -SO2NY2 (wherein Y is independently H, aryl or alkyl), phosphono (-P(O)(OH)2), phosphonato (-P(O)(O-)2), phosphinato (-P(O)(O-)), phospho (-PO2), phosphino (--PH2), polyalkyl ethers (-[(CH2)nO]m), phosphates, phosphate esters [- OP(O)(OR)2 where R = H, methyl or other alkyl], groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof; wherein R12 and R13 may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl, n2 is 0-4, and each R15 is the same or different. [00250] Examples of 15-PGDH inhibitors having formulas (IB), (IBa), (IBb), (IBc), (IBd), (IBe), (IIB), (IIBa), (IIBb), (IIBc), (IIBd), (IBe), or (IIBf) can include the following compounds:
, or a pharmaceutically acceptable salt thereof, a tautomer thereof, and a solvate thereof [00251] Still other examples of 15-PGDH inhibitors include compounds described in WO2022/032230A1, WO2021/236779A1, WO2020/106998A1, WO2018/218251A1, WO2018/145080A1, WO2016/168472A1, WO2015/065716A1, WO2013/158649A1, WO2024/233550A1, U.S. Patent Application Publication No.2024/0294519A1, U.S. Patent Application Publication No.2024/0374579A1, and U.S. Patent Application Publication No. 2024/0409557 all of which are herein incorporated by reference in its entirety. [00252] For example, the 15-PGDH inhibitor can be a 5,6-fused and 6,6-fused bicyclic alcohol or ether described in U.S. Patent Application Publication No.2024/0409557. A 5,6- fused and 6,6-fused bicyclic alcohol or ether can be a compound of Formula (A): or pharmaceutically acceptable salts thereof; m is 0 or 1; X is N or CH; Y is N or CR3; Z is N or CR5; b is N or CR4; R1a is H, deuterium, C1-6 alkyl, or C1-6 haloalkyl; wherein, when R1a is C1-6 alkyl or C1-6 haloalkyl, then R1a may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, -N(Rb)2, C1-3 alkyl, or C1-3 alkoxy; R1b is -H, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, -(C1-6 alkylene)-O-( C1-6 alkyl), C3-10 cycloalkyl, or heterocyclyl having 3 to 10 ring members; wherein, when R1b is C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, -(C1-6 alkylene)-O-( C1-6 alkyl), C3-10 cycloalkyl, or heterocyclyl having 3 to 10 ring members, then R1b may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, -N(Rb)2, C1-3 alkyl, or C1-3 alkoxy; wherein each of the C1-3 alkyl and C1-3 alkoxy may be unsubstituted or substituted with 1 to 6 F groups; or, alternatively, R1a and R1b together form a C3-10 cycloalkyl, C3-10 cycloalkenyl, or heterocyclyl having 3 to 10 ring members; wherein the R1a and R1b cycle may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, -N(Rb)2, C1-3 alkyl, C1-3 alkoxy, -CN, C1-6 heteroalkyl, C3-10 cycloalkyl, or heterocyclyl having 3 to 10 ring members; wherein each of the C1-3 alkyl and C1-3 alkoxy may be unsubstituted or substituted with 1 to 9 halogen groups or C1-3 alkoxy; R1c is -H, C1-6 alkyl, or C3-6 cycloalkyl; wherein, when R1c is C1-6 alkyl or C3-6 cycloalkyl, then R1c may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, -N(Rb)2, C1-3 alkyl, C1-3 alkoxy, or C1-6 heteroalkyl; R2 is C3-20 cycloalkyl, C3-20 cycloalkenyl, C6-18 aryl, heteroaryl having 5 to 20 ring members, or heterocyclyl having 3 to 20 ring members; wherein R2 may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, -N(Rb)2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylene-OH, C1-6 alkylene-O- C1-6 alkyl, or C1-6 heteroalkyl; R3 is -H, C1-6 alkyl, C1-6 haloalkyl C3-6 cycloalkyl, amino, C1-4 alkyl-amino, di- C1-4 alkyl-amino, C6-10 aryl, heteroaryl having 5 to 10 ring members, or heterocyclyl having 5 to 10 ring members; wherein, when R3 is C1-6 alkyl, C1-6haloalkyl, C3-6 cycloalkyl, C1-4 alkyl- amino, di- C1-4 alkyl-amino, C6-10 aryl, heteroaryl having 5 to 10 ring members, or heterocyclyl having 5 to 10 ring members, then R3 may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, -N(Rb)2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 alkylene-C1-3 alkoxy, C1-6 heteroalkyl, or two R3 substituents together form a C3-6 carbocyclyl or a heterocyclyl having 3 to 6 ring members; R4 is -H, C1-3 alkyl, C1-3 haloalkyl, -CN, halogen, or -N(Ra)2 where each instance of Ra, where present, independently is -H, C1-6 alkyl, or -C(O) C1-6 alkyl; or, alternatively, two Ra substituents together form a heterocyclyl having 3 to 6 ring members; wherein Ra may be unsubstituted or substituted with one or more substituents, each of which independently is -F, -Cl, -OH, C1-3 alkoxy; R5 is —H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, or C1-6 heteroalkyl; wherein, when R5 is C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, or C1-6 heteroalkyl, then R may be unsubstituted or substituted one or more substituents, each of which independently is halogen, -OH, C1-3 alkyl, or C1-3 alkoxy; where each instance of Rb, where present, independently is -H or C1-6 alkyl; or, alternatively, two Rb substituents together form a heterocyclyl having 3 to 6 ring members; and wherein, when Rb is C1-6 alkyl or, alternatively, two Rb substituents together form a heterocyclyl having 3 to 6 ring members, then Rb may be unsubstituted or substituted with one or more substituents, each of which independently is -F, -Cl, -OH, C1-3 alkoxy. [00253] In certain embodiments, the small molecule 15-PGDH inhibitor can be selected that can ia) at 2.5 µM concentration, stimulate a Vaco503 reporter cell line expressing a 15- PGDH luciferase fusion construct to a luciferase output level of greater than 70 (using a scale on which a value of 100 indicates a doubling of reporter output over baseline); iia) at 2.5 µM concentration stimulate a V9m reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 75; iiia) at 7.5 µM concentration stimulate a LS174T reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 70; and iva) at 7.5 µM concentration, does not activate a negative control V9m cell line expressing TK-renilla luciferase reporter to a level greater than 20; and va) inhibits the enzymatic activity of recombinant 15-PGDH protein at an IC50 of less than 1 µM. [00254] In other embodiments, the small molecule 15-PGDH inhibitor can ib) at 2.5 µM concentration, stimulate a Vaco503 reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output; iib) at 2.5 µM concentration stimulate a V9m reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output; iiib) at 7.5 µM concentration stimulate a LS174T reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output; ivb) at 7.5 µM concentration, does not activate a negative control V9m cell line expressing TK-renilla luciferase reporter to a luciferase level greater than 20% above background; and vb) inhibits the enzymatic activity of recombinant 15-PGDH protein at an IC50 of less than 1 µM. [00255] In other embodiments, the small molecule 15-PGDH inhibitor can inhibit the enzymatic activity of recombinant 15-PGDH at an IC50 of less than 1 µM, or preferably at an IC50 of less than 250 nM, or more preferably at an IC50 of less than 50 nM, or more preferably at an IC50 of less than 10 nM, or more preferably at an IC50 of less than 5 nM at a recombinant 15-PGDH concentration of about 5 nM to about 10 nM. [00256] It will be appreciated that other 15-PGDH inhibitors can be used in the methods described herein. These other 15-PGDH inhibitors can include known 15-PGDH inhibitors including, for example, tetrazole compounds of formulas (I) and (II), 2-alkylideneaminooxyacetamide compounds of formula (I), heterocyclic compounds of formulas (VI) and (VII), and pyrazole compounds of formula (III) described in U.S. Patent Application Publication No.2006/0034786 and U.S. Patent No.7,705,041; benzylidene-1,3- thiazolidine compounds of formula (I) described in U.S. Patent Application Publication No.2007/0071699; phenylfurylmethylthiazolidine-2,4-dione and phenylthienylmethylthiazolidine-2,4-dione compounds described in U.S. Patent Application Publication No.2007/0078175; thiazolidenedione derivatives described in U.S. Patent Application Publication No.2011/0269954; phenylfuran, phenylthiophene, or phenylpyrrazole compounds described in U.S. Patent No.7,294,641, 5-(3,5-disubstituted phenylazo)-2-hydroxybenzene-acetic acids and salts and lactones described in U.S. Patent No.4,725,676, and azo compounds described in U.S. Patent No.4,889,846. [00257] Still other examples of 15-PGDH inhibitors are described in the following publications: Seo SY et al. Effect of 15-hydroxyprostaglandin dehydrogenase inhibitor on wound healing. Prostaglandins Leukot Essent Fatty Acids.2015;97:35-41. doi: 10.1016/j.plefa.2015.03.005. PubMed PMID: 25899574; Piao YL et al. Wound healing effects of new 15-hydroxyprostaglandin dehydrogenase inhibitors. Prostaglandins Leukot Essent Fatty Acids.2014;91(6):325-32. doi: 10.1016/j.plefa.2014.09.011. PubMed PMID: 25458900; Choi D et al. Control of the intracellular levels of prostaglandin E(2) through inhibition of the 15-hydroxyprostaglandin dehydrogenase for wound healing. Bioorg Med Chem.2013;21(15):4477-84. doi: 10.1016/j.bmc.2013.05.049. PubMed PMID: 23791868; Wu Y et al. Synthesis and biological evaluation of novel thiazolidinedione analogues as 15- hydroxyprostaglandin dehydrogenase inhibitors. J Med Chem.2011;54(14):5260-4. Epub 2011/06/10. doi: 10.1021/jm200390u. PubMed PMID: 21650226; Duveau DY et al. Structure-activity relationship studies and biological characterization of human NAD(+)- dependent 15-hydroxyprostaglandin dehydrogenase inhibitors. Bioorg Med Chem Lett. 2014;24(2):630-5. doi: 10.1016/j.bmcl.2013.11.081. PubMed PMID: 24360556; PMCID: PMC3970110; Duveau DY et al. Discovery of two small molecule inhibitors, ML387 and ML388, of human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase. Probe Reports from the NIH Molecular Libraries Program. Bethesda (MD)2010; Wu Y et al. Synthesis and SAR of thiazolidinedione derivatives as 15-PGDH inhibitors. Bioorg Med Chem.2010;18(4):1428-33. doi: 10.1016/j.bmc.2010.01.016. PubMed PMID: 20122835; Wu Y et al. Synthesis and biological evaluation of novel thiazolidinedione analogues as 15- hydroxyprostaglandin dehydrogenase inhibitors. J Med Chem.2011;54(14):5260-4. Epub 2011/06/10. doi: 10.1021/jm200390u. PubMed PMID: 21650226; Jadhav A et al. Potent and selective inhibitors of NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (HPGD). Probe Reports from the NIH Molecular Libraries Program. Bethesda (MD)2010; Niesen FH et al. High-affinity inhibitors of human NAD-dependent 15-hydroxyprostaglandin dehydrogenase: mechanisms of inhibition and structure-activity relationships. PLoS One. 2010;5(11):e13719. Epub 2010/11/13. doi: 10.1371/journal.pone.0013719. PubMed PMID: 21072165; PMCID: 2970562; Michelet, J. et al. Composition comprising at least one 15- PGDH inhibitor. US20080206320 A1, 2008; and Rozot, R et al. Care/makeup compositions comprising a 2-alkylideneaminooxyacetamide compound for stimulating the growth of the hair or eyelashes and/or slowing loss thereof. US7396525 B2, 2008. Inhibitory Nucleic Acids [00258] In some embodiments, the 15-PGDH inhibitor can include an inhibitory nucleic acid, e.g., antisense DNA or RNA, morpholino oligomer, small interfering RNA (siRNA), microRNA (miRNA), or short hairpin RNA (shRNA). In some embodiments, the inhibitory RNA targets a sequence that is identical or substantially identical (e.g., at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical) to a target sequence in a 15-PGDH polynucleotide (e.g., a portion comprising at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 contiguous nucleotides, e.g., from 20-500, 20-250, 20-100, 50-500, or 50-250 contiguous nucleotides of a 15-PGDH-encoding polynucleotide sequence (e.g., the human HPGD gene, Gene ID: 3248, including of any of its transcript variants, e.g., as set forth in GenBank Accession Nos. NM_000860.6, NM_001145816.2, NM_001256301.1, NM_001256305.1. NM_001256306.1, NM_001256307.1, or NM_001363574.1). [00259] In some embodiments, the methods described herein comprise treating a subject with diseases or disorders characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species within the nervous system using an shRNA or siRNA. A shRNA is an artificial RNA molecule with a hairpin turn that can be used to silence target gene expression via the siRNA it produces in cells. See, e.g., Fire et. al., Nature 391:806-811, 1998: Elbashir et al., Nature 411:494-498, 2001; Chakraborty et al., Mol Ther Nucleic Acids 8:132-143, 2017; and Bouard et al., Br. J. Pharmacol.157:153- 165, 2009. In some embodiments, a method of treating a subject, e.g., a subject with diseases or disorders characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species within the nervous system, comprises administering to the subject a therapeutically effective amount of a modified RNA or a vector comprising a polynucleotide that encodes an shRNA or siRNA capable of hybridizing to a portion of a 15-PGDH mRNA (e.g., a portion of the human 15-PGDH-encoding polynucleotide sequence set forth in any of GenBank Accession Nos. NM_000860.6. NM_001145816.2, NM_001256301.1, NM_001256305.1, NM_001256306.1, NM_001256307.1, or NM_001363574.1). In some embodiments, the vector further comprises appropriate expression control elements known in the art, including, e.g., promoters (e.g., inducible promoters or tissue specific promoters), enhancers, and transcription terminators. [00260] In some embodiments, the 15-PGDH inhibitor is a 15-PGDH-specific microRNA (miRNA or miR). A microRNA is a small non-coding RNA molecule that functions in RNA silencing and post-transcriptional regulation of gene expression. miRNAs base pair with complementary sequences within the mRNA transcript. As a result, the mRNA transcript may be silenced by one or more of the mechanisms, such as cleavage of the mRNA strand, destabilization of the mRNA through shortening of its poly(A) tail, and decrease in the translation efficiency of the mRNA transcript into proteins by ribosomes. [00261] In some embodiments, the 15-PGDH inhibitor may be a morpholino oligomer, an antisense oligonucleotide, e.g., an RNase H-dependent antisense oligonucleotide (ASO), or combinations thereof. ASOs are single-stranded, chemically modified oligonucleotides that bind to complementary sequences in target mRNAs and reduce gene expression both by RNase H-mediated cleavage of the target RNA and by inhibition of translation by steric blockade of ribosomes. In some embodiments, the oligonucleotide is capable of hybridizing to a portion of a 15-PGDH mRNA (e.g., a portion of a human 15-PGDH-encoding polynucleotide sequence as set forth in any of GenBank Accession Nos. NM_000860.6, NM_001145816.2, NM_001256301.1, NM_001256305.1, NM_001256306.1, NM_001256307.1, or NM_001363574.1). In some embodiments, the oligonucleotide has a length of about 10-30 nucleotides (e.g., 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or 30 nucleotides). In some embodiments, the oligonucleotide has 100% complementarity to the portion of the mRNA transcript it binds. In other embodiments, the DNA oligonucleotide has less than 100% complementarity (e.g., about 95%, about 90%, about 85%, about 80%, about 75%, or about 70% complementarity) to the portion of the mRNA transcript it binds, but can still form a stable RNA:DNA duplex for the RNase H to cleave the mRNA transcript. [00262] Suitable antisense molecules, siRNA, miRNA, and shRNA can be produced by standard methods of oligonucleotide synthesis or by ordering such molecules from a contract research organization or supplier by providing the polynucleotide sequence being targeted. The manufacture and deployment of such antisense molecules in general terms may be accomplished using standard techniques described in contemporary reference texts: for example, Gene and Cell Therapy: Therapeutic Mechanisms and Strategies.4th edition by N. S. Templeton; Translating Gene Therapy to the Clinic: Techniques and Approaches, 1.sup.st edition by J. Laurence and M. Franklin; High-Throughput RNAi Screening: Methods and Protocols (Methods in Molecular Biology) by D. O. Azorsa and S. Arora; and Oligonucleotide-Based Drugs and Therapeutics: Preclincal and Clinical Considerations by N. Ferrari and R. Segui. [00263] Inhibitory nucleic acids can also include morpholino oligomers (DNA bases attached to a backbone of methylenemorpholine rings linked through phosphordiamidate groups), which block access to short (approximately 25 bases) specific sequences of the base- pairing surfaces of ribonucleic acid and are used to knock down gene function. Also included are RNA aptamers, which are short, synthetic oligonucleotide sequences that bind to proteins (see, e.g., Li et al., Nuc. Acids Res. (2006), 34:6416-24). Both are notable for both high affinity and specificity for the targeted molecule, and have the additional advantage of being smaller than antibodies (usually less than 6 kD). RNA aptamers with a desired specificity are generally selected from a combinatorial library, and can be modified to reduce vulnerability to ribonucleases, using methods known in the art. Antibodies [00264] In some embodiments, the 15-PGDH inhibitor is an anti-15-PGDH antibody or an antigen-binding fragment thereof. In some embodiments, the antibody is a blocking antibody (e.g., an antibody that binds to a target and directly interferes with the target's function, e.g., 15-PGDH enzyme activity). In some embodiments, the antibody is a neutralizing antibody (e.g., an antibody that binds to a target and negates the downstream cellular effects of the target). In some embodiments, the antibody binds to human 15-PGDH. [00265] In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is an antigen-binding fragment, such as a F(ab′)2, Fab′, Fab, scFv, and the like. The term “antibody or antigen-binding fragment” can also encompass multi-specific and hybrid antibodies, with dual or multiple antigen or epitope specificities. [00266] In some embodiments, an anti-15-PGDH antibody comprises a heavy chain sequence or a portion thereof, and/or a light chain sequence or a portion thereof, of an antibody sequence disclosed herein. In some embodiments, an anti-15-PGDH antibody comprises one or more complementarity determining regions (CDRs) of an anti-15-PGDH antibody as disclosed herein. In some embodiments, an anti-15-PGDH antibody is a nanobody, or single-domain antibody (sdAb), comprising a single monomeric variable antibody domain, e.g., a single VHH domain. [00267] For preparing an antibody that binds to 15-PGDH, many techniques known in the art can be used. See, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4: 72 (1983); Cole et al., pp.77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies: Principles and Practice (2nd ed.1986)). In some embodiments, antibodies are prepared by immunizing an animal or animals (such as mice, rabbits, or rats) with an antigen for the induction of an antibody response. In some embodiments, the antigen is administered in conjugation with an adjuvant (e.g., Freund's adjuvant). In some embodiments, after the initial immunization, one or more subsequent booster injections of the antigen can be administered to improve antibody production. Following immunization, antigen-specific B cells are harvested, e.g., from the spleen and/or lymphoid tissue. For generating monoclonal antibodies, the B cells are fused with myeloma cells, which are subsequently screened for antigen specificity. [00268] The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody. Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Additionally, phage or yeast display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992); Lou et al. m PEDS 23:311 (2010); and Chao et al., Nature Protocols, 1:755-768 (2006)). Alternatively, antibodies and antibody sequences may be isolated and/or identified using a yeast-based antibody presentation system, such as that disclosed in, e.g., Xu et al., Protein Eng Des Sel, 2013, 26:663-670; WO 2009/036379; WO 2010/105256; and WO 2012/009568. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby, Immunology (3rd ed.1997)). Techniques for the production of single chain antibodies or recombinant antibodies (U.S. Pat. Nos.4,946,778, 4,816,567) can also be adapted to produce antibodies. [00269] Antibodies can be produced using any number of expression systems, including prokaryotic and eukaryotic expression systems. In some embodiments, the expression system is a mammalian cell, such as a hybridoma, or a CHO cell. Many such systems are widely available from commercial suppliers. In embodiments in which an antibody comprises both a VH and VL region, the VH and VL regions may be expressed using a single vector, e.g., in a di-cistronic expression unit, or be under the control of different promoters. In other embodiments, the VH and VL region may be expressed using separate vectors. [00270] In some embodiments, an anti-15-PGDH antibody comprises one or more CDR, heavy chain, and/or light chain sequences that are affinity matured. For chimeric antibodies, methods of making chimeric antibodies are known in the art. For example, chimeric antibodies can be made in which the antigen binding region (heavy chain variable region and light chain variable region) from one species, such as a mouse, is fused to the effector region (constant domain) of another species, such as a human. As another example, “class switched” chimeric antibodies can be made in which the effector region of an antibody is substituted with an effector region of a different immunoglobulin class or subclass. [00271] In some embodiments, an anti-15-PGDH antibody comprises one or more CDR, heavy chain, and/or light chain sequences that are humanized. For humanized antibodies, methods of making humanized antibodies are known in the art. See, e.g., U.S. Pat. No. 8,095,890. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. As an alternative to humanization, human antibodies can be generated. As a non-limiting example, transgenic animals (e.g., mice) can be produced that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production. For example, it has been described that the homozygous deletion of the antibody heavy-chain joining region (JH) gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production. Transfer of the human germ-line immunoglobulin gene array in such germ-line mutant mice will result in the production of human antibodies upon antigen challenge. See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90:2551 (1993); Jakobovits et al., Nature, 362:255-258 (1993); Bruggermann et al., Year in Immun., 7:33 (1993); and U.S. Pat. Nos.5,591,669, 5,589,369, and 5,545,807. [00272] In some embodiments, antibody fragments (such as a Fab, a Fab′, a F(ab′)2, a scFv, nanobody, or a diabody) are generated. Various techniques have been developed for the production of antibody fragments, such as proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., J. Biochem. Biophys. Meth., 24:107-117 (1992); and Brennan et al., Science, 229:81 (1985)) and the use of recombinant host cells to produce the fragments. For example, antibody fragments can be isolated from antibody phage libraries. Alternatively, Fab′-SH fragments can be directly recovered from E. coli cells and chemically coupled to form F(ab′)2 fragments (see, e.g., Carter et al., BioTechnology, 10:163-167 (1992)). According to another approach, F(ab′)2 fragments can be isolated directly from recombinant host cell culture. Other techniques for the production of antibody fragments will be apparent to those skilled in the art. [00273] Methods for measuring binding affinity and binding kinetics are known in the art. These methods include, but are not limited to, solid-phase binding assays (e.g., ELISA assay), immunoprecipitation, surface plasmon resonance (e.g., Biacore™ (GE Healthcare, Piscataway, NJ)), kinetic exclusion assays (e.g., KinExA®), flow cytometrv, fluorescence- activated cell sorting (FACS), BioLayer interferometry (e.g., Octet™ (FortdBio, Inc., Menlo Park, CA)), and western blot analysis. Gene Editing [00274] Provided herein are nucleic acid molecules to inhibit 15-PGDH and/or activate or upregulate PGE2 synthesis. The nucleic acid molecules may be used in a TALEN (transcription activator-like effector nuclease technology), zinc-finger nuclease or CRISPR- Cas system to target a nucleic acid sequence for genetic screening, targeted transcriptional regulation, targeted knock-in, and targeted genome editing, including base editing, epigenetic editing, and introducing double strand breaks (DSBs) for homologous recombination- mediated insertion of a nucleotide sequence. Genome editing can refer to the targeted modification of a DNA sequence, including but not limited to, adding, removing, replacing, or modifying existing DNA sequences, and inducing chromosomal rearrangements or modifying transcription regulation elements (e.g., methylation/demethylation of a promoter sequence of a gene) to alter gene expression. In some embodiments, inhibiting 15-PGDH expression comprises inserting a silencer sequence near a polynucleotide sequence encoding 15-PGDH. In yet other embodiments, upregulating PGE2 synthesis comprises inserting an enhancer sequence near a polynucleotide sequence encoding PGE2. [00275] CRISPR-Cas system requires a guide system that can locate Cas protein to the target DNA site in the genome. In some instances, the guide system comprises a crispr RNA (crRNA) with a 17-20 nucleotide sequence that is complementary to a target DNA site and a trans-activating crRNA (tracrRNA) scaffold recognized by the Cas protein (e.g., Cas9). The 17-20 nucleotide sequence complementary to a target DNA site is referred to as a spacer while the 17-20 nucleotide target DNA sequence is referred to a protospacer. While crRNAs and tracrRNAs exist as two separate RNA molecules in nature, single guide RNA (sgRNA or gRNA) can be engineered to combine and fuse crRNA and tracrRNA elements into one single RNA molecule. Thus, in one embodiment, the CRISPR guide system comprises two or more RNAs, e.g., crRNA and tracrRNA. In another embodiment, the CRISPR guide system comprises a sgRNA comprising a spacer sequence for genomic targeting and a scaffold sequence for Cas protein binding. In some instances, the guide system naturally comprises a sgRNA. For example, Cas12a/Cpf1 utilizes a guide system lacking tracrRNA and comprising only a crRNA containing a spacer sequence and a scaffold for Cas12a/Cpf1 binding. While the spacer sequence can be varied depending on a target site in the genome, the scaffold sequence for Cas protein binding can be identical for all gRNAs. [00276] CRISPR-Cas systems described herein can comprise different CRISPR enzymes. For example, the CRISPR-Cas system can comprise Cas9, Cas12a/Cpf1, Cas12b/C2c1, Cas12c/C2c3, Cas12d/CasY, Cas12e/CasX, Cas12g, Cas12h, or Cas12i. Non- limiting examples of Cas enzymes include, but are not limited to, Cas1, CasiB, Cas2, Cas3, Cas4, Cas5, Cas5d, Cas5t, Cas5h, Cas5a, Cas6, Cas7, Cas8, Cas8a, Cas8b, Cas8c, Cas9 (also known as Csn1 or Csx12), Cas10, Cas10d, Cas12a/Cpf1, Cas12b/C2c1, Cas12c/C2c3, Cas12d/CasY, Cas12e/CasX, Cas12f/Cas14/C2c10, Cas12g, Cas12h, Cas12i, Cas12k/C2c5, Cas13a/C2c2, Cas13b, Cas13c, Cas13d, C2c4, C2c8, C2c9, Csy1, Csy2, Csy3, Csy4, Cse1, Cse2, Cse3, Cse4, Cse5e, Csc1, Csc2, Csa5, Csn1, Csn2, Csm1, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx1S, Csx11, Csf1, Csf2, CsO, Csf4. Csd1, Csd2, Cst1, Cst2, Csh1, Csh2, Csa1, Csa2, Csa3, Csa4, Csa5, GSU0054, Type II Cas effector proteins, Type V Cas effector proteins, Type VI Cas effector proteins, CARF, DinG, homologues thereof, or modified or engineered versions thereof such as dCas9 (endonuclease-dead Cas9) and nCas9 (Cas9 nickase that has inactive DNA cleavage domain). In some cases, the compositions, methods, devices, and systems, described herein, may use the Cas9 nuclease from Streptococcus pyogenes, of which amino acid sequences and structures are well known to those skilled in the art. [00277] Binding of a Cas protein to its target DNA sequence (i.e. target dsDNA) requires the presence of a protospacer adjacent motif (PAM), i.e., a short sequence adjacent to the protospacer, on the non-targeted DNA strand, which limits the region in the genome that can be targeted by Cas proteins. Cas proteins from different bacterial species recognize different PAM sequences and make cuts 3-4 nucleotides upstream (e.g., Cas9) or 18-23 nucleotides downstream (e.g., Cas12a/Cpf1) of the PAM sequence. For example, Cas9 from Streptococcus pyogene recognizes the PAM sequence 5′-NGG-3′ (wherein “N” can be any nucleotide) and cleaves 3 nucleotide upstream of the PAM sequence. In another example, Cas9 from Staphylococcus aureus recognizes the PAM sequence 5′-NNGRRN-3′ (wherein “N” can be any nucleotide) and cleaves 4 nucleotide upstream of the PAM sequence. Although the PAM sequence is essential for Cas-mediated cleavage, in some instances, the gRNA sequence does not comprise a PAM sequence. [00278] Provided herein are nucleic acid molecules comprising a target sequence comprising a spacer that is complementary to a sequence at a target site in the genome. A spacer, as described herein, can comprise about 10 to about 25 nucleotides in length. For example, a spacer sequence that is complementary to a target site sequence in the genome can be about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 27, 28, 30, or more nucleotides in length. A target site, as described herein, can comprise a sequence of about 20 nucleotides immediately upstream or 5′ of the first nucleotide of the PAM. Provided herein are guide system nucleic acid molecules, wherein at least 1, at least 2, or at least 3 consecutive nucleotides at the 5′ terminus of the guide system nucleic acid molecules are 100% identical to the 3′ terminus of the target sequence in a genome. Guide system nucleic acid molecules synthesized by the compositions, methods, devises, and systems, described herein, exhibit improved or enhanced pairing with a target sequence via complementary base pairing with the target sequence in a target gene compared to a guide system nucleic acid molecule comprising additional 5′ terminal G nucleotide that is not present in the protospacer sequence or complementary to the 3′ terminus of the target sequence. [00279] Provided herein are guide system nucleic acid molecules exhibiting enhanced editing efficiency of a target sequence when guide system nucleic acid molecules are contacted with the target sequence in a complex with a CRISPR-Cas system (e.g., CRISPR- Cas9, CRISPR-Cas12a/Cpf1, etc.). For example, gRNA (guide RNA) provided herein can exhibit enhanced editing efficiency of a target sequence when in complex with a CRISPR- Cas system compared to a gRNA comprising additional one or more 5′ terminal G nucleotides, wherein the additional one or more 5′ terminal G nucleotides are not present in the protospacer sequence or not complementary to one or more nucleotides at the 3′ terminus of the target sequence in a genome. As used herein, the term “codon” generally refers to three consecutive nucleotides, which may or may not encode an amino acid. As used herein, the efficiency of editing” or “editing efficiency” can refer to the ability of a guide system nucleic acid molecule directed effector protein (e.g., CRISPR-Cas protein) to modify a target DNA sequence. Non-limiting examples of modification of a target sequence can include introducing a double stranded break, modifying a nucleobase, inducing chromosomal rearrangements, and modifying methylation/demethylation of a promoter sequence of a gene. A target sequence may be located in a gene or in a promoter region in a genome. An effector protein may be a gRNA directed nuclease, e.g., Cas protein such as Cas9 or any other Cas protein described herein. The editing efficiency can be measured by using any methods well known to one skilled in the art. For example, the efficiency of genome editing or editing efficiency can be measured by using tracking of indels by decomposition (TIDE) analysis, surveyor nuclease assay, junction PCR, droplet digital PCR (ddPCR), denaturing high- performance liquid chromatography (DHPLC), PCR single-stranded conformational polymorphism (SSCP), high-resolution melting (HRM), restriction enzyme digestion- suppressed PCR (RE-PCR), engineered nuclease-induced translocations (ENIT), restriction enzyme digestion, Sanger DNA sequencing, deep sequencing such as next generation sequencing (NGS), or any combination thereof. The term “indel(s)”, as used herein, refers to the insertion or deletion of a nucleotide base within a nucleic acid. In some embodiments, the efficiency of genome editing, e.g., generating a double-strand break, can be measured by TIDE analysis, a three-step method whereby the region targeted by the nuclease (e.g., Cas9) is PCR-amplified from DNA isolated from cells transfected with CRISPR-Cas system and gRNAs. Amplicons of 500-1500 bp generated around the target site are subject to conventional Sanger DNA sequencing followed by analysis using the web-based TIDE software. Any sequence modifications made by the nuclease are visualized in a graph of the sequence with the aberrant base signal. The software also provides precise localization of break sites and estimated statistical significance of each indel. In some embodiments, the editing efficiency e.g., the efficiency of generating a DNA break in the intended target site, is at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. [00280] Further provided herein are guide system nucleic acid molecules that exhibit reduced off-target editing (e.g., editing of a non-target sequence) when guide system nucleic acid molecules are contacted with the target sequence in a complex with a CRISPR-Cas system (e.g., CRISPR-Cas9, CRISPR-Cas12a/Cpf1, etc.). For example, gRNA provided herein can exhibit reduced off-target editing when in complex with a CRISPR-Cas system compared to a gRNA comprising additional one or more 5′ terminal G nucleotides, wherein the additional one or more 5′ terminal G nucleotides are not present in the protospacer sequence or not complementary to one or more nucleotides at the 3′ terminus of the target sequence in a genome. In some embodiments, the off-target editing can be reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. [00281] Provided herein are guide system nucleic acid molecules comprising a secondary structure. For example, the scaffold region of the guide system nucleic acid molecule recognized by the Cas protein may form a secondary structure such as a stem, a hairpin, and/or a loop. Stems or hairpins, described herein, can be about 3-10 nucleotides in length. Loops can be about 6-20 nucleotides in length. Stems may comprise one or more bulges of 1-10 nucleotides in length. [00282] Further provided herein are guide system nucleic acid molecules comprising a target sequence comprising one or more mismatched nucleotide, i.e., the spacer sequence may comprise one or more nucleotides that are not complementary to the target site sequence in the genome. Spacers described herein may harbor various number of mismatches, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mismatches. In some embodiments, a spacer comprises at most 1, 2, 3, 4, or 5 mismatches. In some embodiments, a spacer does not comprise any mismatch as compared to a protospacer sequence at the target site, i.e., the spacer hybridizes with the target sequence at 100%. Spacers described herein may comprise at least 1 to at least 5 mismatched nucleotides. For example, the spacer may comprise at least 1, at least 2, at least 3, at least 4, or at least 5 mismatched nucleotides. In some embodiments, the spacer may comprise at most 3, at most 4, at most 5, at most 6, or at most 7 mismatched nucleotides. In some embodiments, the one or more mismatched nucleotides may be located at the 5′ terminus of the spacer sequence. In some embodiments, the one or more mismatched nucleotides may be located at the 3′ terminus of the spacer sequence. In some embodiments, the one or more mismatched nucleotides may be internally located in the spacer sequence. [00283] Provided herein are guide system nucleic acid molecules comprising a sequence extension. A sequence extension can be on the 5′ or 3′ terminus or can be added internally. For example, the 5′ terminus of the gRNA Cas12a/Cpf1 (e.g., crRNA) can be extended by 2- 59 nucleotides. Extending the 5′ terminus of the Cas12a/Cpf1 gRNA, which comprises a scaffold sequence for Cas12a/Cpf1 binding on the 5′ terminus and a target sequence on the 3′ terminus, can increase the editing efficiency and delivery of Cas12a/Cpf1 in vitro and in vivo. It can also increase tolerance of gRNAs to chemical modifications, leading to enhanced stability of gRNAs. In another example, a gRNA of Cas9 comprising an internal extension of 2-10 nucleotides to extend the stem region of the stem loop structure can increases gene knockout efficiency in CRISPR-Cas9-mediated genome editing. In some instances, a gRNA may comprise two or more of crRNA sequences and tracrRNA sequence and bind two or more Cas proteins and a target DNA sites at two or more distinct regions in the genome. In some embodiments, the gRNAs described herein may comprise a 5′ sequence extension. In some embodiments, the gRNAs described herein may comprise a 3′ sequence extension. In some embodiments, the gRNAs described herein may comprise an internal sequence extension. In some embodiments, the sequence extension can comprise about at least 1 to at least 70 nucleotides. In some embodiments, the sequence extension can comprise at least 1, at least 5, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, or at least 70 nucleotides. [00284] Provided herein are guide system nucleic acid molecules comprising a nucleotide analog, e.g., guanine (G) analog. A nucleotide analog comprises an alteration in a phosphate backbone, a sugar, and/or nucleobases. Non-limiting examples of nucleotide analog include 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5- iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2- aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 0(6)-methylguanine, 2-thiocytidine, 2′-fluororibose, ribose, 2′-deoxyribose, arabinose, hexose, phosphorothioate linkages, 5′-N-phosphoramidite linkages, intercalated bases, and/or chemically modified bases. Provided herein are gRNAs comprising a 5′ terminal G analog that can exhibit enhanced editing efficiency of a target sequence when in complex with a CRISPR-Cas system compared to a gRNA lacking 5′ terminal G analog. [00285] Further provided herein are nucleic acid molecules comprising 10 to 100 nucleotides in length. In some embodiments, the synthesized nucleic acid molecules comprises 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nucleotides in length. In some embodiments, the synthesized nucleic acid molecules comprises 10 to 20 nucleotides, 10 to 30 nucleotides, 10 to 40 nucleotides, 10 to 50 nucleotides, 10 to 60 nucleotides, 10 to 70 nucleotides, 10 to 80 nucleotides, 10 to 90 nucleotides, 10 to 100 nucleotides, 20 to 30 nucleotides, 20 to 40 nucleotides, 20 to 50 nucleotides, 20 to 60 nucleotides, 20 to 70 nucleotides, 20 to 80 nucleotides, 20 to 90 nucleotides, 20 to 100 nucleotides, 30 to 40 nucleotides, 30 to 50 nucleotides, 30 to 60 nucleotides, 30 to 70 nucleotides, 30 to 80 nucleotides, 30 to 90 nucleotides, 30 to 100 nucleotides, 40 to 50 nucleotides, 40 to 60 nucleotides, 40 to 70 nucleotides, 40 to 80 nucleotides, 40 to 90 nucleotides, 40 to 100 nucleotides, 50 to 60 nucleotides, 50 to 70 nucleotides, 50 to 80 nucleotides, 50 to 90 nucleotides, 50 to 100 nucleotides, 60 to 70 nucleotides, 60 to 80 nucleotides, 60 to 90 nucleotides, 60 to 100 nucleotides, 70 to 80 nucleotides, 70 to 90 nucleotides, 70 to 100 nucleotides, 80 to 90 nucleotides, 80 to 100 nucleotides, or 90 to 100 nucleotides in length. In some embodiments, the synthesized nucleic acid molecules comprises at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, or at least 90 nucleotides in length. In some embodiments, the synthesized nucleic acid molecules comprises at most 20, at most 30, at most 40, at most 50, at most 60, at most 70, at most 80, at most 90, or at most 100 nucleotides in length. In some embodiments, the synthesized nucleic acid molecules comprises at least 20 nucleotides in length. In some embodiments, the synthesized nucleic acid molecules comprises at least 80 nucleotides in length. In some embodiments, the synthesized nucleic acid molecules comprises at most 30 nucleotides in length. [00286] The synthesized nucleic acid molecules, as described herein, can comprise one or more modifications. For example, the synthesized nucleic acid molecules can comprise synthetic nucleotide, synthetic nucleotide analog, nucleotide derivatives, and/or modified nucleotides. In some embodiments, the one or more modification can increase stability of the synthesized nucleic acid molecules. In some embodiments, the one or more modification can enhance biological activity of the synthesized nucleic acid molecules. In some embodiments, a modification of internucleotide linkage using phosphorothioate (PS) bond substitutes can be introduced to inhibit exonuclease-mediated degradation of nucleic acid molecules. In some embodiments, the one or more modifications can be made at any location of the synthesized nucleic acid molecule. The synthesized nucleic acid molecule, as described herein, can comprise natural nucleosides (e.g., adenosine, guanosine, cytidine, and uridine), nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5- iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2- aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 0(6)-methylguanine, and 2-thiocytidine), chemically modified bases, biologically modified bases (e.g., methylated bases), intercalated bases, modified sugars (e.g., 2′-fluororibose, ribose, 2′-deoxyribose, arabinose, and hexose), and/or modified phosphate groups (e.g., phosphorothioates and 5′-N-phosphoramidite linkages). [00287] Provided herein are nucleic acid molecule comprising a chemical modification. Chemical modifications as described herein may comprise one or more 5′ modifications selected from the group consisting of 5′ triphosphate, 5′ diphosphate, 5′ monophosphate, and 5′ hydroxyl. In another embodiment, the chemical modification comprises one or more ribose modifications selected from the group consisting of 2′-O-methylation (2′OMe), 2′-O- methoxy-ethyl (2′-MOE), 2′-fluoro (2′F), 2-deoxy-2′-thio, and 2′-azido. In some embodiments, the chemical modification comprises one or more internucleotide linkage modifications selected from the group consisting of phosphorothioate, methylphosphonate, phosphonocarboxylate phosphonothiocarboxylate, boranophosphonate, alkylphosphonate, and alkylphosphonate. [00288] Chemical modifications can further comprise modified nucleotides comprising one or more heterocyclic modifications selected from the group consisting of 2,6- Diaminopurine, 2-Aminopurine, inosine, 2-aminoadenosine, N6-methyladenosine, N6,2′-O- dimethyladenosine, N1-methyladenosine, 2-amino-6-chloropurineriboside, 5-methylcytidine, 5-hydroxymethylcytidine, 8-oxo-7,8-dihydroguanosine, pseudouridine, N4-acetylcytidine, 5- bromo-uridine, 5-methyluridine, and 5-nitroindole. In some embodiments, the chemical modification comprises, but is not limited to, modified nucleotides comprising one or more 5′ cap modifications selected from the group consisting of GpppG, 7-methylguanylate (m7GpppG), m2,2,7GpppG, and m7-3′-OGpppG (ARCA). [00289] In some instances, the chemical modification comprises modified nucleotides comprising one or more 5′ cap modifications selected from the group consisting of an attachment chemistry (e.g., biotin), a dye, a cell targeting moiety, an active chemistry, and an amino modifier. In some embodiments, the attachment chemistry can comprise biotin. In some embodiments, the dye comprises fluorescein. In some embodiments, the cell targeting moiety comprises digoxigenin. In some embodiments, the active chemistry comprises azides, acrydite, thiols, or alkynes. In some embodiments, the amino modifier comprises aminoallyl. Protein Level Control [00290] In some embodiments, the 15-PGDH inhibitor can provide regulated degradation of 15-PGDH by incorporating a degron into the amino acid sequence of 15- PGDH that allows recruitment to the endogenous protein turnover machinery. Mechanisms for targeted protein degradation include, but are not limited to, recruitment to an E3 ligase for ubiquitination and subsequent proteasomal degradation, direct recruitment to the proteasome, and recruitment to the lysosome. [00291] Fusion of inducible degron motifs to 15-PGDH enables exogenous control over the stability of the molecule through the addition or removal of small molecules that stabilize or destabilize the degron, and thus 15-PGDH. [00292] In some embodiments, methods for inducible protein degradation by a degron includes, but is not limited to, ligand induced degradation (LID) using a SMASH tag, ligand induced degradation using Shield-1, ligand induced degradation using auxin, ligand induced degradation using rapamycin, peptidic degrons (e.g., IKZF3 based degrons), and proteolysis- targeting chimeras (PROTACs). In some embodiments of a ligand induced degradation method, a degron tag that is held in an inactive conformation but is induced to adopt a conformation capable of recognition by the proteasome upon binding of a specific molecule, such as but not limited to, a Shield-1 molecule. See, e.g., Roth et al., Cellular Molecular Life Sciences, 2019, 76(14), 2761-2777, which is herein incorporated by reference in its entirety. Detailed descriptions of SMASH degron technology can be found in Hannah and Zhou, Nat Chem Biol, 2015, 11:637-638 and Chung et al., Nat Chem Biol, 2015, 11:713-720, which are herein incorporated by reference in their entireties. Detailed descriptions of LID degron technologies can be found in Bonger et al., Nat Chem Biol, 2011, 7(8):531-7, which is herein incorporated by reference in its entirety. [00293] In some embodiments, the inducible degron element is selected from the group consisting of a ligand inducible degron element such as a small molecule-assisted shutoff (SMASH) degron element, Shield-1 responsive degron element, auxin responsive degron element, and rapamycin responsive degron element; a peptidic degron element; and a peptidic proteolysis targeting chimera (PROTAC) element. In useful embodiments, the ligand inducible degron element is a small molecule-assisted shutoff (SMASH) degron element and the exogenous factor for controlling immunogenicity is asunaprevir. [00294] In some embodiments of a peptidic degron, a peptide tag is used that confers small molecule-mediated recruitment to an E3 ligase. In some embodiments, the peptide tag comprises the lymphoid-restricted transcription factor IKZF3 that is recruited to the E3 ligase receptor (CRBN) in an immunomodulatory drug (IMiD) dependent manner, as described in Koduri et al., Proc Natl Acad Sci, 2019, 116(7), 2539-2544, which is herein incorporated by reference in its entirety. In certain embodiments, the degron is capable of targeting immunosuppressive factors for degradation (e.g., through a ubiquitination pathway), inducing protein degradation, or degrading proteins. Subjects to be treated [00295] The 15-PGDH inhibitors and/or 15-PGDH substrates described herein can be used to treat, prevent, or reduce the symptoms or severity of any neural injury, neurodegeneration, neurodegenerative and/or neuropsychiatric conditions, diseases, and/or disorders characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species within the nervous system of a subject in need thereof. In some embodiments, a subject having the neural injury, neurodegeneration, neurodegenerative and/or neuropsychiatric conditions, diseases, and/or disorders characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species within the nervous system of a subject in need thereof can have or be at risk of memory loss, cognitive decline, axonal degeneration, neuronal cell death, glia cell damage, and/or blood brain barrier permeability, and the 15-PGDH inhibitor can be administered to the subject at an amount effective to decrease structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species within the nervous system of a subject in need thereof. [00296] Subjects amenable to treatment by 15-PGDH inhibitors and/or 15-PGDH substrates as disclosed herein include subjects having structural deterioration of the blood- brain barrier and/or increased generation of reactive oxygen species within the nervous system and at risk of a neurodegenerative condition, disease, or disorder but not showing symptoms (for example asymptomatic subjects), as well as subjects presently showing symptoms. In the case of dementia diseases, virtually anyone is at risk of suffering from dementia if he or she lives long enough. Therefore, the present methods can be administered prophylactically to the general population characterized by structural deterioration of the blood-brain barrier and/or by increased generation of reactive oxygen species within the nervous system without any assessment of the risk of the subject patient. The methods as disclosed herein are especially useful for individuals who do have a known genetic risk of neurodegenerative condition, disease, of disorder and exhibiting structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system. [00297] Subjects can be further screened for their likelihood of having or developing a neurodegenerative condition, disease, or disorder based on a number of biochemical and genetic markers in addition to structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system. For example, one can also diagnose a subject with increased risk of developing Alzheimer's Disease using genetic markers for Alzheimer's Disease. Genetic abnormality in a few families has been traced to chromosome 21 (St. George-Hyslop et al., Science 235:885-890, 1987). One genetic marker is, for example mutations in the APP gene, particularly mutations at position 717 and positions 670 and 671 referred to as the Hardy and Swedish mutations respectively (see Hardy, TINS, supra). Other markers of risk are mutations in the presenilin genes, PS1 and PS2, and ApoE4, family history of Alzheimer's Disease, hypercholesterolemia or atherosclerosis. Subjects with APP, PS1 or PS2 mutations are highly likely to develop Alzheimer's disease. ApoE is a susceptibility gene, and subjects with the e4 isoform of ApoE (ApoE4 isoform) have an increased risk of developing Alzheimer's disease. Test for subjects with ApoE4 isoform are disclosed in U.S. Pat. No.6,027,896, which is incorporated in its entirety herein by reference. Other genetic links have been associated with increased risk of Alzheimer's disease, for example variances in the neuronal sortilin-related receptor SORL1 may have increased likelihood of developing late-onset Alzheimer's disease (Rogaeva et al., Nat. Genet.2007 February; 39(2):168-77). Other potential Alzheimer disease susceptibility genes, include, for example ACE, CHRNB2, CST3, ESR1, GAPDH, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF and be used to identify subjects with increased risk of developing Alzheimer's disease (Bertram et al, Nat. Genet.2007 January; 39(1):17-23), as well as variances in the alpha-T catenin (VR22) gene (Bertram et al, J Med. Genet.2007 January; 44(1):e63) and Insulin-degrading enzyme (IDE) and Kim et al, J Biol. Chem.2007; 282:7825-32). [00298] Neurodegenerative conditions, disease, or disorders associated with cognitive decline or memory loss can be diagnosed using standard practice and the progression can be monitored over an extended period of time. One such method includes at least one of the following; (i) a memory assessment, (ii) an extensive neuropsychological exam, (iii) an examination by a geriatric neurologist and (iv) MRI imaging of the brain. Disease progression can be documented by changes in these parameters over time. In some embodiments, changes in the parameters of at least one of these assessments can be used to assess the efficacy of the 15-PGDH inhibitors and/or 15-PGDH substrates in the subject over time. [00299] Other methods to diagnose a patient at risk of or having a neurodegenerative condition, disease or disorder, such as vascular dementia or Alzheimer's Disease, includes measurement of blood-brain barrier permeability and/or generation of reactive oxygen species within the nervous system and 15-PGDH activity and/or expression in the neurotissue, such as brain tissue, wherein increased blood-brain barrier permeability and/or increased generation of reactive oxygen species within the nervous system of the subject and 15-PGDH activity and/or expression compared to a control (e.g., normal or healthy neurotissue) is indicative of the subject having or at increased risk of the neurodegenerative condition, disease, or disorder. [00300] In some embodiments, where the subject has or is at risk of blood brain barrier breakdown, direct detection of BBB breakdown can be assessed using MRI and injection of contrasting agent. Improvements in the resolution of MRIs and in the use of special contrasting agents can be used to detect BBB permeability. In one method, subjects are administered a contrasting agent immediately prior to brain imaging, such as MRI imaging. In cases of intact BBB, the contrasting agents are confined to brain blood vessels whereas, in subjects with a disrupted BBB, the contrasting agent is "sprayed out" into the brain tissue, which can be visualized. Thus, the brain locations, the size of BBB breakdown and extent of BBB compromise, such as extent of vascular leak in subjects can be directly and quantitatively assessed as measurable parameters of BBB permeability. Furthermore, such methods can be used to assess any improvements in these parameters resulting from treatment of the subject with an agent that inhibits 15-PGDH activity. Direct visualization of BBB breakdown and its associated vascular leak into the brain is useful in the methods as disclosed herein for monitoring the beneficial effects of treating a subject with BBB permeability with a 15-PGDH inhibitor and/or 15-PGDH substrate. An improvement in at least one measurable parameter of BBB permeability, such as location, size of BBB breakdown and extent of vascular leak in subjects administered a 15-PGDH inhibitor and/or 15-PGDH substrate indicates a positive outcome from administration of an inhibitor of 15- PGDH. Parameters of BBB permeability can be monitored by direct visualization and quantified by MRI-associated image analysis and are useful in the methods as disclosed herein. [00301] In some embodiments, the 15-PGDH inhibitors and/or 15-PGDH substrates described herein are useful in preventing and treating neurodegenerative conditions, diseases and disorders, such as those characterized by structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system, aberrant 15-PGDH activity, and risk of memory loss, cognitive decline, axonal degeneration, neuronal cell death, or glia cell damage. As discussed previously, such neurodegenerative conditions, diseases, or disorders can include subarachnoid hemorrhage, schizophrenia, depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury and/or a visual symptom associated therewith, post-traumatic stress disorder, Parkinson’s disease, Parkinson Plus syndromes, Lewy Body Dementia, multiple system atrophy, corticobasal neurodegeneration, progressive supranuclear palsy, Alexander’s disease, Alzheimer’s disease, Alzheimer's disease related dementias, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington’s disease, stroke, brain radiation therapy, chronic stress, abuse or cellular toxicity of a neuro-active drug, retinal degeneration, spinal cord injury, peripheral nerve injury, idiopathic peripheral neuropathy, cognitive decline and/or general frailty associated with normal aging and/or chemotherapy, chemotherapy induced neuropathy, concussive injury, peripheral nerve crush injury, peripheral neuropathy, diabetic neuropathy, post-traumatic headache, multiple sclerosis, retinal degeneration and dystrophy, Leber congenital amaurosis, retinitis pigmentosa, cone-rod dystrophy, microphthalmia, anophthalmia, myopia, and hyperopia, spinal cord injury, traumatic spinal cord injury, peripheral nerve injury, retinal neuronal death related diseases, retinal trauma, Autism, Stargardt disease, Kearns-Sayre syndrome, Pure neurosensory deafness, Hereditary hearing loss with retinal diseases, Hereditary hearing loss with system atrophies of the nervous system, Progressive spinal muscular atrophy, Progressive bulbar palsy, Primary lateral sclerosis, Hereditary forms of progressive muscular atrophy and spastic paraplegia, Frontotemporal dementia, Dementia with Lewy bodies, Corticobasal degeneration, Progressive supranuclear palsy, Prion disorders causing neurodegeneration, Multiple system atrophy, Hereditary spastic paraparesis, Friedreich ataxia, Non-Friedreich ataxia, Spinocerebellar atrophies, Amyloidoses, Metabolic-related neurodegenerative disorders, Toxin-related neurodegenerative disorders, Multiple sclerosis, Charcot Marie Tooth, Diabetic neuropathy, Metabolic neuropathies, Endocrine neuropathies, Creutzfeldt-Jacob Disease, Primary progressive aphasia, Frontotemporal Lobar Degeneration, Cortical blindness, Shy- Drager Syndrome, Diffuse cerebral cortical atrophy of non-Alzheimer type, Lewy-body dementia, Pick disease, Thalamic degeneration, Mesolimbocortical dementia of non- Alzheimer type, Nonhuntingtonian types of chorea and dementia, Cortical-striatal-spinal degeneration, Dementia-Parkinson-amyotrophic lateral sclerosis complex, Cerebrocerebellar degeneration, Cortico-basal ganglionic degeneration, Familial dementia with spastic paraparesis or myoclonus, Tourette syndrome, or viral infection. [00302] Additional examples of neurodegenerative diseases or disorders associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system include, for example, polyglutamine repeat disorders such as Spinocerebellar ataxias (e.g., types 1, 2, 3, 6, 7 and 17), Machado-Joseph disease, Spinal and Bulbar muscular atrophy (SBMA or Kennedy's disease), Dentatorubral Pallidoluysian Atrophy (DRPLA) and other neurological conditions arising from polyglutamine expansions, or disease arising from non-coding DNA repeat expansions such as Fragile X syndrome, Fragile XE mental retardation, Friedreich ataxia, myotonic dystrophy, Spinocerebellar ataxias (types 8, 10 and 12) or other neurodegenerative diseases such as spinal muscular atrophy (Werdnig-Hoffman disease, Kugelberg-Welander disease), and spongiform encephalopathies. [00303] Additional neurodegenerative diseases associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system for which agents inhibiting 15-PGDH can be useful include, for example, age-related memory impairment, agyrophilic grain dementia, Parkinsonism-dementia complex of Guam, auto-immune conditions (eg Guillain-Barre syndrome, Lupus), Biswanger's disease, brain and spinal tumors (including neurofibromatosis), cerebral amyloid angiopathies (Journal of Alzheimer's Disease vol 3, 65-73 (2001)), cerebral palsy, chronic fatigue syndrome, corticobasal degeneration, conditions due to developmental dysfunction of the CNS parenchyma, conditions due to developmental dysfunction of the cerebrovasculature, dementia--multi infarct, dementia--subcortical, dementia with Lewy bodies, dementia of human immunodeficiency virus (HIV), dementia lacking distinct histology, Dementia Pugilistica, diffies neurofibrillary tangles with calcification, diseases of the eye, ear and vestibular systems involving neurodegeneration (including macular degeneration and glaucoma), dyskinesias (Paroxysmal), dystonias, essential tremor, Fahr's syndrome, fronto-temporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration, frontal lobe dementia, hepatic encephalopathy, hereditary spastic paraplegia, hydrocephalus, pseudotumor cerebri and other conditions involving CSF dysffunction, Gaucher's disease, Hallervorden-Spatz disease, Korsakoff's syndrome, mild cognitive impairment, monomeric amyotrophy, motor neuron diseases, multiple system atrophy, multiple sclerosis and other demyelinating conditions (e.g., leukodystrophies), myalgic encephalomyelitis, myoclonus, neurodegeneration induced by chemicals, drugs and toxins, neurological manifestations of AIDS including AIDS dementia, neurological/cognitive manifestations and consequences of bacterial and/or virus infections, including but not restricted to enteroviruses, Niemann-Pick disease, non-Guamanian motor neuron disease with neurofibrillary tangles, non-ketotic hyperglycinemia, olivo-ponto cerebellar atrophy, oculopharyugeal muscular dystrophy, neurological manifestations of Polio myelitis including non-paralytic polio and post-polio-syndrome, primary lateral sclerosis, prion diseases including Creutzfeldt-Jakob disease (including variant form), kuru, fatal familial insomnia, Gerstmann-Straussler-Scheinker disease and other transmissible spongiform encephalopathies, prion protein cerebral amyloid angiopathy, postencephalitic Parkinsonism, progressive muscular atrophy, progressive bulbar palsy, progressive subcortical gliosis, progressive supranuclear palsy, restless leg syndrome, Rett syndrome, Sandhoff disease, spasticity, sporadic fronto-temporal dementias, striatonigral degeneration, subacute sclerosing panencephalitis, sulphite oxidase deficiency, Sydenham's chorea, tangle only dementia, Tay-Sach's disease, Tourette's syndrome, vascular dementia, and Wilson disease. [00304] Additional neurodegenerative diseases associated with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system for which 15-PGDH inhibitors and/or 15-PGDH substrates are useful include other dementias not listed above, such as but without limitation, other mixed dementia, frontotemporal dementia, progressive supranuclear palsy (PSP), Parkinson's Disease with associated dementia, corticobasal degeneration, multiple system atrophy, HIV-induced dementia, white matter disease-associated dementias, mild cognitive impairment (MCI). [00305] In some embodiments, the 15-PGDH inhibitors and/or 15-PGDH substrates described herein are useful in preventing and treating blood brain barrier (BBB) permeability in a subject. Additional examples of diseases and disorders where BBB permeability occurs include, for example, multiple sclerosis, cerebral amyloid angiopathy, diabetic retinopathy, prion disorders, amyotrophic lateral sclerosis (ALS), Stiff-person Syndrome, Spinocerebellar Ataxias, Friedreich Ataxia, Ataxia Telangiectasia, Bulbospinal Atrophy (Kennedy Syndrome), Spinal Muscular Atrophy, Neuronal storage diseases (lipofuscinoses), Mitochondrial encephalomyopathies, Leukodystrophies, Neural sequelae of spinal shock/blunt trauma, Hypertensive Cerebrovascular disease, such as Lacunar Infarcts, Slit hemorrhages, Hypertensive encephalopathy. BBB permeability also occurs in brain tumors such as those with `sinusoidal` (aka high nutrient) vascular supply. [00306] In other embodiments, the 15-PGDH inhibitor and/or 15-PGDH substrate can be administered to a subject with structural deterioration of the blood-brain barrier and/or increased generation of reactive oxygen species within the nervous system associated with or caused by administration of a drug or therapeutic agent to the subject. The drug or therapeutic agent can be one that interacts with brain-located cellular receptors (membranous and cytosolic) or one that interacts with physiological pathways in the brain (action on a transporter), or a drug targeted to an organ other than the brain that interacts with brain- located cellular receptors or impacts/interferes physiological pathways of the brain. Alternatively, the drug is for use in treating a brain-related pathology; the brain-related pathology may include depression, anxiety, stress, panic disorder, pain, epilepsy, dementia, suicidal ideation, Alzheimer's disease, Parkinson's disease. The drug may include a selective- serotonin reuptake inhibitor (SSRI), a selective norepinephrine reuptake inhibitor (SNRI), a selective dopamine reuptake inhibitor (SDRI), serotonin receptor agonist/antagonists (interacting with the ‘5-HT’ receptor family), dopamine receptor agonist/antagonists (interacting with the ‘DT’ receptor family), adrenergic receptor agonist/antagonists (interacting with the ‘alpha’ and ‘beta’ receptor families, including beta-2-adrenergic receptor agonists), GABA receptor agonist/antagonists (interacting with the ‘GABAA’ and ‘GABAB’ receptor families), acetylcholine receptor agonist/antagonists (interacting with the ‘muscarinic’ and ‘nicotinic’ receptor families), glutamate receptor agonists/antagonists (e.g., NMDA receptor agonist/antagonists), opioid receptor agonist/antagonists (interacting with the ‘delta’, ‘kappa’, ‘mu’, ‘nociception’ receptor families), histamine receptor agonist/antagonists (the ‘H3’ receptor); or a drug targeting an organ other than the brain that interacts with brain-located cellular receptors or indirectly disrupts brain physiological pathways. The drug can result in a change in homeostasis to neurotransmitter-related physiological pathways. The drug can be intended for use in or is used in treating a neuropsychiatric condition. The condition can be, for example, depression, anxiety, panic disorder, suicidal ideation or stress. The drug can be any drug tested for use in or used to treat a neuropsychiatric condition but is preferably a neurotransmitter reuptake inhibitor such as an SSRI, SNRI, or SDRI or a neurotransmitter receptor agonist or antagonist (includes partial agonists/antagonists), especially a serotonin or dopamine receptor. Pharmaceutical composition [00307] In some embodiments, the 15-PGDH inhibitors and/or 15-PGDH substrates described herein can be provided in a pharmaceutical composition. A pharmaceutical composition containing the 15-PGDH inhibitors and/or 15-PGDH substrates described herein as an active ingredient may be manufactured by mixing the derivative with a pharmaceutically acceptable carrier(s) or an excipient(s) or diluting the 15-PGDH inhibitors and/or 15-PGDH substrates with a diluent in accordance with conventional methods. The pharmaceutical composition may further contain fillers, anti-cohesives, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives and the like. The pharmaceutical composition may be formulated into a suitable formulation in accordance with the methods known to those skilled in the art so that it can provide an immediate, controlled or sustained release of the 15-PGDH inhibitors and/or 15-PGDH substrates after being administered into a mammal. [00308] In some embodiments, the pharmaceutical composition may be formulated into a parenteral or oral dosage form. The solid dosage form for oral administration may be manufactured by adding excipient, if necessary, together with binder, disintegrants, lubricants, coloring agents, and/or flavoring agents, to the 15-PGDH inhibitors and shaping the resulting mixture into the form of tablets, sugar-coated pills, granules, powder or capsules. The additives that can be added in the composition may be ordinary ones in the art. For example, examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicate and the like. Exemplary binders include water, ethanol, propanol, sweet syrup, sucrose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphonate and polypyrrolidone. Examples of the disintegrant include dry starch, sodium arginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic monoglyceride and lactose. Further, purified talc, stearates, sodium borate, and polyethylene glycol may be used as a lubricant; and sucrose, bitter orange peel, citric acid, tartaric acid, may be used as a flavoring agent. In some embodiments, the pharmaceutical composition can be made into aerosol formulations (e.g., they can be nebulized) to be administered via inhalation. [00309] The 15-PGDH inhibitors and/or 15-PGDH substrates described herein may be combined with flavoring agents, buffers, stabilizing agents, and the like and incorporated into oral liquid dosage forms such as solutions, syrups or elixirs in accordance with conventional methods. One example of the buffers may be sodium citrate. Examples of the stabilizing agents include tragacanth, acacia and gelatin. [00310] In some embodiments, the 15-PGDH inhibitors and/or 15-PGDH substrates described herein may be incorporated into an injection dosage form, for example, for a subcutaneous, intramuscular or intravenous route by adding thereto pH adjusters, buffers, stabilizing agents, relaxants, topical anesthetics. Examples of the pH adjusters and the buffers include sodium citrate, sodium acetate and sodium phosphate. Examples of the stabilizing agents include sodium pyrosulfite, EDTA, thioglycolic acid and thiolactic acid. The topical anesthetics may be procaine HCl, lidocaine HCl and the like. The relaxants may be sodium chloride, glucose and the like. [00311] In other embodiments, the 15-PGDH inhibitors and/or 15-PGDH substrates described herein may be incorporated into suppositories in accordance with conventional methods by adding thereto pharmaceutically acceptable carriers that are known in the art, for example, polyethylene glycol, lanolin, cacao butter or fatty acid triglycerides, if necessary, together with surfactants such as Tween. [00312] The pharmaceutical composition may be formulated into various dosage forms as discussed above and then administered through various routes including an oral, inhalational, transdermal, subcutaneous, intravenous or intramuscular route. The dosage can be a pharmaceutically or therapeutically effective amount. [00313] Therapeutically effective dosages of 15-PDGH inhibitor is one that reduces activity and/or expression of 15-PGDH and structural deterioration of the blood-brain barrier and/or generation of reactive oxygen species within the nervous system and generates the maximum protective effect in preventing a neurodegenerative disease or disorder, or reduces a symptom of a neurodegenerative disease or disorder. [00314] In some embodiments, an optimum dosage of the 15-PGDH inhibitor and/or 15- PGDH substrate is one generating the maximum beneficial effect on damaged tissue. An effective dosage causes at least a statistically or clinically significant attenuation of at least one marker, symptom, or histological evidence characteristic of neurodegenerative condition, disease, or disorder. Markers, symptoms and histological evidence characteristic of neurodegenerative condition, disease, or disorder include memory loss, confusion, disturbances in axonal transport, demyelination, induction of metalloproteinases (MMPs), activation of glial cells, infiltration of lymphocytes, edema and immunological reactions that lead to tissue damage and further vascular injury. Stabilization of symptoms or diminution of tissue damage, under conditions wherein control patients or animals experience a worsening of symptoms or tissue damage, is one indicator of efficacy of a suppressive treatment. [00315] Therapeutically effective dosage amounts of the 15-PGDH inhibitor and/or 15- PGDH substrate may be present in varying amounts in various embodiments. For example, in some embodiments, a therapeutically effective amount of the 15-PGDH inhibitor may be an amount ranging from about 10-1000 mg (e.g., about 20 mg-1,000 mg, 30 mg-1,000 mg, 40 mg-1,000 mg, 50 mg-1,000 mg, 60 mg-1,000 mg, 70 mg-1,000 mg, 80 mg-1,000 mg, 90 mg- 1,000 mg, about 10-900 mg, 10-800 mg, 10-700 mg, 10-600 mg, 10-500 mg, 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 200-1000 mg, 200-900 mg, 200-800 mg, 200-700 mg, 200-600 mg, 200-500 mg, 200-400 mg, 300-1000 mg, 300-900 mg, 300-800 mg, 300-700 mg, 300-600 mg, 300-500 mg, 400 mg-1,000 mg, 500 mg-1,000 mg, 100 mg-900 mg, 200 mg-800 mg, 300 mg-700 mg, 400 mg- 700 mg, and 500 mg-600 mg). In some embodiments, the 15-PGDH inhibitor is present in an amount of or greater than about 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg. In some embodiments, the 15-PGDH inhibitor is present in an amount of or less than about 1000 mg, 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, 500 mg, 450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, or 100 mg. [00316] In other embodiments, a therapeutically effective dosage amount may be, for example, about 0.001 mg/kg weight to 500 mg/kg weight, e.g., from about 0.001 mg/kg weight to 400 mg/kg weight, from about 0.001 mg/kg weight to 300 mg/kg weight, from about 0.001 mg/kg weight to 200 mg/kg weight, from about 0.001 mg/kg weight to 100 mg/kg weight, from about 0.001 mg/kg weight to 90 mg/kg weight, from about 0.001 mg/kg weight to 80 mg/kg weight, from about 0.001 mg/kg weight to 70 mg/kg weight, from about 0.001 mg/kg weight to 60 mg/kg weight, from about 0.001 mg/kg weight to 50 mg/kg weight, from about 0.001 mg/kg weight to 40 mg/kg weight, from about 0.001 mg/kg weight to 30 mg/kg weight, from about 0.001 mg/kg weight to 25 mg/kg weight, from about 0.001 mg/kg weight to 20 mg/kg weight, from about 0.001 mg/kg weight to 15 mg/kg weight, from about 0.001 mg/kg weight to 10 mg/kg weight. [00317] In still other embodiments, a therapeutically effective dosage amount may be, for example, about 0.0001 mg/kg weight to 0.1 mg/kg weight, e.g. from about 0.0001 mg/kg weight to 0.09 mg/kg weight, from about 0.0001 mg/kg weight to 0.08 mg/kg weight, from about 0.0001 mg/kg weight to 0.07 mg/kg weight, from about 0.0001 mg/kg weight to 0.06 mg/kg weight, from about 0.0001 mg/kg weight to 0.05 mg/kg weight, from about 0.0001 mg/kg weight to about 0.04 mg/kg weight, from about 0.0001 mg/kg weight to 0.03 mg/kg weight, from about 0.0001 mg/kg weight to 0.02 mg/kg weight, from about 0.0001 mg/kg weight to 0.019 mg/kg weight, from about 0.0001 mg/kg weight to 0.018 mg/kg weight, from about 0.0001 mg/kg weight to 0.017 mg/kg weight, from about 0.0001 mg/kg weight to 0.016 mg/kg weight, from about 0.0001 mg/kg weight to 0.015 mg/kg weight, from about 0.0001 mg/kg weight to 0.014 mg/kg weight, from about 0.0001 mg/kg weight to 0.013 mg/kg weight, from about 0.0001 mg/kg weight to 0.012 mg/kg weight, from about 0.0001 mg/kg weight to 0.011 mg/kg weight, from about 0.0001 mg/kg weight to 0.01 mg/kg weight, from about 0.0001 mg/kg weight to 0.009 mg/kg weight, from about 0.0001 mg/kg weight to 0.008 mg/kg weight, from about 0.0001 mg/kg weight to 0.007 mg/kg weight, from about 0.0001 mg/kg weight to 0.006 mg/kg weight, from about 0.0001 mg/kg weight to 0.005 mg/kg weight, from about 0.0001 mg/kg weight to 0.004 mg/kg weight, from about 0.0001 mg/kg weight to 0.003 mg/kg weight, from about 0.0001 mg/kg weight to 0.002 mg/kg weight. In some embodiments, the therapeutically effective dose may be 0.0001 mg/kg weight, 0.0002 mg/kg weight, 0.0003 mg/kg weight, 0.0004 mg/kg weight, 0.0005 mg/kg weight, 0.0006 mg/kg weight, 0.0007 mg/kg weight, 0.0008 mg/kg weight, 0.0009 mg/kg weight, 0.001 mg/kg weight, 0.002 mg/kg weight, 0.003 mg/kg weight, 0.004 mg/kg weight, 0.005 mg/kg weight, 0.006 mg/kg weight, 0.007 mg/kg weight, 0.008 mg/kg weight, 0.009 mg/kg weight, 0.01 mg/kg weight, 0.02 mg/kg weight, 0.03 mg/kg weight, 0.04 mg/kg weight, 0.05 mg/kg weight, 0.06 mg/kg weight, 0.07 mg/kg weight, 0.08 mg/kg weight, 0.09 mg/kg weight, or 0.1 mg/kg weight. The effective dose for a particular individual can be varied (e.g., increased or decreased) over time, depending on the needs of the individual. [00318] In some embodiments, a therapeutically effective dosage may be a dosage of 10 μg/kg/day, 50 μg/kg/day, 100 μg/kg/day, 250 μg/kg/day, 500 μg/kg/day, 1000 μg/kg/day or more. In various embodiments, the amount of the 15-PGDH inhibitor or pharmaceutical salt thereof is sufficient to provide a dosage to a patient of between 0.01 μg/kg and 10 μg/kg; 0.1 μg/kg and 5 μg/kg; 0.1 μg/kg and 1000 μg/kg; 0.1 μg/kg and 900 μg/kg; 0.1 μg/kg and 900 μg/kg; 0.1 μg/kg and 800 μg/kg; 0.1 μg/kg and 700 μg/kg; 0.1 μg/kg and 600 μg/kg; 0.1 μg/kg and 500 μg/kg; or 0.1 μg/kg and 400 μg/kg. [00319] Particular doses or amounts to be administered in accordance with the present invention may vary, for example, depending on the nature and/or extent of the desired outcome, on particulars of route and/or timing of administration, and/or on one or more characteristics (e.g., weight, age, personal history, genetic characteristic, lifestyle parameter, severity of cardiac defect and/or level of risk of cardiac defect, etc., or combinations thereof). Such doses or amounts can be determined by those of ordinary skill. In some embodiments, an appropriate dose or amount is determined in accordance with standard clinical techniques. For example, in some embodiments, an appropriate dose or amount is a dose or amount sufficient to reduce a disease severity index score by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100% or more. For example, in some embodiments, an appropriate dose or amount is a dose or amount sufficient to reduce a disease severity index score by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100%. Alternatively, or additionally, in some embodiments, an appropriate dose or amount is determined through use of one or more in vitro or in vivo assays to help identify desirable or optimal dosage ranges or amounts to be administered. [00320] Various embodiments may include differing dosing regimen. In some embodiments, the 15-PGDH inhibitor and/or 15-PGDH substrate can be administered via continuous infusion. In some embodiments, the continuous infusion is intravenous. In other embodiments, the continuous infusion is subcutaneous. Alternatively, or additionally, in some embodiments, the 15-PGDH inhibitor can be administered bimonthly, monthly, twice monthly, triweekly, biweekly, weekly, twice weekly, thrice weekly, daily, twice daily, or on another clinically desirable dosing schedule. The dosing regimen for a single subject need not be at a fixed interval, but can be varied over time, depending on the needs of the subject. [00321] For topical application, the composition can be administered in the form of aqueous, alcoholic, aqueous-alcoholic or oily solutions or suspensions, or of a dispersion of the lotion or serum type, of emulsions that have a liquid or semi-liquid consistency or are pasty, obtained by dispersion of a fatty phase in an aqueous phase (O/W) or vice versa (W/O) or multiple emulsions, of a free or compacted powder to be used as it is or to be incorporated into a physiologically acceptable medium, or else of microcapsules or microparticles, or of vesicular dispersions of ionic and/or nonionic type. It may thus be in the form of a salve, a tincture, milks, a cream, an ointment, a powder, a patch, an impregnated pad, a solution, an emulsion or a vesicular dispersion, a lotion, aqueous or anhydrous gels, a spray, a suspension, a shampoo, an aerosol or a foam. It may be anhydrous or aqueous. It may also comprise solid preparations constituting soaps or cleansing cakes. [00322] Pharmaceutical compositions including the 15-PGDH inhibitor described herein can additionally contain, for example, at least one 15-PGHD substrate chosen from prostaglandins, in particular prostaglandin PGE1, PGE2, their salts, their esters, their analogues and their derivatives, in particular those described in WO 98/33497, WO 95/11003, JP 97-100091, JP 96-134242, in particular agonists of the prostaglandin receptors. It may in particular contain at least one compound such as the agonists (in acid form or in the form of a precursor, in particular in ester form) of the prostaglandin F2α receptor, such as for example latanoprost, fluprostenol, cloprostenol, bimatoprost, unoprostone, the agonists (and their precursors, in particular the esters such as travoprost) of the prostaglandin E2 receptors such as 17-phenyl PGE2, viprostol, butaprost, misoprostol, sulprostone, 16,16-dimethyl PGE2, 11-deoxy PGE1, 1-deoxy PGE1, the agonists and their precursors, in particular esters, of the prostacycline (IP) receptor such as cicaprost, iloprost, isocarbacycline, beraprost, eprostenol, treprostinil, the agonists and their precursors, in particular the esters, of the prostaglandin D2 receptor such as BW245C ((4S)-(3-[(3R,S)-3- cyclohexyl-3-isopropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid), BW246C ((4R)-(3- [(3R,S)-3-cyclohexyl-3-isopropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid), the agonists and their precursors, in particular the esters, of the receptor for the thromboxanes A2 (TP) such as I-BOP ([1S-[1a,2a(Z), 3b(1E,3S),4a]]-7-[3-[3-hydroxy-4-[4-(iodophenoxy)-1- butenyl]-7-oxabicyclo- [2.2.1]hept-2-yl]-5-heptenoic acid). [00323] Advantageously, the composition can include at least one 15-PGDH inhibitor as defined above and at least one prostaglandin or one prostaglandin derivative such as for example the prostaglandins of series 2 including in particular PGF2α and PGE2 in saline form or in the form of precursors, in particular of the esters (example isopropyl esters), their derivatives such as 16,16-dimethyl PGE2, 17-phenyl PGE2 and 16,16-dimethyl PGF2α 17- phenyl PGF2α, prostaglandins of series 1 such as 11-deoxyprostaglandin E1, 1- deoxyprostaglandin E1 in saline or ester form, is their analogues, in particular latanoprost, travoprost, fluprostenol, unoprostone, bimatoprost, cloprostenol, viprostol, butaprost, misoprostol, their salts or their esters. Example [00324] In addition to aging, a major risk factor for Alzheimer’s Disease (AD) is traumatic brain injury (TBI). TBI is defined as any injury resulting from an external force that disrupts normal brain function. Common causes of TBI include falls, motor vehicle accidents, explosions, interpersonal violence, and sports injuries. Although the mechanistic links between TBI and AD remain unclear, TBI-induced vascular dysfunction at the BBB has been proposed as a contributing factor. Given the central role of BBB deterioration in declining brain health associated with aging, TBI, and AD, protecting the BBB represents a new direction that merits therapeutic exploration. [00325] In this context, we report that inhibiting the enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a novel neuroprotective approach by virtue of protecting the BBB. We find that 15-PGDH is enriched in myeloid cells associated with the BBB, and that its elevated expression and activity are tightly associated with BBB disruption in both AD and TBI. Importantly, inhibiting 15-PGDH confers neuroprotection and preserves cognitive function in preclinical models of both conditions. Encoded by the Hpgd gene, 15-PGDH is a short chain dehydrogenase/reductase that catalyzes nicotinamide adenine dinucleotide (NAD+)-dependent oxidative degradation of various substrates throughout the body, including prostaglandin E2 (PGE2), PGF2α, resolvin D1 (RvD1), lipoxin A4 (LXA4), and 15-hydroxyeicosatetranenoic acid (15-HETE). Although studies using the small molecule 15-PGDH inhibitor (+)-SW033291 and Hpgd knockout mice have demonstrated that inhibition of 15-PGDH promotes tissue regeneration and repair in models of peripheral disease and ischemic damage, investigation of 15-PGDH in the brain remains limited. Materials and Methods Study Design [00326] The primary objective was to determine whether inhibition of 15-PGDH protects against AD related pathology in 5xFAD mouse model of AD and in traumatic brain injury. 5xFAD mice overexpress the K670N/M671L (Swedish), I716V (Florida), and V717I (London) mutations in human amyloid precursor protein (APP) isoform 695, as well as M146L and L286V mutations in human presenilin 1 (PS1) and were generated as described previously. Each experimental study design is described in more detail in the figure legends. Briefly, for AD genetic studies, male and female 5xFAD (C57BL/6J background, Stock No: 034848, Jackson Laboratory) were bred with Hpgd-/- mice (C57BL/6J background) to generate Tg-WT Hpgd+/+, Tg-WT Hpgd+/-, Tg-5xFAD Hpgd+/+, and Tg-5xFAD Hpgd+/- mice. Genotypes of the animals were blinded until they were euthanized. For TBI genetic studies, Hpgd-/- mice were also backcrossed for 14 generations onto an FVB background for generation of complete knockout animals for studies with TBI. For pharmacologic studies, animals were randomly assigned to the treatment groups until we have similar number in each treatment groups. For AD pharmacologic studies, male and female 5xFAD (B6SjLF1/J background, Stock No: 034840, Jackson Laboratory) and corresponding WT littermates (B6SjLF1/J, Stock No: 100012, Jackson Laboratory) were purchased and bred to generate either WT or 5xFAD heterozygous mice. Twice daily IP administration of (+)-SW033291 (5mg/kg x 2/day = 10 mg/kg/day) was initiated at 2 month of their age and continued until 6 month, which is the end time point for experiments. For TBI pharmacologic studies, twice daily IP administration of (+)-SW033291 (5mg/kg x 2/day = 10 mg/kg/day) was initiated 24 hours after TBI or sham injury. Details of our TBI model are described in the supplementary materials. Research endpoints were chosen based on the time point at which affected animals showed behavioral phenotypes and remained the same for each experiment. In MWM studies, if an animal did not move for the entire duration of the training days, it was excluded from the analysis. Sample size and replicates also differ by experiments and are described in the figure legends. Animals [00327] All animal work was approved by the Louis Stokes Cleveland VA Medical Center Institutional Animal Care and Use Committee. All animals were kept in environments in which temperature, lighting, and humidity were regulated. Animals had unrestricted access to food and water, and they were randomly allocated to various experimental groups. Hpgd-/- mice, the kind gift of Dr. Beverly Koller in whose laboratory the mice were derived, were backcrossed for 12 generations onto a C57BL/6J background for studies involving crosses to 5xFAD mice. In the AD rat study, six-month-old male TgF344-AD rats and WT littermates were used. Human subjects [00328] Experiments with human brain samples were approved by Institutional Review Board (IRB): Northwestern ADRC IRB Number STU00023196 and Case Western Reserve University IRB Number 03-00-26. Human subjects or their representative provided written informed consent. Sex and age information of samples related to Fig.1A. Drug preparation [00329] (+)-SW033291 compound was custom synthesized by WuXi AppTec. The compound dissolved in two parts pre-warmed ethanol at 10 mg/ml concentration by incubation at 37°C for at least 15 minutes with vortexing every 5 minutes. One part of Kolliphor EL was added, followed by further dilution with 17 parts of 5% D-Glucose water. The final working concentration of (+)-SW033291 compound was 1 mg/ml in 10% ethanol, 5.0% Kolliphor EL, and 4.25% d-glucose water. Behavioral analysis [00330] The Morris water maze (MWM) test was conducted in a 128-cm diameter tank filled with 22-23°C water. Four visual cues with different shapes and colors were equally spaced inside the tank and a translucent acrylic platform (9 cm in diameter) was placed in the middle of the southwestern quadrant 1.5 - 2 cm under the surface of the water. Mice were trained to find a hidden platform over four trials per day (maximum 60 s per trial) for three or four consecutive days, for AD and TBI studies, respectively. For each trial, the start position was changed, following the published MWM protocol. Twenty-four hours after the last training, the platform was removed and animals were allowed to swim for 60 seconds, starting from the northeastern position. The latency time to first cross the former platform area, the number of platform area crossings, and the average swim speed were measured. Any-maze video tracking software (Stoelting Co.) was used to acquire measurements. Behavior experiment was conducted in a blinded manner with respect to genotype and treatment group. Immunohistochemistry [00331] Mice were transcardially perfused with cold phosphate-buffered saline (PBS) followed by 4% paraformaldehyde in PBS at pH 7.4 under anesthesia. Brains were carefully removed and post-fixed in 4% paraformaldehyde overnight at 4°C. Brains were then immersed in 30% sucrose in PBS for 3 days at 4°C and subsequently rapidly frozen in pre- cooled 2-methylbutane on dry ice. Brains were coronally sectioned (40µm thick) and brain sections were stored in cryoprotective solution (150 mM Ethylene glycol, 100 mM glycerol, 250 mM PBS) at – 20°C. Before staining, brain sections were washed with PBS three times to remove the cryoprotective solution. For Congo Red staining, the Congo Red kit (Sigma- Aldrich, HT60) was used according to the manufacturer’s instruction. Briefly, sections were mounted on slides and dried overnight at room temperature. Tissues were quickly rinsed with tap water 3 times and then incubated with hematoxylin solution for 10 mins. After rinsing in tap water two times, sections were placed in alkaline sodium chloride solution for 20 mins and then stained with alkaline Congo Red solution for 20 mins. Sections were rinsed with absolute ethanol 3 times, cleared in xylene, and cover slipped with Surgipath MM24 (Leica, #3801120). For Aβ (4G8) staining, brain sections were blocked in 5% normal horse serum (NHS) and 5% bovine serum albumin (BSA) in PBS with 0.25% Triton-X (PBS-T) for 2 hours. Then, tissues were incubated with Alexa Fluor 647 conjugated anti-Aβ 4G8 antibody (BioLegend, #800718) in 1:500 dilution in 1% NHS, 1% BSA, in PBS with 0.25% Triton-X at 4°C overnight. Brain sections were mounted on charged glass slides and 0.1% Sudan Black B (Sigma-Aldrich, #199694) in 70% ethanol was applied to the sections to reduce autofluorescence signals. After rising with PBS, slides were cover slipped with Vectashield antifade mounting medium (Vector Laboratories, H-1000-10). For BrdU staining, endogenous peroxidase activity was blocked with 1% hydrogen peroxide (H2O2). Then, sections were incubated in 50% formamide and 2x SSC at 65°C for 2 hours to denature DNA, followed by 5 minute washing with 2xSSC. Next, sections were incubated in 2M HCl at 37°C for 30 minutes for additional denaturation. To neutralize the acid, sections were rinsed in 0.1M borate buffer followed by PBS washing. For blocking, sections were incubated in 5% BSA and 5% normal horse serum in 0.1% T-PBS for 1 hour at room temperature. Anti-BrdU antibody was used at 1:1,000 in 5% BSA and 5% normal horse serum in T-PBS and sections were incubated at 4°C overnight. After washing with T-PBS 3 times, sections were incubated in biotinylated anti-mouse IgG antibody (Vector Laboratories, BA-2000) (1:500 dilution) overnight at 4°C. After washing with PBS 3 times, sections were incubated with avidin–biotin complex (Vector Laboratories, ABC kit, PK-4000) and developed using 3,3-diaminobenzidine (DAB) (Vector Laboratories, DAB Peroxidase Substrate Kit, SK-4100). All sections were incubated with the same batch of DAB, and all reactions were performed at the same time and exposed for the same amount of time until washed with distilled water. Brain sections were mounted on charged glass slides and cover slipped with Permount mounting medium (Fisher Scientific, SP15100). For IgG staining, endogenous peroxidase activity was blocked with 1% H2O2. Then, non-specific binding was blocked by 5% NHS and 5% BSA in PBS. Sections were then incubated in biotinylated anti- mouse IgG antibody (Vector Laboratories, BA-2000) (1:500 dilution) overnight at 4°C. After washing with PBS 3 times, sections were incubated with avidin–biotin complex (Vector Laboratories, ABC kit, PK-4000) and developed using 3,3-diaminobenzidine (DAB) (Vector Laboratories, DAB Peroxidase Substrate Kit, SK-4100). All sections were incubated with the same batch of DAB, and all reactions were performed at the same time and exposed for the same amount of time until washed with distilled water. Brain sections were mounted on charged glass slides and cover slipped with Permount mounting medium (Fisher Scientific, SP15100). For 4-HNE and 3-NT staining, sections of 40 µm thickness were prepared, rinsed in PBS containing 0.3% Triton X-100, and blocked with 5% normal goat serum. They were then rinsed with PBS and left to incubate overnight at 4°C with rabbit anti-4-HNE (1:500, HNE11S, Alpha diagnostic International) or rabbit anti-3-NT (1:500, AB5411, Millipore Sigma). The following day, sections were washed with PBS and then incubated for two hours at room temperature with either goat anti-rabbit Alexa 594 or 488 (Invitrogen). After another rinse in PBS, sections were mounted using an antifade aqueous media (Vectashield® Plus with DAPI, Vector Laboratories). Silver staining was processed with FD NeuroSilver kit (FD NeuroTechnologies Inc, #PK301A) by FD NeuroTechnologies Inc. (Columbia, MD, United States). In situ hybridization [00332] Two slides each with four 5µm sections (eight levels in total) of FFPE brains from each vehicle-treated male WT and 5xFAD mice with optimal hippocampus structures were prepared for duplex mRNA in situ hybridization using Advanced Cell Diagnostics™ mRNAscope® probes and protocol for a duplex immunofluorescent detection. Baked sections were deparaffinized and rehydrated through graded ethanol series. Protocol for multiplex fluorescent detection (ACD, #323110) of probe for mouse 15-PGDH (Hpgd, #456681), mouse CD206 (Mrc1, #437511), mouse Tmem119 (Tmem119, #472901) was performed according to manufacturer specifications. Fluorescent reagents were employed as per protocol from Akoya Biosciences™ for the Fluorescein green (#FP1487991KT) and Texas red (#FP1495001KT) to detect Tmem119, CD206, and 15-PGDH, respectively. All sections were counterstained with Akoya Spectral DAPI mounting medium. Slides were stored at 4°C in the dark until high magnification perivascular imaging could be performed. Transmission electron microscopy [00333] For pharmacologic study in AD, mice were anesthetized and euthanized by transcardial perfusion with a fixative solution (1/4 strength Karnovsky’s fixative) at a flow rate of 10 ml/min for 10 min. The brains were carefully removed and then sliced into thin slices (4 mm x 4 mm x 2 mm). Tissues were fixed with 2.5% glutaraldehyde, 2% paraformaldehyde in 0.1 M HEPES buffer, pH 7.4 for 2h at room temperature. The specimens were thoroughly rinsed in 0.1 M phosphate buffer, pH7.4, and then postfixed for 2 h in an unbuffered 1:1 mixture of 2% osmium tetroxide and 3% potassium ferricyanide. After rinsing with distilled water, specimens were soaked overnight in an acidified solution of 0.25% uranyl acetate. After another rinse in distilled water, specimens were dehydrated in ascending concentrations of ethanol, passed through propylene oxide, and embedded in EMbed 812 resin mixture (Electron Microscopy Sciences, PA). For genetic study in AD and TBI studies, free-floating sections were used. Thin sections (70 nm) were cut on an RMC MT6000-XL ultramicrotome and mounted on Gilder square 300 mesh nickel grids (Electron Microscopy Sciences, PA). Thin sections were sequentially stained with acidified uranyl acetate followed by a modification of Sato’s triple lead stain and examined in a FEI Tecnai Spirit (T12) with a Gatan US40004k x 4k CCD. Microglia and non-microglia isolation for western blot [00334] Each mouse was perfused with DPBS for 5 min at 15.5rpm and whole brain tissue was collected in DPBS and processed using the MACS Adult Brain dissociation kit (Miltenyi Biotec, 130-107-677) to generate a single cell suspension. Each sample was digested using a combination of enzymatic and mechanical dissociation after being finely sliced with a scalpel. For enzymatic dissociation, enzyme mixes 1 and 2 (provided in the kit) were used for mechanical dissociation. Samples immersed in the enzyme mixes were placed in MACS C-tubes, which were then placed in the MACS Octo dissociator with heaters for 30 min at 37°C using ABDK_01 protocol. The dissociated samples were further processed for debris removal by first passing them through a MACS 70µm smart strainer and then using MACS Debris Removal reagent. This brain single cell suspension was further processed using CD11b (Microglia) microbeads (Miltenyi Biotec, 130-093-634). CD11b positive cells were magnetic labeled and separated following the manufacturer’s protocol. After a 15-min incubation at 4°C, cells were passed through a column attached to a magnetic stand, which resulted in binding of CD11b positive cells (labeled by microbead-CD11b antibodies) to the column, and the flow-though was collected as the CD11b negative population. The CD11b positive cell population was collected by removing the column from the magnetic stand and placing the plunger into the column to flush out the cells. After centrifugation, cells were lysed in in RIPA buffer (Sigma-Aldrich, R0278) containing protease and phosphatase inhibitor cocktail (Thermo Scientific, #1861284) for subsequent western blot analysis. 15-PGDH enzymatic activity assay [00335] For pharmacologic studies, mice were euthanized 30 minutes after the last dose of vehicle or (+)-SW033291 injection and brain tissues were excised. Then, tissues were further rinsed in ice-cold PBS only, and snap-frozen in liquid nitrogen. Frozen samples were pulverized over liquid nitrogen. The powder was transferred to an Eppendorf tube with 500μL of cold lysis buffer (50 mM Tris-HCl, pH 7.5, 0.1 mM DTT, 0.1 mM EDTA) and then homogenized using Kimble Kontes Pellet Pestle Cordless Motor (Fisher, K749540-0000) with Kimble Kontes blue pellet pestles (Fisher, K749521-1590) for ~ 30s on ice. The suspension was centrifuged for 10 min at 12,000rpm. The enzyme activity was measured by transfer of tritium from a tritiated PGE2 substrate to glutamate by coupling 15-PGDH to glutamate dehydrogenase in a 1 hour reaction with 1mM NAD+, 5 mM NH4Cl, 1 mM α- keto-glutarate (Sigma#75890), and 16 U of bovine liver glutamic dehydrogenase (Sigma, cat. #G-2501), as described previously. The activity was normalized to protein concentration measured by BCA assay (Thermo Scientific, cat. #23225) and expressed as CPM/Hour/mg protein. In vivo multimodal traumatic brain injury [00336] Eight-week-old male C57BL/6J (WT) and Hpgd-/- mice were anesthetized with ketamine (100 mg/kg) and xylazine (10 mg/kg) via IP injection and positioned within a confined chamber crafted from an air tank divided into two sections, with a partitioned port covered by a mylar membrane. The pressure on the side opposite to where the mouse was located was elevated to induce membrane rupture at 20 pounds per square inch (PSI). This generates an airflow jet lasting approximately 1-2 milliseconds with a pressure of 137.9 ± 13.79 kPa passing through the animal's head. The head is secured in a cushioned holder without any restraints, while the body is entirely protected by a metal tube. The air jet resulting from membrane rupture causes a concussive injury, accompanied by acceleration/deceleration of the head and exposure to the subsequent early phase of a blast wave within a confined space, as previously characterized. Twice daily IP administration of (+)-SW033291 (5mg/kg x 2/day = 10 mg/kg/day) was initiated 24 hours after TBI or sham injury. Microglia and non-microglia isolation for 15-PGDH activity assays [00337] Whole brain tissue was collected in DPBS with calcium, magnesium, glucose, and pyruvate (Thermo Fisher Scientific, 14287080) and processed using the MACS Adult Brain dissociation kit (Miltenyi Biotec, 130-107-677) to generate a single cell suspension. Each sample was digested using a combination of enzymatic and mechanical dissociation after being finely sliced with a scalpel. For enzymatic dissociation, enzyme mixes 1 and 2 (provided in the kit) were used for mechanical dissociation. Samples immersed in the enzyme mixes were placed in MACS C-tubes, which were then placed in the MACS Octo dissociator with heaters for 30 min at 37°C. The dissociated samples were further processed for debris removal by first passing them through a MACS 70 mm smart strainer and then using MACS Debris Removal reagent. Lastly, RBC lysis was performed to achieve the final single cell suspension of brain cells. This single cell suspension was further processed using the CD11b (Microglia) microbeads (Miltenyi Biotec, 130-093-634). CD11b positive cells were magnetic labeled and separated following the manufacturer’s protocol. After a 15-min incubation at 4°C, cells were passed through a column attached to a magnetic stand, which resulted in binding of CD11b positive cells (labeled by microbead-CD11b antibodies) to the column, and the flow-though was collected as CD11 negative population. The CD11b positive cell population was collected by removing the column from the magnetic stand and placing the plunger in the column to flush out the cells. In situ hybridization combined with immunohistochemistry [00338] Two 40µm sections of PFA-fixed frozen brains from each vehicle-treated male WT and 5xFAD mice with optimal hippocampus structures were prepared for duplex mRNA in situ hybridization using Advanced Cell Diagnostics™ mRNAscope® probes and protocol for a duplex immunofluorescent detection. Protocol for multiplex fluorescent detection (ACD, #323110) of probe for mouse 15-PGDH (Hpgd, #456681), mouse CD11b (Itgam, #311491) was performed according to manufacturer specifications. Fluorescent reagents of Opal 570 (Akoya Biosciences, #FP1488001KT) and Opal 650 (Akoya Biosciences, #FP1495001KT) were used to detect 15-PGDH and CD11b mRNA, respectively. Next, brain sections were blocked in 5% normal donkey serum (NDS) and 5% bovine serum albumin (BSA) in PBS with 0.25% Triton-X (PBS-T) for 1 hour. Then, tissues were incubated with anti-CD31 antibody (BD #550274) in 1:50 dilution in 1% NHS, 1% BSA, in PBS with 0.25% Triton-X for 1hr. After 3 times of PBS wash, tissues were incubated with Donkey anti-rat 488 antibody (1:500, #A21208, Invitrogen). Then, tissues were washed with PBS three times and stained with DAPI (Thermo Scientific, D3571).0.1% Sudan Black B (Sigma-Aldrich, #199694) in 70% ethanol was applied to the sections to reduce autofluorescence signals. After rising with PBS, slides were cover slipped with Vectashield antifade mounting medium (Vector Laboratories, H-1000-10). Fluorescence images were acquired using a z-stack approach with a 0.5µm interval, spanning a total depth of 2µm, across five optical sections. Orthogonal projection was performed for visualization and analysis. Cell detection and quantification was performed using QuPath. Nuclei were identified based on DAPI staining, and the proximity of each detected cell to the nearest CD31+ endothelial cell to determine the distance to the closest blood vessel. Quantification of immunohistochemistry [00339] Images were acquired with Axiolmager.M2 with monochromatic digital camera (Zeiss Ax- ioCam MRm Rev.3) and Zeiss Axio Scan.Z1. ImageJ version 1.42 software (National Institutes of Health, Bethesda, MD) was used to analyze the integrated density of silver staining with the plugin of the color deconvolution method, as previously described. BrdU-labelled cells were counted manually using AxioImager.M2 and normalized by the total area of hippocampus. The percentage of Congo Red-positive area was analyzed by measuring total percent area in ImageJ. 4-HNE and 3-NT staining images were captured on LSM 880, and the mean fluorescence intensities and number of colocalized cells were quantified using Fiji Image J. Sample preparation for in situ hybridization [00340] Following intracardiac perfusion with 4% paraformaldehyde, mouse brains were carefully removed from the skull to include the entire brain, cerebellum, and the proximal brainstem, and placed in fresh 10% neutral buffered formalin (NBF) and stored at 4°C for 24 hours. The fixed brains were then rinsed in PBS and placed in an adult mouse Zivic instrument device (Pittsburgh, PA) (coronal 1 mm divisions) (BSMAA001-1) and sectioned to provide seven to eight 2 mm thick sections ranging from immediately posterior to the olfactory lobe to the proximal brain stem. The 2 mm sections were then placed serially on three glass slides to preserve left-right orientation and anterior to posterior order and coated with a thin layer of 2% Sea Plaque Agarose (Lonza, #50104) to maintain optimal flat sections. Once solidified, the composite slabs of brain sections were wrapped in Histowrap®, placed in routine depth processing cassettes, returned to fresh cold 10% NBF, and stored for up to 2 days at 4°C. The fixed tissue slabs were processed for paraffin embedding (FFPE) using an 8-hour standard schedule at the shared Tissue Resource Core within the Case Comprehensive Cancer Center. Paraffin blocks were sectioned at 5µm for initial hematoxylin and eosin staining. The paraffin tissue block containing optimal hippocampus morphology was used for further sectioning at 5 µm for mRNA in situ hybridization. Quantification of in situ hybridization [00341] Whole section scans were acquired with Keyence BZ-X810, which is an inverted fluorescence phase contrast microscope with 2/3 inch, 2.83-million-pixel monochrome CCD (colorized with LC filter). Each field of view was stitched together with BZ-H4XD/Advanced Observation Module. QuPath version 0.3.2 software with the built in Cell detection method was used to identify DAPI positive nuclei, and the QuPath built in Subcellular detection method was used to quantify 15-PGDH, CD206, and TMEM119 positive cells. Data from each mouse was the result of averaging 2-8 separately analyzed coronal hippocampal regions per mouse. Cell counts were normalized by the total area of cortex and hippocampus. Representative 40x images of perivascular structures from the somatosensory cortex and hippocampus ventral to CA1 were taken using the Nikon E800 microscope with MetaMorph® imaging software for Tmem119, CD206, PGDH, and nuclear counterstain (DAPI) expression. All images were taken at 300ms exposure time as a monochrome image for the respective target and blended using color combine option for their respective channels to demonstrate colocalization in these perivascular cell populations. Western blotting [00342] Brain tissues was homogenized in RIPA buffer (Sigma-Aldrich, R0278) containing protease and phosphatase inhibitor cocktail (Thermo Scientific, #1861284). Lysates were centrifuged at 14,000rpm at 4°C for 30 minutes and supernatants were collected. For 15-PGDH western blot, mouse IgG was depleted using anti-mouse IgG agarose beads (Millipore Sigma, A6531) for one hour at 4°C. Protein concentrations were measured by Pierce Rapid Gold bicinchoninic acid (BCA) assay (Thermo Scientific, A53225). Proteins were heated at 95°C in either 2x or 4x Laemmli Sample Buffer (Bio-Rad Laboratories, Inc., #1610737 or #1610747) with beta-mercaptoethanol (Bio-Rad Laboratories, Inc., #1610710) for 5 min, and then resolved in 4%–20% Criterion TGX Stain- Free gels (Bio-Rad Laboratories, Inc., #5678095). Proteins were transferred onto 0.2 mm polyvinylidene fluoride (Bio-Rad Laboratories, Inc., #1704157) or nitrocellulose membranes (Bio-Rad Laboratories, Inc., #1704271) with the Trans-Blot Turbo system (Bio-Rad Laboratories, Inc.). Membranes were blocked with 5% nonfat dry milk (Research Products International, #M17200) in tris-buffered saline-tween 20 (TBS-T) for 1 hour at room temperature, and then incubated with primary antibodies at 4°C overnight. The following antibodies were used to probe target proteins: mouse anti-15-PGDH (Markowitz laboratory MM1, 1:1,000), mouse anti-GFAP (Thermo Fisher, MA5-12023, 1:1,000), rabbit anti-IBA1 (Wako, #019-19741, 1:1,000), rabbit anti-APP (Sigma Aldrich, #A8717, 1:5,000) and mouse anti-GAPDH (EMD Millipore Corp, MAB 374, 1:5,000). After primary antibody incubation, membranes were rinsed with TBST (3 times, 5 minutes each) and subsequently incubated with horseradish peroxidase conjugated-secondary antibodies. After secondary antibody incubation, membranes were rinsed with TBS-T again (3 times, 5 minutes each). SuperSignalTM West Femto Maximum Sensitivity Substrate (Thermo Scientific, #34096) was used to develop the membranes. Membranes were imaged using BioSpectrum 810 Imaging System (UVP, Upland, CA). Densitometry quantification of western blot signal was conducted by ImageJ version 1.42 software (National Institutes of Health, Bethesda, MD). Quantitative real-time PCR [00343] Frozen cortex, hippocampus, and whole brain tissues were homogenized, and RNA was isolated using High Pure RNA Isolation Kit (Roche Life Science, USA) according to the manufacturer’s protocol. RNA concentrations, 260/230 ratio, and 260/280 ratio were determined by UV visible absorption spectra, using Nanodrop 2000 (Thermo Scientific, USA). First-strand cDNA was synthesized from total RNA (500ng) using iScript cDNA Synthesis Kit (Bio-Rad Laboratories Inc., #1708891), according to the manufacturer’s instruction. Quantitative PCR was performed in triplicate using Fast Taqman Master Mix (Thermo Fisher Scientific, #444964) on the QuantStudio 6 Pro real-time PCR systems (Applied Biosystems). Taqman probes were used to examine the relative expression of human HPGD gene (Thermo Fisher Scientific, #Hs00168359_m1) and mouse Hpgd (Thermo Fisher Scientific, #Mm00515121_m1) gene. Fold change of gene expression was calculated by the comparative CT quantification method. Mouse gene expression was normalized to expression of Gapdh (Thermo Fisher Scientific, #Mm99999915_g1) and human gene expression was normalized to the geometric mean of three housekeeping genes, ACTB (Thermo Fisher Scientific, #Hs01060665_g1), LDHA (Thermo Fisher Scientific, #Hs01378790_g1), and POLR1B (Thermo Fisher Scientific, #Hs00219263_m1). Geometric mean was used to minimize the effect of possible outliers and abundance differences between different housekeeping genes. Single cell transcriptomic data reprocessing [00344] We used single cell transcriptomic profiles of mouse hippocampal formation (HPF) and isocortex (CTX) regions provided by Yao et al. to analyze Hpgd expressing cell populations. The single cell transcriptomic profiles of the HPF region are divided into two main parts: (1) the hippocampal region, including fields CA1, CA2, CA3, and dentate gyrus; and (2) the retrohippocampal region, including lateral entorhinal area, medial entorhinal area, parasubiculum, postsubiculum, presubiculum, subiculum, prosubiculum, and the immune/vascular region that includes endothelial cells, smooth muscle cells and pericytes, vascular/leptomeningeal cells, and microglia/perivascular macrophages (Micro-PVM). In the cortex (CTX), the following areas were profiled for single cell transcriptomics: frontal pole, primary motor, secondary motor, primary somatosensory (SSp), and supplemental somatosensory. We employed primary somatosensory (SSp) single cell transcriptomic profiles with 23 different cell subpopulations that mainly included astrocytes, glutamatergic neurons (L2/3 IT, L4/5 IT, Car3, and L6b), vascular/leptomeningeal cells (VLMC), and microglia/perivascular macrophages (Micro-PVM). The Seurat pipeline v4 was employed to study the single cell transcriptomic profile. The preprocessing was performed by removing low-quality cells or empty droplets and dying cells. Expression profiles were normalized using sctransform (SCT) and subsequently scaled to the expression of each gene, so that the mean expression across cells was 0 and variance across cells was 1. The SCT computes Pearson residuals from regularized negative binomial regression, where sequencing depth is utilized as a covariate in a generalized linear model to remove the influence of technical characteristics while preserving biological heterogeneity. Subsequently, principal component analysis was performed on the top 2000 highly variable genes and the top 10 principal components were inputted to visualization methodologies, including uniform manifold approximation and projection (UMAP) and t-distributed stochastic neighbor embedding (TSNE). Differentially expressed genes have been computed over log2SCT normalized profiles. Finally, the subgroup of Micro-PVM was used for subsequent analysis of differential gene expression analysis and heatmaps. Aβ peptide preparation [00345] The one milligram of Aβ1-42 peptide (Anygen, Cat. No. AGP-8338) was dissolved in 1 mL of 1,1,1,3,3,3,-hexafluoro-2-propanol (HFIP; Sigma, Cat. No.105228) and incubated at room temperature in the dark for three days with daily vertexing. The solution was then aliquoted into 20 tubes (50 µg per tube), dried using a SpeedVac, sealed, and stored at −80°C until further use. Aβ oligomers were prepared by dissolving the Aβ peptide stock in 11.07 µL of anhydrous dimethyl sulfoxide and subsequently diluting it with ice-cold 1× phosphate-buffered saline to a final concentration of 0.1 mM. The solution was then incubated at 4°C in the dark for 24 hours. ROS measurement [00346] BV2 cells (1.5 × 10⁴ cells/well) were seeded in a 24-well plate using DMEM supplemented with 10% FBS and 1% Antibiotics/antimycotic. After 24 hours, 15-PGDH substrates (PGE2, PGF2α, RvD1, RvD2, LXA4, 15-HETE) from Cayman were added to the wells at a final concentration of 5 µM and incubated for 24 hours. The culture medium was then replaced with 500 µL of phenol red-free medium containing 5.7µM CM-H₂DCFDA, followed by treatment with Aβ oligomers (5 µM). ROS levels were immediately measured using the Incucyte live-cell imaging system (IncuCyte S3, Sartorius, Germany). (+)-SW033291 pharmacokinetics [00347] Studies to evaluate (+)-SW033291 pharmacokinetics were approved and conducted under the oversight of the UT Southwestern IACUC. Twenty-one female CD-1 mice were dosed IP with 10 mg/kg (+)-SW033291. For plasma measurements, whole blood was collected, and plasma was processed from whole blood by centrifugation of the ACD anticoagulant-treated blood for 10 minutes at 9600 x g in a microcentrifuge. For measurement of brain levels, brain tissues were collected, rinsed to remove surface adhering blood, weighed, and snap frozen in liquid nitrogen. Then, brain tissue was homogenized in a 3-fold volume of PBS so that the total volume of homogenate in mL was 4 times the weight of tissue in g. Samples were stored at -80°C until analysis. For analytical processing, plasma or brain homogenate was diluted with 2 parts methanol containing 0.15% formic acid, 3mM ammonium acetate (final conc.2mM), and 37.5ng/ml internal standard (IS, final conc. 25ng/ml, n-benzylbenzamide, Sigma Aldrich, 02914LH). Samples were vortexed for 15 seconds, incubated at room temperature for 10 minutes, and centrifuged twice at 16,100 x g for 5 minutes at 4ºC in a standard microcentrifuge. Supernatants were collected for analysis, and (+)-SW033291 levels in mouse plasma and brain were monitored by LC-MS/MS using an AB Sciex 3200 QTRAP mass spectrometer coupled to a Shimadzu (Columbia, MD) Prominence LC. Vendor supplied plasma (Bioreclamation, LLC; #MSE176045) spiked with known concentrations of (+)-SW033291 was used for standards and quality control (QC) samples. An Agilent C18 XDB column (5 micron, 50 X 4.6 mm) was used for chromatography with the following conditions: Buffer A: dH2O + 2 mM ammonium acetate + 0.1% formic acid; Buffer B: MeOH + 2 mM ammonium acetate + 0.1% formic acid; flow rate 1.5 ml/min; 0 - 1.5 min 97% A, 1.5 - 2.5 min gradient to 100% B, 2.5 - 3.5 min 100% B, 3.5- 3.6 min gradient to 97% A, 3.6 - 4.597% A. (+)-SW033291 was detected with the mass spectrometer in multiple reaction monitoring (MRM) mode with compound transition 413.1 to 339.2 and n-benzylbenzamide internal standard transition 212.1 to 91.1. The concentration of (+)-SW033291 in each time-point sample was quantified using Sciex Analyst software. A value of 3-fold above the signal obtained from blank plasma or tissue homogenate was designated as the limit of detection (LOD). The limit of quantitation (LOQ) was defined as the lowest concentration for which back calculation yielded a concentration within 15% of theoretical and which was above the LOD. Brain concentrations were adjusted to remove the amount of compound present in murine brain vasculature (30 µl/g brain tissue) according to literature values and measured plasma concentrations. Results Elevated 15-PGDH expression and activity in the brains of mice and people with AD, TBI, and aging, with notable enrichment in microglia and perivascular macrophages [00348] In human AD brains, we identified a significant 75% increase in 15-PGDH mRNA compared to controls (Fig.1A). This finding was corroborated by RNA sequencing data from the Allen brain atlas, which revealed elevated 15-PGDH mRNA levels in hippocampus of human AD subjects (Fig.5A). The amyloid beta (Aβ)-driven 5xFAD mouse model of AD recapitulated these human findings, displaying increased brain expression of 15-PGDH mRNA (Fig.1B). Notably, 6-month-old symptomatic 5xFAD mice exhibited a 2- fold increase in brain 15-PGDH enzymatic activity relative to wild-type (WT) littermates, escalating to over 3-fold by 12-months of age and paralleling disease progression (Fig.1C). Similarly, symptomatic 6-month-old TgF-344 AD rats, an additional preclinical model of AD, showed elevated brain 15-PGDH activity relative to WT littermates (Fig.5B). [00349] TBI is a major risk factor for AD, and these conditions also display various common pathological features. To interrogate a potential role for 15-PGDH in TBI, we next analyzed transcriptomic microarray data from human chronic traumatic encephalopathy (CTE) cases, a neurodegenerative condition of the brain caused by repetitive TBI. We identified a significant 30% elevation in 15-PGDH brain mRNA in CTE compared to non- CTE controls (Fig.1D). Supporting these human findings, brain 15-PGDH activity was also comparably elevated in the well-established preclinical mouse model of multimodal TBI (Fig.1E). [00350] Aging is another major risk factor for AD. To investigate whether 15-PGDH increases in the aging brain, we analyzed publicly available human brain microarray data from individuals aged 24 to 106 years. This analysis revealed a significant positive correlation between brain 15-PGDH mRNA levels and advancing age (Fig.5C). Mirroring these human findings, aged (22–24-month-old) WT littermate mice also exhibited increased brain 15-PGDH mRNA and enzymatic activity levels compared to younger (5–7-month-old) WT littermate mice (Fig.5D and E). Thus, brain 15-PGDH is increased in human and mouse AD, as well as in the AD risk factors of aging and TBI. [00351] These results motivated us to more deeply explore the possible role of 15-PGDH in AD pathogenesis. Through RNA-fluorescence in situ hybridization (RNA-FISH), we visualized Hpgd-expressing cells and quantified a two- to three-fold increase in both the cortex and the hippocampus of 5xFAD mice, compared to WT littermates (Fig.1F). To explore the identity of these cells, we analyzed public single-cell RNA-sequencing (sc- RNAseq) data of mouse brain cortex, which revealed that 15-PGDH expression was most prominent in a myeloid cell cluster annotated as microglial and peri-vascular macrophages (PVMs) (Fig.6A, annotated as micro-PVM), with 48% of these myeloid cells expressing Hpgd (average expression level of 0.64 log2(sctransform normalized units) (log2(SCT)) (Fig.6B-G). By contrast, the next highest Hpgd-expressing population comprised a rare subset of Layer L2/3 glutamatergic cortical neurons, with only 9% of these neurons showing expression (average expression level of 0.1 log2(SCT) (Fig.6B-E). Notably, 15-PGDH enrichment was similarly observed in the hippocampal myeloid cell (micro-PVM) cluster (Fig.6F and G). [00352] Bead fractionation of murine cortical cells into CD11b+ and CD11b- populations confirmed an approximately 200-fold enrichment of 15-PGDH enzyme activity in the CD11b+ myeloid cell population (Fig.7A). Visualization by dual RNA-FISH further confirmed prominent localization of cortical Hpgd mRNA expression to Itgam (encoding CD11b)-marked myeloid cells (Fig.7B). Furthermore, combination of dual RNA-FISH plus CD31+ immunofluorescence staining revealed that the 15-PGDH-expressing myeloid cells were localized near cerebral vasculature, with approximately 50% of 15-PGDH and CD11b double positive (Hpgd+:Itgam+) cells residing within 5 µm of CD31+ blood vessel endothelial cells (Fig.7B). Additionally, western blot analysis detected 15-PGDH protein expression in CD11b+ but not CD11b- cells (Fig.7C). Furthermore, consistent with elevation of 15-PGDH in AD, an ~ 5-fold increase in 15-PGDH protein was observed in CD11b+ cells from 5xFAD versus WT mice as revealed by western blot analysis (Fig.1G and Fig.7C). [00353] Subcluster analysis of the sc-RNAseq-defined Hpgd+ microglial-PVM populations revealed Hpgd to be expressed by two distinct myeloid cell subsets: Mrc1+ (PVMs) and Tmem119+ (brain microglia) (Fig.1H). Dual RNA-FISH confirmed 15-PGDH colocalization with both microglia (Hpgd+ red and Tmem119+ green, double positive) and PVMs (Hpgd+ red and Mrc1+ green, double positive) in both 5xFAD and WT mice (Fig.1I and J). Notably, 5xFAD mice exhibited a two-fold increase in both 15-PGDH-expressing microglia and PVMs within both the cortical and hippocampal regions, as compared to WT littermates (Fig.1I and J). In sum, our findings demonstrate that 15-PGDH is predominantly enriched in brain myeloid cells tightly associated with the BBB, with 15-PGDH level and cellular prevalence markedly elevated in AD mouse brain. 15-PGDH inhibition prevents cognitive impairment in AD without reducing amyloid pathology [00354] Given the established roles of microglia and PVMs in AD pathogenesis, we hypothesized that pharmacologic or genetic inhibition of elevated 15-PGDH activity would mitigate cognitive impairment in 5xFAD mice. To test our hypothesis, we administered the 15-PGDH inhibitor (+)-SW033291 (5 mg/kg twice daily via intraperitoneal (IP) injection, or vehicle) to 5xFAD mice and WT littermates from two to six months of age (Fig.2A). This regimen was selected based on the therapeutic efficacy of (+)-SW033291 in prior disease models and the onset of cognitive deficits in 5xFAD mice at 6 months. Pharmacokinetic analysis confirmed sustained elevation of (+)-SW033291 in plasma and brain for up to 6 hours post-injection (Fig.8A and B), with brain concentrations sufficient to nearly abolish 15- PGDH enzymatic activity (Fig.2B). [00355] Consistent with prior observations, 6-month-old 5xFAD VEH (vehicle treated) mice exhibited significant deficits in the Morris water maze (MWM) probe test as demonstrated by both prolonged latency and decreased number of platform crossings (Fig.2C and Fig.8C), measures of hippocampal-dependent spatial memory. Strikingly, (+)- SW033291 treatment fully prevented this impairment (Fig.2C and Fig.8C). No differences in learning and swim speed were observed between treatment or genotype groups, confirming the absence of confounding motor effects (Fig.8D-F). [00356] To independently validate these findings, we generated 5xFAD mice with genetic 15-PGDH reduction via Hpgd haploinsufficiency (heterozygous deletion, Fig.2D). At 9 months of age, when pathology in 5xFAD mice has greatly advanced, Hpgd haploinsufficiency suppressed elevated brain 15-PGDH enzymatic activity (Fig.2E) and prevented 5xFAD mice from developing learning and memory deficits (Fig.2F and Fig.8G and H). Notably, cognitive protection occurred without alterations in swim speed (Fig.8I and J). Additionally, both pharmacologic and genetic inhibition of 15-PGDH did not affect body weight gain over the treatment period or throughout the experimental period (Fig.9A and B). These concordant pharmacologic and genetic results demonstrate that holding 15- PGDH activity to normal levels is sufficient to prevent AD-associated cognitive decline. [00357] Critically, neither 15-PGDH inhibition strategy altered amyloid pathology. (+)- SW033291-treated and Hpgd-haploinsufficient 5xFAD mice both exhibited Aβ deposition equivalent to vehicle-treated AD mice (4G8 antibody; Fig.2 G, H, and Fig.9C and D), with similar equivalency for Congo red-positive amyloid structures (Fig.9E and F). These findings establish that inhibiting 15-PGDH effectively dissociates cognitive protection from amyloid pathology in AD, highlighting 15-PGDH as a novel therapeutic target for AD. 15-PGDH inhibition preserves BBB integrity and attenuates neurodegeneration in AD [00358] Given the observed upregulation of 15-PGDH in AD and its prominent localization within brain myeloid cells at the BBB, we hypothesized that 15-PGDH inhibition could mitigate BBB dysfunction in AD. Transmission electron microscopy (TEM) analysis of symptomatic 5xFAD mice revealed major structural BBB impairments, most notably astrocytic endfeet swelling surrounding cerebral vasculature, a phenotype absent in age- matched WT littermates (Fig.2I and J). Notably, both pharmacologic and genetic inhibition of 15-PGDH robustly prevented BBB structural degradation in 5xFAD mice (Fig.2I and J). [00359] The glial limitans barrier, formed through astrocytic endfeet interactions with endothelial cells, normally prevents infiltration of blood-derived components into brain tissue and represents a region of functional compromise associated with astrocytic endfeet swelling. To assess functional consequences, we confirmed that both pharmacologic and genetic 15- PGDH inhibition preserved effectual BBB integrity by blocking pathological leakage of immunoglobulin (IgG) demonstrated in the brain parenchyma of 5xFAD mice (Fig.2K and L). These findings demonstrate that inhibiting 15-PGDH rescues both BBB architecture and function in AD. [00360] We next investigated whether preserving the BBB via 15-PGDH-inhibition also conferred neuroprotection. The hippocampus, a region exquisitely vulnerable to BBB disruption, exhibits early neurodegeneration in human AD and mouse models, characterized by progressively increased rate of loss of newborn hippocampal neurons. Survival of these neurons is critical for memory formation, and impairment in their survival is a hallmark of AD in humans and 5xFAD mice. We therefore labeled newborn hippocampal neurons with a single bolus injection of bromodeoxyuridine (BrdU) and assessed their survival following genetic or pharmacologic 15-PGDH inhibition. [00361] In non-AD mice, genetic deletion of Hpgd doubled the survival of BrdU-tagged newborn hippocampal neurons compared to WT littermates (Fig.10A). Similarly, pharmacological 15-PGDH inhibition in (+)-SW033291-treated WT mice enhanced survival of newborn hippocampal neurons by over 2-fold (Fig.10B), but showed no additional effect when given to 15-PGDH KO mice (Fig.10B), thereby confirming the on-target specificity of drug effect in WT mice. Notably, we observed that increased numbers of newborn hippocampal neurons were due to 15-PGDH inhibition improving neuronal survival, and not to increasing neural precursor cell proliferation, as 15-PGDH inhibition did not alter BrdU+ counts at 1-hour post-labelling (Fig.10C). Furthermore, administering P7C3-A20, a validated pro-survival aminopropyl carbazole, enhanced newborn neuron survival in 15- PGDH KO mice (Fig.10D), indicating that 15-PGDH KO does not simply saturate the capacity for further augmenting neuronal survival with a drug. [00362] In 6-month-old 5xFAD mice, newborn hippocampal neuron survival was reduced to approximately 50% that of WT mice (Fig.3A). Remarkably, pharmacologic 15- PGDH inhibition fully rescued this neurodegeneration and attenuated axonal degeneration in the dorsal fornix, a major hippocampal output tract (Fig.3A and Fig.10E). Genetic 15- PGDH haploinsufficiency (Hpgd+/-) similarly restored survival of adult-born neurons in 5xFAD mice to WT levels (Fig.3B), showing that even partial 15-PGDH suppression suffices for neuroprotection. 15-PGDH inhibition attenuates astrocyte reactivity and microglial oxidative stress in AD [00363] Given the enrichment of 15-PGDH in myeloid cells, we hypothesized that in addition to protecting the BBB, inhibiting 15-PGDH would also reduce AD associated neuroinflammation and oxidative stress. To evaluate this, we first measured protein levels of GFAP, a marker of astrocyte reactivity, and IBA1, a marker of microglia activation, in 5xFAD mice. Elevated GFAP and IBA1 expression in 5xFAD mice (Fig.3C, D and Fig.11A-D) confirmed heightened neuroinflammatory responses. Strikingly, both pharmacologic and genetic 15-PGDH inhibition significantly reduced GFAP levels, indicating suppression of astrocyte-driven neuroinflammation, while IBA1 levels remained unchanged (Fig.3C, D, and Fig.11A-D). [00364] Increased susceptibility to oxidative stress is a hallmark of the AD brain, driven by high oxygen demand, lipid-rich neuronal membranes prone to peroxidation, and increased generation of reactive oxygen species (ROS) from activated immune cells. We assessed 4- hydroxy-2-nonenal (4-HNE), a ROS-generated lipid peroxidation byproduct known to be elevated in human AD and 5xFAD brains. 5xFAD mice exhibited approximately a 3-fold increase in 4-HNE, which could be fully prevented by pharmacologically and genetically inhibiting 15-PGDH (Fig.3E and F). Similarly, 3-nitrotyrosine (3-NT), a deleterious protein modification caused by reaction of superoxide radicals with nitric oxide, is also elevated in human AD and 5xFAD mice, and we observed that 3-NT was reduced to baseline levels by pharmacologic and genetic 15-PGDH inhibition (Fig.3G and H). [00365] To further investigate microglial involvement in mediating 15-PGDH inhibition’s protection from neuroinflammation, we studied mouse microglia BV2 cells treated with oligomerized Aβ, an in vitro model known to induce ROS (Fig.12A). Remarkably, ROS generation was significantly suppressed by treating BV2 cells with 5 µM concentrations of any five different substrates that 15-PGDH normally acts to limit and degrade: PGE2, PGF2a, RvD1, LXA4, and 15-HETE (Fig.3I and J). All these treatments had no effect on BV2 cell confluency (Fig.12A-C). [00366] Thus, our results show that 15-PGDH inhibition-mediated protection of the BBB in AD is tightly associated with attenuation of neuroinflammation and oxidative stress, likely through preservation of a family of anti-inflammatory lipid mediators whose degradation is directly catalyzed by 15-PGDH. These findings highlight 15-PGDH as a therapeutic target whose inhibition directly disrupts neuroinflammation and oxidative damage in AD. 15-PGDH inhibition preserves BBB integrity and mitigates neurodegeneration in TBI [00367] As TBI is a major risk factor for AD and is associated with elevated 15-PGDH, we also investigated the neuroprotective potential of 15-PGDH inhibition in TBI. To begin, we administered the 15-PGDH inhibitor (+)-SW033291 (5mg/kg twice daily, IP) beginning 24 hours after TBI (Fig.4A). We tested this time point because we reasoned that most patients experiencing a TBI could likely access medical care within a day of injury. [00368] Pharmacologic inhibition with (+)-SW033291 robustly suppressed TBI-induced 15-PGDH enzymatic activity (Fig.4B) and completely prevented cognitive deficits in the MWM (Fig.4C and D), without affecting swim speed or learning (Fig.13A-C). Notably, severe axonal neurodegeneration induced 3 weeks after TBI in WT mice was also fully prevented by (+)-SW033291 treatment (Fig.4E), as was TBI-induced BBB disruption (Fig.4F) and oxidative stress damage assayed by 3-NT (Fig.4G) and 4-HNE (Fig.13D). As in AD, oxidative stress damage is a key pathway in the pathogenesis of TBI-induced neurodegeneration. In particular, lipid peroxidation is known to rapidly accumulate within hours of TBI, thereby driving the acute phase of pathology, and also to persist chronically and increase the risk of developing other forms of aging related neurodegeneration, such as AD. Consistent with our previous reports in this model, we detected no changes in IBA1 or GFAP expression after TBI (Fig.13E-G). [00369] To validate target specificity, we further performed TBI studies in Hpgd+/+ and Hpgd-/- mice (Fig.4H). Genetic ablation of 15-PGDH mirrored pharmacologic inhibition, conferring complete protection against axonal neurodegeneration (Fig.4I), BBB damage (Fig.4J), and oxidative stress (Fig.4K and Fig.13H). Cognitive testing in Hpgd-/- mice was precluded due to their FVB strain background, which impairs visual acuity required for MWM, unlike the C57BL/6J strain used in the AD studies. [00370] This Example identifies 15-PGDH as a novel therapeutic target for AD and TBI, demonstrating that its inhibition preserves BBB integrity and cognitive function. We observed elevated 15-PGDH in aging, TBI, and AD in both human and mouse brains, with prominent localization to brain myeloid cells, including microglia and PVMs at the BBB. Genetic or pharmacologic inhibition of 15-PGDH in mouse models of AD and TBI mitigated perivascular inflammation, protected BBB integrity, and prevented downstream neuroinflammation, oxidative stress, and neurodegeneration. Notably, cognitive function was preserved in 5xFAD mice despite unchanged amyloid pathology, underscoring a therapeutic mechanism distinct from amyloid clearance, that has heretofore been the only target of clinically tested agents for attempting to slow AD progression in patients. Inhibiting 15- PGDH thus provides a novel route for AD treatment and prevention and addresses the clear and significant unmet need for new and effective therapies for patients with this disease. [00371] Our findings align with prior evidence that depletion of PVMs leads to vascular damage, indicating a protective role for normal PVM physiology in BBB homeostasis. However, the interplay between myeloid cells, neuroinflammation, and vascular dysfunction in AD remains mechanistically unclear. We hypothesize that 15-PGDH inhibition is critically positioned to therapeutically interrupt the self-amplifying pathogenic cycle created as ROS generation and BBB degradation reciprocally drive and reinforce one another. [00372] 15-PGDH acts to catalyze the degradation of a diverse array of bioactive molecules with context-dependent pro- or anti-inflammatory effects. Our attempts to define global eicosanoid profile changes after 15-PGDH inhibition were confounded by the rapid induction and lability of these signaling molecules. However, our in vitro model of Aβ- mediated ROS induction in cultured microglia cells demonstrates that the protective effect of 15-PGDH inhibition strongly aligns with the resultant blocking of degradation of multiple anti-inflammatory 15-PGDH substrates, each of which is individually able to block ROS generation, and that in vivo are expected to act in combination. Furthermore, these individual 15-PGDH substrates act via multiple different receptors, some with opposing actions, such as raising versus lowering cyclic AMP [00373] Collectively, our findings establish 15-PGDH as a guardian of BBB integrity, a critical node in regulating brain ROS generation, and a compelling new target for protection from neurodegenerative disease. The translational potential of 15-PGDH inhibition is underscored by the strong therapeutic efficacy in a mouse AD model of even the partial 15- PGDH inhibition achieved by genetic haploinsufficiency. Importantly, biotechnology and pharmaceutical companies have already identified small-molecule 15-PGDH inhibitors as targets for development as therapeutics for peripheral disease indications. Now, our findings additionally position these agents as promising candidates for repurposing for treating neurodegenerative disorders. Given the enormous unmet need, 15-PGDH inhibition represents a paradigm-shifting therapeutic strategy for AD, TBI, and potentially other neurodegenerative conditions marked by BBB dysfunction. [00374] From the above description of the invention, those skilled in the art will perceive improvements, changes and modifications. Such improvements, changes and modifications within the skill of the art are intended to be covered by the appended claims. All references, publications, and patents cited in the present application are herein incorporated by reference in their entirety.

Claims

Having described the invention, we claim: 1. A method of treating diseases or disorders characterized by structural deterioration of the blood-brain barrier in a subject in need thereof, the method comprising: administering to the subject an amount of a 15-PGDH inhibitor and/or 15- PGDH substrate effective to prevent the onset of deterioration and/or the progression of further deterioration of the blood-brain barrier and/or prevent the neurodegeneration associated with blood-brain barrier deterioration and/or prevent the impaired neuronal function associated with blood-brain barrier deterioration and/or restore the integrity and/or structure and/or function of the blood-brain barrier.
2. A method of treating diseases or disorders characterized by increased generation of reactive oxygen species within the nervous system of a subject in need thereof, the method comprising: administering to the subject an amount of a 15-PGDH inhibitor and/or 15- PGDH substrate effective to prevent and/or decrease reactive oxygen species generation and/or neurodegeneration and/or impaired neuronal function associated with reactive oxygen species.
3. A method of treating diseases or disorders characterized by increased generation of reactive oxygen species within the central nervous system of a subject in need thereof, the method comprising: administering to the subject an amount of a 15-PGDH inhibitor and/or 15- PGDH substrate effective to prevent and/or decrease reactive oxygen species generation and/or neurodegeneration and/or impaired neuronal associated with reactive oxygen species.
4. The method of any of claims 1 to 3, wherein the subject has memory loss and/or cognitive decline and the 15-PGDH inhibitor and/or 15-PGDH substrate is administered at amount effective to improve memory and/or cognition.
5. The method of any of claims 1 to 4, wherein the 15-PGDH inhibitor and/or 15-PGDH substrate is administered to the subject at amount effective to block aberrantly increased 15-PGDH enzymatic activity and prevent perivascular inflammation.
6. The method of any of claims 1 to 5, wherein the subject is asymptomatic for Alzheimer’s dementia, has preclinical Alzheimer’s disease, or prodromal Alzheimer’s disease.
7. The method of any of claims 1 to 6, wherein the 15-PGDH inhibitor and/or 15-PGDH substrate is administered to the subject at amount effective to decrease 4-hydroxy- 2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or more.
8. The method of any of claims 1 to 7, wherein the 15-PGDH inhibitor is a small molecule that binds to 15-PGDH protein.
9. The method of any of claims 1 to 8, wherein the 15-PGDH inhibitor can inhibit enzymatic activity of recombinant 15-PGDH at an IC50 of less than 1 µM, or preferably at an IC50 of less than 250 nM, or more preferably at an IC50 of less than 50 nM, or more preferably at an IC50 of less than 10 nM, or more preferably at an IC50 of less than 5 nM at a recombinant 15-PGDH concentration of about 5 nM to about 10 nM.
10. The method of any of claims 1 to 9, wherein the 15-PGDH inhibitor has the following formula (V): pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein n is 0-2 X6 is independently is N or CRc R1, R6, R7, and Rc are the same or different each independently hydrogen or a substituted or unsubstituted group selected from C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, -Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C2-C24 alkylamido substituted with a hydroxyl, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5- C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, and phosphate esters, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof, and wherein R6 and R7 may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl; and U1 is N, C-R2, or C-NR3R4, wherein R2 is selected from the group consisting of a H, a lower alkyl group, O, (CH2)n1OR’ (wherein n1=1, 2, or 3), CF3, CH2-CH2X, O-CH2- CH2X, CH2-CH2-CH2X, O-CH2-CH2X, X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, O(CO)R’, COOR’ (wherein R’ is H or a lower alkyl group), and wherein R1 and R2 may be linked to form a cyclic or polycyclic ring, wherein R3 and R4 are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH2)n1OR’ (wherein n1=1, 2, or 3), CF3, CH2-CH2X, CH2-CH2-CH2X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, COOR’ (wherein R’ is H or a lower alkyl group), and R3 or R4 may be absent.
11. The method of any of claims 1 to 7, wherein the 15-PGDH inhibitor is a molecule or generates a molecule that binds to 15-PGDH mRNA to promote degradation 15- PGDH mRNA and/or inhibit expression of 15-PGDH.
12. The method of claim 11, wherein the molecule comprises an RNA interference (RNAi) molecule, preferably at least one of a small interfering RNA (siRNA) or microRNA (miRNA).
13. The method of any of claims 1 to 7, wherein the 15-PGDH inhibitor comprises an agent or method of gene editing that inactivates or alters the HPGD gene that encodes 15- PGDH.
14. The method of claim 13, wherein the 15-PGDH inhibitor comprises at least one nuclease that can remove, cut, or alter a target nucleic acid sequence of the HPGD gene.
15. The method of any of claims 1 to 7, wherein the 15-PGDH inhibitor is an agent that promotes the degradation of 15-PGDH protein.
16. The method of claim 15, wherein the agent comprises at least one of a small molecule-assisted shutoff (SMASh) system, a Shield-1-inducible degron, an auxin inducible degron, an IMid-inducible degron, a peptidic degron, a proteolysis targeting chimera, or an antibody for targeted 15-PGDH degradation.
17. The method of any of claims 1 to 7, wherein the 15-PGDH substrate comprises at least one of PGE2, PGF2α, RvD1, LXA4, or 15-HETE.
18. The method of any of claims 1 to 17, further comprising measuring 4- hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels of the subject following administration of the 15-PGDH inhibitor and/or 15-PGDH substrate and comparing the measured 4-hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels to a control, wherein a decrease in 4-hydroxy-2-nonenal (4-HNE) and/or 3-nitrotyrosine (3-NT) levels is indicative of efficacy of the 15-PGDH inhibitor and/or PGDH substrate in treating neurodegeneration and/or impaired neuronal function in the subject.
19. The method of claim 18, wherein the control is the 4-hydroxy-2-nonenal (4- HNE) and/or 3-nitrotyrosine (3-NT) levels of the subject prior to administration of the 15- PGDH inhibitor and/or 15-PGDH substrate.
20. The method of any of claims 1 to 17, further comprising measuring blood- brain barrier (BBB) permeability of the subject following administration of the 15-PGDH inhibitor and/or 15-PGDH substrate and comparing the measured BBB permeability to a control, wherein a decrease in BBB permeability is indicative of efficacy of the 15-PGDH inhibitor and/or PGDH substrate in treating neurodegeneration and/or impaired neuronal function in the subject.
21. The method of claim 20, wherein the control is the BBB permeability of the subject prior to administration of the 15-PGDH inhibitor and/or 15-PGDH substrate.
PCT/US2025/035911 2024-06-28 2025-06-30 Compositions and methods of treating diseases and disorders characterized by blood-brain barrier deterioration or reactive oxygen species generation Pending WO2026006830A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202463665460P 2024-06-28 2024-06-28
US63/665,460 2024-06-28
US202563774295P 2025-03-19 2025-03-19
US63/774,295 2025-03-19

Publications (1)

Publication Number Publication Date
WO2026006830A1 true WO2026006830A1 (en) 2026-01-02

Family

ID=98222956

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/035911 Pending WO2026006830A1 (en) 2024-06-28 2025-06-30 Compositions and methods of treating diseases and disorders characterized by blood-brain barrier deterioration or reactive oxygen species generation

Country Status (1)

Country Link
WO (1) WO2026006830A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230082516A1 (en) * 2019-01-08 2023-03-16 Kyorin Pharmaceutical Co., Ltd. 15-pgdh inhibitor
US20230210829A1 (en) * 2020-06-11 2023-07-06 The Board Of Trustees Of The Leland Stanford Junior University Rejuvenation of aged tissues by inhibition of the pge2 degrading enzyme, 15-pgdh
US20230310390A1 (en) * 2020-08-07 2023-10-05 Case Western Reserve University Inhibitors of short-chain dehydrogenase activity for treating neurodegeneration
US20240043443A1 (en) * 2012-04-16 2024-02-08 Case Western Reserve University Compositions and methods of modulating 15-pgdh activity
US20250034134A1 (en) * 2021-11-18 2025-01-30 Wuhan Humanwell Innovative Drug Research and Development Center Limited Company 15-pgdh inhibitor and use thereof
US20250154162A1 (en) * 2022-01-28 2025-05-15 Scinnohub Pharmaceutical Co., Ltd. Compound for regulating and controlling 15-pgdh activity and preparation method therefor

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20240043443A1 (en) * 2012-04-16 2024-02-08 Case Western Reserve University Compositions and methods of modulating 15-pgdh activity
US20230082516A1 (en) * 2019-01-08 2023-03-16 Kyorin Pharmaceutical Co., Ltd. 15-pgdh inhibitor
US20230210829A1 (en) * 2020-06-11 2023-07-06 The Board Of Trustees Of The Leland Stanford Junior University Rejuvenation of aged tissues by inhibition of the pge2 degrading enzyme, 15-pgdh
US20230310390A1 (en) * 2020-08-07 2023-10-05 Case Western Reserve University Inhibitors of short-chain dehydrogenase activity for treating neurodegeneration
US20250034134A1 (en) * 2021-11-18 2025-01-30 Wuhan Humanwell Innovative Drug Research and Development Center Limited Company 15-pgdh inhibitor and use thereof
US20250154162A1 (en) * 2022-01-28 2025-05-15 Scinnohub Pharmaceutical Co., Ltd. Compound for regulating and controlling 15-pgdh activity and preparation method therefor

Similar Documents

Publication Publication Date Title
Zeidler et al. The CD38 glycohydrolase and the NAD sink: implications for pathological conditions
EP2560008B1 (en) Pharmaceutical compositions for preventing or treating degenerative brain disease and method of screening the same
JP7212781B2 (en) Inhibitors of SARM1 in combination with neuroprotective agents
US10065951B2 (en) Small molecule transcription modulators of bromodomains
JP2024037770A (en) SARM1 inhibitor
US20230310390A1 (en) Inhibitors of short-chain dehydrogenase activity for treating neurodegeneration
JP7285599B2 (en) Amyotrophic lateral sclerosis therapeutic agent and therapeutic composition
US9149492B2 (en) Method for selectively inhibiting ACAT1 in the treatment of alzheimer&#39;s disease
JP2016539188A (en) Treatment of autoimmune and / or inflammatory diseases using novel caveolin modulators
WO2021197389A1 (en) Applications of pi4k inhibitor in intracellular protein misfolding-related diseases and lysosomal storage diseases
US8802646B2 (en) Method for selectively inhibiting the activity of ACAT1 in the treatment of alzheimer&#39;s disease
US9388413B2 (en) Method for selectively inhibiting ACAT1 in the treatment of neurodegenerative diseases
CN110121361A (en) For treating the gangliosides metabolic poison of motor neuron disease
US9388414B2 (en) Method for selectively inhibiting ACAT1 in the treatment of neurodegenerative diseases
EP3955742A1 (en) Neurogenesis
WO2026006830A1 (en) Compositions and methods of treating diseases and disorders characterized by blood-brain barrier deterioration or reactive oxygen species generation
AU2019385480B2 (en) Compositions and methods for treating neurodegenerative, myodegenerative, and lysosomal storage disorders
US10100308B2 (en) Method for selectively inhibiting ACAT1 in the treatment of neurodegenerative diseases
Bales et al. Phosphodiesterase inhibition to target the synaptic dysfunction in Alzheimer’s disease
RU2722018C2 (en) Pharmaceutical composition for inhibiting apoptosis of neurons or neurodegeneration
TW200946119A (en) 1,2,3,4-tetrahydroisoquinoline derivatives, manufacturing method thereof, and pharmaceutical compositions containing the same
Lata et al. HDAC inhibitors rescue MeCP2T158M speckles in a high content screen
CA3159374C (en) Methods and compositions for neuroprotection
WO2024020091A1 (en) Inhibitors of short-chain dehydrogenase activity for reducing glial fibrillary acidic protein levels
Yeboah Characterizing the Role of Histone Deacetylase 2 (HDAC2) in Mitochondria Function and Alzheimer’s Disease

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25827699

Country of ref document: EP

Kind code of ref document: A1