WO2014110185A1 - Procédés, systèmes et compositions associés au traitement d'états, d'une maladie ou de lésions neurologiques - Google Patents

Procédés, systèmes et compositions associés au traitement d'états, d'une maladie ou de lésions neurologiques Download PDF

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WO2014110185A1
WO2014110185A1 PCT/US2014/010755 US2014010755W WO2014110185A1 WO 2014110185 A1 WO2014110185 A1 WO 2014110185A1 US 2014010755 W US2014010755 W US 2014010755W WO 2014110185 A1 WO2014110185 A1 WO 2014110185A1
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treatment
angl
stroke
mcao
angiopoietin
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Jieli CHEN
Michael Chopp
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Henry Ford Health System
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1891—Angiogenesic factors; Angiogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • some embodiments comprise methods, systems, and
  • compositions relating to treatment of neurological conditions, disease, or injuries, and the use of same in the research, diagnosis, and treatment of injury or disease are particularly useful in the research, diagnosis, and treatment of injury or disease.
  • Stroke is a major cause of cerebral white matter and vascular damage, which induces long-term disability as a result of limited axonal regeneration (axon- regrowth or sprouting) and vascular remodeling (e.g., neovascularization and vascular stabilization) in the inhibitory environment of the adult mammalian central nervous system.
  • Axonal damage and degeneration are prominent components of acute neurological disorders such as stroke and other neurological conditions, diseases, or injuries.
  • Successful axonal outgrowth in the adult central nervous systems (“CNS”) is central to the process of nerve regeneration and brain repair.
  • DM diabetes mellitus
  • DM patients have a 3-4 fold higher risk of experiencing ischemic stroke.
  • DM adversely influences the post-stroke level of disability, increasing the extent of the cerebral injured area and promoting worse outcome compared to the general population.
  • Diabetes also induces neuroaxonal dystrophy, synaptic dysplasia and defective axonal regeneration. Restriction of axonal regeneration and neuro-plasticity contributes to the worse functional recovery after stroke.
  • neurodegenerative disease and/or to be suitable for use across patient populations in need of treatment.
  • Some embodiments provide methods, systems, and compositions for promoting, increasing, and/or improving white matter remodeling, neurite outgrowth, and/or neurological function in a patient in need thereof , including in mammals, and specifically in human beings. Some embodiments comprise the administration to the subject in need thereof of a composition comprising a pharmaceutically effective amount of one or more of a group comprising, or consisting of,
  • Angiopoietin-1 a promoter of Angiopoietin 1 expression
  • D-4F human umbilical cord blood cells
  • HUCBCs human umbilical cord blood cells
  • Niacin Niaspan a promoter of Angiopoietin 1 expression
  • D-4F human umbilical cord blood cells
  • HUCBCs human umbilical cord blood cells
  • Niacin Niaspan a promoter of Angiopoietin 1 expression
  • D-4F human umbilical cord blood cells
  • HUCBCs human umbilical cord blood cells
  • Niacin Niaspan GW3965
  • FIG. 1 is comprised of images and a data representation showing that
  • Angiopoietin 1 increases neurite outgrowth in cultured primary cortical neurons (“PCN”).
  • FIG. 2 is data representations showing that Angl treatment decreases
  • oligodendrocyte (“OL") death and increases OL differentiation
  • FIG. 3 is images showing that D-4F treatment increases Angl expression in
  • FIG. 4 is data representations and images showing that D-4F treatment of stroke promotes white matter ("WM”) remodeling and dose-dependently improves functional outcome in WT mice.
  • WM white matter
  • FIG. 5 is images showing that D-4F treatment of stroke significantly increases
  • FIG. 6 is data representations and images and graphs showing D-4F has a
  • FIG. 7 is images and data representations showing that HUCBC treatment of stroke in Type two diabetic (T2DM) rats improves functional outcome, and increases Angl and decreases "receptor of advanced glycation end- products""("RAGE") expression in the ischemic brain.
  • FIG. 8 is data representations showing that TlDM-MCAo rats have worse
  • FIG. 9 is images and data representation showing that TlDM-MCAo rats exhibit decreased axonal density in the ischemic brain compared to WT-MCAo rats.
  • FIG. 10 is images and data representations showing that Niaspan treatment of stroke in T1DM rats promotes axonal remodeling and synaptic plasticity.
  • FIG. 11 is images and data representations showing that Niacin increases Angl expression in cultured hypoxic PCN; Niacin and Angl increase neurite outgrowth under HG conditioned media; and inhibition of the Angl, but not Tie2-FC, decreased neurite outgrowth in cultured hypoxic PCN under HG conditions.
  • FIG. 12 is data representations showing that GW3965 treatment increases HDL-C levels and improves functional outcome in mice 14 days after MCAo.
  • FIG. 13 is images and data representations showing that GW3965 treatment increases Synaptophysin expression and axonal and myelin growth and decreases axon damage in the IBZ 14 days after MCAo.
  • FIG. 14 is images and data representations showing that GW3965 treatment increases angiogenesis, arteriogenesis, and vascular stabilization in the IBZ 14 days after MCAo.
  • FIG. 15 is images and data representations showing that GW3965 treatment increases Angl and Tie2 expression in the IBZ 14 days after MCAo.
  • FIG. 16 is images and data representations showing t GW3965 increases neurite outgrowth, capillary-like tube formation, and artery explant cell migration.
  • some embodiments comprise the administration to a mammalian subject in need thereof of a composition comprising a pharmaceutically effective amount of agent which provides or promotes Angiopoetin-1 activity and provides, increases, and/or improves white matter remodeling, neurite outgrowth, and/or neurological function in the subject.
  • agents may comprise, without limitation,
  • Angiopoietin-1 a promoter of Angiopoietin-1 expression
  • D-4F a promoter of Angiopoietin-1 expression
  • HUCBCs a promoter of Angiopoietin-1 expression
  • Niaspan/Niacin a promoter of Angiopoietin-1 expression
  • HUCBCs a promoter of Angiopoietin-1 expression
  • Niaspan/Niacin GW3965.
  • Angiopoietin-1 signaling activity promotes white matter remodeling and neurorestorative effects after stroke in subjects in need of treatment.
  • Angiopoietinl treatment promotes neurite outgrowth in cultured primary cortical neurons and increases oligodendrocyte differentiation in cultured premature oligodendrocytes.
  • Treatment of stroke with agents or cells that increase Angiopoietin-1 expression as nonlimiting examples, bone marrow stromal cells (BMSCs), human umbilical cord blood cells
  • HUCBCs D-4F (a reconstituted fragment of HDL, 18-amino acid peptide that mimics the tertiary structure of ApoA-I)(SEQ ID NO: 1 : Ac-D-W-F-K-A-F-Y-D- -V-A-E-K-F-K-E-A-F-NH2 (4F)),or Niaspan (prolonged released Niacin), and/or agents that increase HDL, including without limitation, GW3965 (synthetic liver x receptor agonist, elevates high density lipoprotein cholesterol), significantly promotes vascular and white matter remodeling and thereby improves functional outcome after stroke.
  • GW3965 synthetic liver x receptor agonist, elevates high density lipoprotein cholesterol
  • HUCBCs Treatment of stroke with restorative agents, as nonlimiting examples, HUCBCs, D-4F or Niaspan (prolonged released Niacin), all significantly increase Angiopoietinl expression and Angiopoietinl/Tie2 activity in the ischemic brain, promote vascular and white matter remodeling, and subsequently improve functional outcome after stroke.
  • restorative agents as nonlimiting examples, HUCBCs, D-4F or Niaspan (prolonged released Niacin)
  • Angiopoietin-1 mediates vascular remodeling, promotes pericyte recruitment, remodeling, maturation, and stabilization of blood vessels, and prevents plasma leakage in the ischemic brain.
  • Angiopoietin-1 has been shown to promote vascular integrity and angiogenesis anti-inflammatory effects, before our discovery, to our knowledge, a direct effect of Angiopoietin-1 on white matter structure and remodeling had not been demonstrated.
  • Angiopoietin-1 or agents which increase Angiopoietin-1, or which increase Angiopoietin-1 related signaling activity will likely promote white matter remodeling which improves neurological function after stroke, brain and spinal cord injury, neural injury, multiple sclerosis and neurodegenerative disease, including without limitation, Alzheimer's disease, vascular dementia, and peripheral neuropathies.
  • white matter remodeling is increased, thereby reducing neurological deficits after stroke, neural trauma, multiple sclerosis, Alzheimer's disease, vascular dementia, and peripheral neuropathies, and neurodegenerative disease.
  • Therapies are needed to remodel the brain which will enhance WM remodeling and recovery of neurological function after an injury, or in other neurological conditions or diseases.
  • Angiopoietin-1 promotes neurite outgrowth and oligodendrocyte differentiation indicate that Angiopoietin-1 or agents which increase Angiopoietin-1 expression and its activity promote white matter remodeling after stroke with or without diabetes, brain injury and neurodegenerative disease and thereby improve neurological function after treatment of these neurological diseases and injury.
  • Angiopoietin-1 and its activity will provide an effective therapy for these pervasive neurological insults.
  • Angiopoietin-1 Angiopoietin-1
  • Angiopoietin-1 mimetics, and agents which promote increase of Angiopoietin-1 are or will be restorative therapies which improve neurological function after stroke in the diabetes and non-diabetes population, neural injury and neurodegenerative disease.
  • Angiopoietin-1 increases neurite outgrowth and oligodendrocyte differentiation and decreases cell death and promotes white matter remodeling.
  • Angiopoietin-1 signaling activity may be administered to patients before or after the onset of injury or disease to reduce the neurological deficits associated with disease and possibly aging.
  • Angiopoietin-1 or any agent that increases Angiopoietin- 1 signaling activity, to improve neurological function.
  • these agents have the property of increasing axonal and white matter remodeling.
  • treatment of neurological disease with such agents is likely to improve neurological function in subjects in need of treatment.
  • Angiopoietin-1 or any agents which increase Angiopoietin-1 signaling activity promote neurological recovery after stroke, brain injury, multiple sclerosis, Alzheimer's disease, vascular dementia, peripheral neuropathies, and neurodegenerative disease.
  • Angiopoietin- 1 an endothelial growth factor, mediates vascular remodeling, promotes pericyte recruitment, remodeling, maturation, and stabilization of blood vessels, and prevents plasma leakage in the ischemic brain.
  • Angiopoietin- 1 has been shown to promote vascular integrity and angiogenesis anti-inflammatory effects, to our knowledge, before our discovery, a direct effect of Angiopoietin-1 on white matter structure and remodeling had not been demonstrated.
  • the Angiopoietin-1 signaling pathway not only regulates vascular remodeling but also promotes neurite outgrowth and oligodendrocyte differentiation.
  • Angiopoietin-1 may have a profound therapeutic neurorestorative effect on cerebral tissue.
  • Our data show that Angiopoietin-1 peptide treatment of primary cortical neurons in normal glucose and high glucose conditions after oxygen glucose deprivation significantly increased neurite outgrowth compared to non-treatment control.
  • Angiopoietin-1 treatment significantly increased differentiation of premature oligodendrocytes into mature oligodendrocytes and decreased cell death under OGD conditions.
  • FIG. 1 comprises images and a data representation showing these discoveries.
  • FIG. 1 shows Tujl immunostaining in control and Angl - treated PCN and quantitative data.
  • PCN were subjected to 2 hours ("h") of oxygen-glucose deprivation ("OGD") and cultured in high glucose (“HG", 37.5 mmol/1 glucose) conditions and were then treated with or without Angl (200ng/ml) for 24h.
  • HG oxygen-glucose deprivation
  • HG high glucose
  • HG high glucose
  • HG high glucose
  • HG high glucose
  • HG high glucose
  • HG high glucose
  • FIG. 2 is a data representation showing these discoveries, with FIG. 2A showing LDH assay, and FIG. 2B showing MBP real time PCR.
  • N20.1 an immortalized mouse premature oligodendrocyte cell line (N20.1) was used. Cultured premature OLs were subjected to 2h of OGD and then were treated with: 1) control; 2) Angl (200ng/ml) for 3 days in normal glucose (lOmmol/1 glucose); and 3) HG
  • FIG. 2A shows that HG significantly increases OL death measured by lactate dehydrogenase (LDH) compared to normal glucose condition, while Angl significantly decreases cell death in both normal and HG conditions.
  • LDH lactate dehydrogenase
  • Angl significantly decreases cell death in both normal and HG conditions.
  • premature-OL were subjected 2h of OGD and were then cultured in differentiation media and treated with: 1) control; or 2) Angl (200ng/ml) for 10 days in normal glucose condition.
  • Myelin basic protein (“MBP") is a mature OL marker.
  • FIG. 2B shows that Angl significantly increased MBP gene expression compared to non-treatment controls.
  • D-4F treatment increases Angl expression in cultured PCN and oligodendrocytes.
  • PCN and an immortalized mouse premature oligodendrocyte cell line (N20.1) were treated with D-4F (lOOng/ml) for 3 days.
  • Angl expression was measured by Western blot.
  • the data shown in FIG. 3 indicate that D-4F treatment increases Angl expression in cultured PCN and OL.
  • D-4F treatment of stroke promotes WM remodeling and dose-dependently improves functional outcome in WT mice.
  • FIGS. 4A-B shows that D-4F treatment of stroke dose-dependently improves functional outcome after stroke compared to WT-MCAo control, and the doses of 16mg/kg and
  • FIGS. 4C-E shows that D-4F (16mg/kg) treatment significantly increases LFB density in the ipsilateral striatal bundles compared to no-treatment control. The data indicate that D-4F dose-dependently improves functional outcome and promotes WM remodeling in the ischemic brain.
  • D-4F has a neurorestorative effect and promotes WM remodeling in WT mice.
  • dMCAo extraluminal distal MCAo
  • D-4F (16mg/kg, gavaged) starting 24h after dMCAo daily for 28 days.
  • the Food pellet reaching test was performed by an investigator blinded to the experimental groups.
  • FIG. 6A shows that D-4F treatment does not decrease lesion volume (D4F-group:10.1 ⁇ 2.5%;Control:l 1.5 ⁇ 2.3%) but significantly improves long term functional outcome at 21 and 28 days after dMCAo compared to non-treatment control.
  • FIGS. 6 B-D show that the positive area of BS in the CC was significantly increased in D-4F treated group compared to non-treatment control (p ⁇ 0.05).
  • BS Bielschowsky silver
  • IBZ ischemic border area
  • CC corpus callosum
  • T2DM tumor necrosis factor-derived neurotrophic factor
  • RAGE receptor of advanced glycation end-products
  • FIG. 7A shows that HUCBC treatment of stroke significantly improves functional outcome in T2DM rats compared to T2DM-MCAo controls (p ⁇ 0.05).
  • immunostaining and Western blot were performed.
  • FIG. 7B-C shows that HUCBC treatment significantly increases Angl and decreases RAGE expression in the ischemic border zone ("IBZ") compared to T2DM-MCAo control at 28 days after MCAo (p ⁇ 0.05), respectively.
  • Western blot shows that HUCBC treatment increases Angl and decreases RAGE level in the IBZ compared to DM-MCAo control.
  • Axonal damage and degeneration are prominent components of some acute neurological disorders, including but not limited to, stroke.
  • Successful axonal outgrowth in the adult central nervous system (“CNS”) is central to the process of nerve regeneration and brain repair.
  • Diabetes mellitus (“DM”) is a major health problem, and DM patients have a 3-4 fold higher risk of experiencing ischemic stroke.
  • DM adversely influences the post-stroke level of disability, increasing the extent of the cerebral injured area and promoting worse outcome compared to the general population. Diabetes also induces neuroaxonal dystrophy, synaptic dysplasia and defective axonal regeneration. Restriction of axonal regeneration and neuro-plasticity contributes to the worse functional recovery after stroke.
  • Angl a family of endothelial growth factors, promotes migration, sprouting, and survival of endothelial cells and mediates vascular remodeling.
  • Angl plays a role in the recruitment of vascular smooth muscle cells ("VSMCs") and pericytes during vascular maturation and the remodeling processes.
  • VSMCs vascular smooth muscle cells
  • pericytes pericytes
  • Angl overexpression of Angl in the brain not only increases vascularization but also alters neuronal dendrite configuration. Angl promotes neuronal differentiation in neural progenitor cells and neurite outgrowth in cultured dorsal root ganglion cells and in PC 12 cells. In addition, neuritogenesis, expression of the presynaptic protein synaptophysin as well of the postsynaptic protein PSD-95 correlates with Ang-1 levels in culture.
  • Niacin (nicotinic acid) is an effective medication in clinical use for increasing high density lipoprotein (“HDL”) cholesterol and is safely used in patients with diabetes. Niacin improves endothelial function, reduces inflammation, and has been used to improve endothelium-dependent vasodilatation in coronary heart disease patients.
  • HDL high density lipoprotein
  • T1DM type one diabetes rats
  • MCAo transient middle cerebral artery occlusion
  • Anterograde tracing using biotinylated dextran amine (BDA) injected into the contralateral motor cortex was performed to assess axonal sprouting in the ipsilateral motor cortex area. Functional outcome, SMI-31 (a pan-axonal microfilament marker), Bielschowsky silver and synaptophysin expression were measured.
  • SMI-31 a pan-axonal microfilament marker
  • Bielschowsky silver and synaptophysin expression were measured.
  • PCN primary cortical neuron
  • Niaspan treatment of stroke in TIDM-MCAo rats significantly improved functional outcome after stroke and increased SMI-31, Bielschowsky silver and synaptophysin expression in the ischemic brain compared to saline treated TIDM-MCAo rats (p ⁇ 0.05).
  • Niacin treatment of PCN significantly increased Angl expression under high glucose condition.
  • Niaspan treatment increased ischemic brain Angl expression and promoted axonal remodeling in the ischemic brain as well as improved functional outcome after stroke, wherein Angl may partially contribute to Niaspan-induced axonal remodeling after stroke in TIDM-rats.
  • Wild type (“WT”) non-diabetic Wistar rats and STZ-induced TIDM rats were anesthetized and transient (2 h) MCAo was induced by using a previously described method of intraluminal vascular occlusion. Briefly, rats were initially anesthetized with 3.5% isoflurane and maintained with 1.0 to 2.0% isoflurane in 70% N 2 0 and 30% 0 2 by a face mask. Rectal temperature was maintained at 37 °C throughout the surgical procedure by means of a feedback-regulated water heating system. A 4-0 nylon suture with its tip rounded by heating near a flame was inserted into the external carotid artery ("ECA”) through a small puncture. The length of nylon suture, determined according to the animal's weight, was gently advanced from the ECA into the lumen of the internal carotid artery ("ICA”) until the suture blocked the origin of the middle cerebral artery
  • Neurological function was graded on a scale of 0 to 18 (normal score 0; maximal deficit score 18.
  • mNSS is a composite of motor, sensory, reflex and balance tests
  • Blood glucose was measured at 24 h after MCAo and at 28 days prior to sacrifice by using test strips for glucose (Polymer Technology System, Inc. Indianapolis, IN 46268) according to the manufacturer's instructions. The data are presented as milligrams per deciliter.
  • BDA Biotinylated dextran amine
  • n-7/group for anterograde labeling of axons and terminals in the ipsilateral hemisphere.
  • rats were sacrificed 28 days after MCAo. Briefly, the animals were placed in a stereotaxic device, and a unilateral craniotomy was performed on the skull overlying the right cerebral cortex.
  • BDA solution 100 nL; a 10% solution dissolved in 0.1 mol/1 phosphate-buffered saline (PBS) (pH 7.4), molecular weight 10,000 mw; Molecular Probes, Eugene, OR
  • PBS phosphate-buffered saline
  • the brains were fixed by transcardial perfusion with saline, followed by perfusion and immersion in 4% paraformaldehyde before being embedded in paraffin.
  • a standard paraffin block was obtained from the center of the lesion (bregma -1 mm to +1 mm).
  • a series of 6 ⁇ thick sections were cut from the block. Every 10th coronal section for a total of 5 sections was used for immunohistochemical staining.
  • Antibody against synaptophysin (monoclonal antibody; dilution 1 :1000, Chemicon, Temecula, CA) and SMI-31 (a pan-axonal neurofilament marker), neurofilaments, phosphorylated monoclonal antibody, 1 : 1000, Covance, CA) was employed.
  • Bielschowsky silver immunostaining was used to demonstrate axons. Briefly, for Bielschowsky staining, slides were placed in 20% silver nitrate in the dark, then ammonium hydroxide was added, and were then treated with NaOH and sodium thiosulfate. Control experiments consisted of staining brain coronal tissue sections as outlined above, but non-immune serum was substituted for the primary antibody. The immunostaining analysis was performed by an investigator blinded to the experimental groups.
  • Bielschowsky silver, SMI-31 and synaptophysin expression quantification [0074] For quantitative measurements of Bielschowsky silver, SMI-31 and synaptophysin, five slides from each brain, with each slide containing 4 fields from striatum for Bielschowsky silver, and 8 fields from the ischemic border (1BZ, cortex and striatum) for SMI-31, synaptophysin were digitized under a 20 x objective (Olympus BX40) using a 3 -CCD color video camera (Sony DXC- 970MD) interfaced with an MCID image analysis system (Imaging Research, St. Catharines, Canada). Positive areas of immunoreactive cells were measured in the IBZ. Data were analyzed in a blinded manner.
  • Angl /SMI-31 double immunofluorescence staining
  • SMI-31 and Angl rabbit polyclonal lgG, 1 :2000, Abeam, Cambridge, MA, USA
  • FITC Calbiochem, Darmstadt, Germany
  • cyanine-5.18 CY5, Jackson Immunoresearch, West Grove, PA
  • Each coronal section was first incubated with the primary and anti-SMI-31 antibodies with Cy5, and was then followed by Angl antibody with FITC.
  • Control experiments consisted of staining brain coronal tissue sections as outlined above, but omitted the primary antibodies.
  • PCNs were obtained from pregnant 17 day Wistar rat embryos and cultured with Neuralbasal-A medium (GIBCO) containing 2% B27 medium-supplement (GIBCO). One hour of oxygen-glucose deprivation (“OGD”) was induced.
  • GID oxygen-glucose deprivation
  • HG high glucose
  • the OGD-PCN cultures were then divided into (n-6/group): 1) HG control (HG, 37.5 mmol/1 glucose); 2) HG+Niacin (1 mM); 3) HG+Angl (100 ng/ml, Chemicon, Temecula, CA); 4) HG+Niacin+anti-Angl antibody (1 ⁇ g/ml, Abeam, Cambridge, MA); 5) HG+Niacin+Tie2-FC (recombinant mouse Tie2/FC, 2 ⁇ , Chimera, R&D System, Cambridge, MA) for 3 days.
  • the PCN cultures were performed for TUJ1 immuno fluorescent staining using a monoclonal anti- TUJ1 antibody (1 : 1000, Covance, Princeton, NJ) with Cy3 for dendrite outgrowth measurement.
  • a monoclonal anti- TUJ1 antibody (1 : 1000, Covance, Princeton, NJ) with Cy3 for dendrite outgrowth measurement.
  • the fluorescent photomicrographs were captured at 20x magnification with a digital camera.
  • the total dendrites of 20 TUJ1 positive neurons were measured using MCID analysis system. The average length of neuronal dendrite outgrowth was presented.
  • Niaspan treatment in TlDM-MCAo rats does not alter blood glucose levels but increases HDL levels after stroke in TIDM rats. There were no significant differences in blood glucose levels between the two groups prior to treatment (TlDM-MCAo control: 367.2 ⁇ 43.6 mg/dl; TlDM-MCAo+Niaspan: 379.2 ⁇ 53.1 mg/dl) and after treatment at 28 days after MCAo (TlDM-MCAo control: 423.7 ⁇ 65.9 mg/dl; Tl DM-MCAo+Niaspan: 458.6 ⁇ 59.1 mg/dl). Niaspan treatment significantly increased HDL level (39.3 ⁇ 2.2 mg/dl) compared to TlDM-MCAo control (31.6 ⁇ 1.3 mg/dl, p ⁇ 0.05).
  • FIGS. 8A-B show that TlDM-MCAo rats exhibit significantly worse functional outcome until one month after MCAo compared to WT-MCAo rats (p ⁇ 0.05).
  • FIGS. 8A-B show that TlDM-MCAo rats exhibit significantly worse functional outcome until one month after MCAo compared to WT-MCAo rats (p ⁇ 0.05).
  • FIGS. 8A-B show that TlDM-MCAo rats exhibit significantly worse functional outcome until one month after MCAo compared to WT-MCAo rats (p ⁇ 0.05).
  • TlDM-MCAo rats have worse neurological outcome after stroke compared to WT-MCAo rats (p ⁇ 0.05). Niaspan treatment of stroke in T1DM rats significantly improves functional outcome after stroke.
  • FIG. 9A Low magnification of BDA injection in the contralateral cortex (brown color, right side) and labeled axon in the ipsilateral cortex (brown color, left side).
  • FIG. 9C Axons are labeled with BDA in the ipsilateral hemisphere in WT-MCAo, TIDM-MCAo and TlDM-MCAo+Niaspan treatment animals.
  • FIG. 9D Correlation analysis of neurological outcome and axonal density.
  • FIG. lOA-C show that T1DM rats exhibit significantly decreased SMI-31 expression in the striatum of the ischemic border zone (IBZ) compared to WT-MCAo control rats (p ⁇ 0.05).
  • TIDM-MCAo did not significantly decrease synaptophysin and Bielschowsky silver density compared to WT-MCAo rats (p>0.05).
  • Niaspan treatment significantly increased SMI-31 , Bielschowsky silver and synaptophysin expression in the ischemic hemisphere in TlDM-MCAo+Niaspan rats compared to non-treatment TIDM-MCAo control rats (p ⁇ 0.05).
  • Niaspan treatment of stroke in T1DM rats promotes axonal remodeling and synaptic plasticity.
  • FIG. 10A Bielschowsky silver (a marker for axons) immuno staining and quantitative data.
  • FIG. 10B SMI-31 (a pan-axonal neurofilament marker) immunostaining and quantitative data;
  • FIG. IOC is a marker for axons
  • Synaptophysin (a marker for presynaptic plasticity) immunostaining and quantitative data.
  • FIG. 10D Angl/SMI31 double immunostaining.
  • FIG. 1 1 A-B Angl immunostaining in cultured hypoxic PCN treated without (A) or with Niacin (B).
  • FIG. 1 1D-H Neurite outgrowth measured by TUJ1 immunostaining in cultured hypoxic PCN under HG condition control (D); HG+Angl (E); HG+Niacin (F); HG+Niacin+anti-Angl (G); HG+Niacin+Tie-2-FC (H) and neurite outgrowth quantitative data (I).
  • N 6/group.
  • Niaspan treatment of stroke in T1DM rats increased Angl expression, promoted axonal remodeling in the IBZ, and improved functional outcome after stroke.
  • High glucose (HG) decreased neurite outgrowth in PCN cultures.
  • Niaspan treatment increased Angl expression in the ischemic brain and in the cultured PCN.
  • Niacin and Angl significantly increased neurite outgrowth in PCN culture under HG condition. Inhibition of Angl , but not Tie2-FC, partially attenuated Niacin-induced PCN dendrite outgrowth. Therefore, Niacin-induced increase of Angl may partially contribute to axonal remodeling in T1DM rats after stroke.
  • axonal density is decreased in TIDM rats after stroke compared to WT-MCAo rats, while Niaspan treatment of stroke increases axonal density in TIDM-MCAo rats.
  • functional recovery following acute CNS injury in humans, such as stroke is exceptionally limited, leaving the affected individual with life-long neurological deficits.
  • Axonal remodeling is related with functional outcome after stroke. Enhancement of plasticity by induction of axonal density has been shown to compensate for formerly lost function in spinal cord injury, as well as in stroke models.
  • anterograde tracing with BDA injected into the right motor cortex was used to assess axonal sprouting in the contralateral motor cortex and ipsilateral rostral forelimb area.
  • TIDM-MCAo rats show decreased axonal density in the ipsilateral in TIDM-MCAo rats compared to WT-MCAo rats.
  • Niaspan treatment significantly attenuated the decreased axonal density in TIDM-MCAo rats.
  • Cortical neurons surviving in the peri-infarct motor cortex undergo axonal sprouting to restore connections between different cerebral areas after stroke, and spontaneous functional recovery after stroke maybe attributed to axonal remodeling in the corticospinal system. Therefore, the increased axonal remodeling of some embodiments may contribute to the Niaspan-induced functional outcome after stroke in TIDM-MCAo rats.
  • axonal remodeling is related to vascular protection/remodeling, such as decrease of BBB leakage and brain hemorrhage.
  • vascular protection/remodeling such as decrease of BBB leakage and brain hemorrhage.
  • Previous studies have found that axonal remodeling starts from 2 to 3 weeks after stroke and could be detected at 28 days after MCAo .
  • Our data also indicate that functional outcome after stroke is significantly correlated with axonal density in the ischemic brain at 28 days after MCAo. Thus, axonal remodeling may be needed for the maintenance of improved neurological benefit.
  • BDNF brain-derived neurotrophic factor
  • NGF nerve growth factor
  • Angl nerve growth factor
  • Niaspan significantly increases both BDNF/TrkB and Angl expression in WT-stroke rats.
  • Niaspan significantly increases Angl expression, but does not increase BDNF expression in the ischemic brain in diabetes stroke rats (data not shown).
  • the response to stroke and treatment differs between diabetic and wild-type stroke animals.
  • Angl is of interest because of its complementary and important role in angiogenesis and vascular maturation.
  • Angl not only promotes angiogenesis and vascular maturation, but is also a neurotrophic/neuritotrophic factor.
  • TIDM-MCAo rats exhibit decreased Angl expression as well as decreased axonal density compared to WT-MCAo rats.
  • Inhibition of Angl using an anti- Angl antibody in cultured PCN partially decreases Niacin-induced neurite outgrowth.
  • HG treatment in cultured PCN also decreases neurite outgrowth.
  • Angl treatment in cultured PCN in vitro attenuates the HG induced decrease of neurite outgrowth. Therefore decreased Angl expression in TIDM-MCAo rats may contribute to the increased axon damage.
  • Angl is an angiogenic factor and also promotes vascular stabilization and maturation.
  • Angl not only regulates vascular change but also directly promotes neurite outgrowth in cultured primary cortical neurons. Therefore, without limitation to any particular mechanism, Angl may couple the vascular and axon remodeling.
  • vascular remodeling includes angiogenesis, vascular stabilization and maturation. Increase of vascular stabilization and maturation will decrease BBB leakage and brain hemorrhagic transformation.
  • GW3965 a synthetic liver X receptor agonist, elevates high-density lipoprotein
  • HDL high-density lipoprotein
  • GW3965 treatment of stroke increases vascular remodeling, promotes synaptic protein expression and axonal growth in the ischemic brain, and improves functional outcome in mice.
  • Stroke is a major cause of cerebral white matter and vascular damage, which
  • vascular remodeling plays an important role in neurological functional recovery after stroke.
  • LXR Liver X receptor
  • HDL-C high- density lipoprotein cholesterol
  • Increasing HDL-C improves functional outcome after stroke.
  • Niacin an effective medication in current clinical use for increasing HDL-C, significantly increases blood HDL-C and improves functional outcome.
  • high doses of Niacin produce adverse side effects of skin flushing, stomach upset, and liver damage, and T0901317 concurrently increases total blood cholesterol and triglycerides and may induce severe liver damage.
  • GW3965 a synthetic LXRJ3 selective agonist, raises HDL-C but without inducing hepatic steatosis and hypertriglyceridemia in rodents.
  • Treatment stroke with GW3965 from early-onset (10 minutes to 2 hours) induces neuroprotection by antineuroinflammation and stabilizes the blood-brain barrier (BBB) integrity in the ischemic brain.
  • BBB blood-brain barrier
  • many neuroprotective treatments have failed in clinical trials because stroke patients are very rarely treated within minutes of stroke onset.
  • mice were subjected to transient middle cerebral artery occlusion and treated without or with different doses of GW3965 (5, 10, or 20 mg/kg) starting 24 hours after middle cerebral artery occlusion daily for 14 days.
  • Neurological functional tests, blood high-density lipoprotein cholesterol measurement, and immunostaining were performed.
  • Mouse brain endothelial cells, primary cultured artery explants, and primary cortical neurons cultures were also used in vitro.
  • GW3965 and high-density lipoprotein cholesterol also significantly increased capillary-like tube formation and artery explant cell migration as well as neurite outgrowth.
  • Angiopoietin-l/Tie2 signaling activity may play an important role in GW3965- induced brain plasticity and neurological recovery from stroke.
  • mice were subjected to 2.5 hours of right middle cerebral artery occlusion ("MCAo") by a filament method. Mice were gavaged starting 24 hours after MCAo with the following: (1) saline for vehicle control; (2) different doses of GW3965 (Sigma, 5, 10, or 20 mg/kg) daily for 14 days. All mice received bromodeoxyuridine (BrdU, 50 mg/kg, Sigma) intraperitoneal injections to label proliferating cells starting 24 hours after MCAo and daily for 14 days.
  • MCAo right middle cerebral artery occlusion
  • the blood level of HDL-C, total cholesterol (“T- CH”), and triglyceride, lesion volume calculation, immunostaining, Western blot, and real-time PCR (“RT-PCR”) were performed 14 days after MCAo. An additional 2 mice were euthanized 24 hours after MCAo to harvest artery explants for the cell migration assay.
  • mNSS Modified neurological severity score
  • the brains were fixed by transcardial perfusion with saline followed by 4%
  • the cerebral tissues were cut into 7 equally spaced (1 mm) coronal blocks.
  • a series of adjacent 6 ⁇ m-thick sections were cut from each block and stained with hematoxylin and eosin ("H&E") for the lesion volumes calculation, as known to the skilled artisan. Every 10th coronal section cut from the center of the lesion (bregma -1 mm to +1 mm) for a total 5 sections was used for immunohistochemical staining.
  • PCNs Primary cortical neurons
  • the ipsilateral common carotid arteries were surgically removed from mice 24 hours after MCAo.
  • the common carotid arteries were cut into 1 mm 3 and randomly divided into 5 groups as follows: (1) Nontreatment for control; (2) Angl 100 ng/ml; (3) HDL 80 (4) GW3965 1 ⁇ ; (5) GW3965 1 ⁇ + Anti-Angl 1 ⁇ g/ml.
  • RT-PCR [0121] The ipsilateral brain tissue and MBECs were harvested, total RNA was isolated, and quantitative PCR was performed. The following primers for RT-PCR were designed using Primer Express software (ABI).
  • GAPDH Fwd, AGA ACA TCA TCC CTG CAT CC (SEQ ID NO: 2); Rev: CAC ATT GGG GGT AGG AAC AC (SEQ ID NO: 3).
  • Angl Fwd, TAT TTT GTG ATT CTG GTG ATT (SEQ ID NO: 4) Rev, GTT TCG CTT TAT TTT TGT AATG (SEQ ID NO: 5).
  • Tie2 Fwd, CGG CCA GGT ACA TAG GAG GAA (SEQ ID NO: 6); Rev, TCA CAT CTC CGA ACA ATC AGC (SEQ ID NO: 7).
  • anti-Angl (1 :2,000, Abeam
  • anti-Synaptophysin (1 : 1000, Chemicon)
  • anti-p-actin (1 :2000; Santa Cruz).
  • FIG. 12A mNSS and left foot-fault test.
  • FIG. 12B HDL-C, triglyceride, and T-CH in blood.
  • HDL-C indicates high-density lipoprotein cholesterol; MCAo, middle cerebral artery occlusion; mNSS, modified neurological severity score; and T-CH, total cholesterol.
  • FIG. 12B shows that 10 mg/kg and 20 mg/kg GW3965-treatment of stroke
  • Synaptophysin a marker for presynaptic plasticity and synaptogenesis
  • FIG. 13 A Schematic map showing the IBZ and quantified regions.
  • FIG. 13B shows
  • FIG. 13C Bielschowsky silver and SMI31 immunostaining and quantitative data.
  • APP amyloid precursor protein
  • IBZ ischemic boundary zone
  • LFB Luxol Fast Blue
  • MCAo middle cerebral artery occlusion.
  • FIG. 14 A vWF-immuno staining and quantitative data.
  • FIG. 14B ccSMA-immunostaining and quantitative data.
  • FIG. 14C BrdU double-immunofluorescent staining with vWF and SMA and quantitative data.
  • FIG. 14D Occludin-immunofluorescent staining and quantitative data.
  • BrdU indicates bromodeoxyuridine; IBZ, ischemic boundary zone; MCAo, middle cerebral artery occlusion; SMA, smooth muscle actin; and vWF, von Willebrand factor.
  • FIG. 15A Angl-immunohistostaining and quantitative data.
  • FIG. 15A Angl-immunohistostaining and quantitative data.
  • FIG. 15B Tie2- immunofluorescent staining and quantitative data.
  • FIG. 15C Western blot showing Angl protein expression and quantitative data.
  • FIG. 16 shows that compared with nontreatment control, Angl and HDL and GW3965 treatment significantly increased the following: (1) the neurite outgrowth in the hypoxic PCNs; (2) the capillary-like tube formation in the cultured MBECs; and (3) the artery explant cell migration in the primary cultured arteries.
  • FIG. 16 GW3965 increases neurite outgrowth, capillary-like tube formation, and artery explant cell migration.
  • FIG. 16A TUJl-immunostaning in PCNs of 1 hour OGD and neurite outgrowth quantitative data.
  • FIG. 16B Capillary-like tube formation in MBECs and quantitative data.
  • FIG. 16C Angl and Tie2 gene expression in MBECs.
  • Ang indicates Angiopoietin
  • CCA common carotid arteries
  • HDL high- density lipoprotein
  • MBEC mouse brain endothelial cell
  • OGD oxygen and glucose deprivation
  • PCN primary cortical neurons.
  • HDL-C is related to stroke recovery. Low levels of HDL-C predict high mortality and rapidly progressive stroke; higher levels of HDL-C are associated with better cognitive recovery after stroke.
  • LXRs belong to the nuclear receptor superfamily that can regulate important lipid metabolic pathways.
  • GW3965 increased expression of the reverse cholesterol transporter ABCAl and increased the plasma concentrations of HDL-C. In our current work, we found that GW3965 treatment significantly increases blood HDL-C level and improves functional outcome after stroke, and the increased HDL-C is significantly correlated with functional outcome. Therefore, increasing HDL-C by GW3965 treatment may contribute to functional outcome.
  • stroke-induced white matter injury may help explain the failure of neuroprotective drugs in clinical trials for stroke because these drugs were rarely characterized for their ability to protect white matter.
  • Cellular cholesterol modulates axon and dendrite outgrowth and neuronal polarization under culture conditions.
  • LXRs are essential for maintenance of motor neurons in the spinal cord and dopaminergic neurons in the substantia nigra.
  • LXRP regulates the formation of superficial cortical layers and migration of later-born neurons.
  • LXR knockout mice exhibit excessive lipid deposits, proliferation of astrocytes, loss of neurons and their dendrites, and disorganized myelin sheaths.
  • LXR activators induce neuronal differentiation in rat
  • GW3965 treatment of stroke significantly decreased APP expression in the ischemic brain.
  • APP is a transmembrane glycoprotein that is widely expressed in mammalian tissues and is transported through axons.
  • Axonal damage evokes a disturbance of fast axonal transport, can occur even in the early stage of white matter lesions, and cannot transport APP. Therefore, the decrease of APP expression by GW3965 treatment of stroke may reflect the decreased axonal damage in the ischemic brain.
  • Axonal plasticity parallels functional recovery after cortical injury, including stroke.
  • Angiogenesis involves the capillary sprouting, branching, splitting, and differential growth of vessels in the primary plexus to form the mature vascular system.
  • Brain capillary ECs representing a physiological barrier to the central nervous system, express apolipoprotein A-I, the major HDL-C, and promote cellular cholesterol mobilization.
  • HDL-C decreases platelet aggregation and inhibits EC apoptosis.
  • HDL-C also enhances EC migration and angiogenesis. Intravenous injection of reconstituted HDL stimulates differentiation of endothelial progenitor cells and enhances ischemia-induced angiogenesis. Arteriogenesis during
  • neovascularization supporting cells such as pericytes and SMCs are recruited to the vessels to provide structural support and stability for the vascular walls.
  • LXR knockout mice exhibit enlarged brain blood vessels with weak staining of aSMA and excessive lipid accumulation around the abnormal vessels, which lose their contractile ability and are susceptible to rupture.
  • GW3965 treatment of stroke induces angiogenesis and arteriogenesis identified by increasing EC/SMC proliferation and vascular density/perimeter/diameter in vessels in the ischemic brain.
  • GW3965 also increases MBEC capillary-like tube formation and artery cell migration in vitro.
  • GW3965 treatment-induced angiogenesis/arteriogenesis may contribute to the functional outcome after stroke.
  • Angl also promotes synaptic plasticity and axon remodeling. Angl stimulates neuronal differentiation and supports neurite outgrowth and synaptogenesis in neuronal progenitor cells, sensory neurons, and PC 12 cells, and Niacin increases Angl gene and protein expression after stroke.
  • GW3965 treatment increases Angl/Tie2 protein expression in the ischemic brain and Angl/Tie2 mRNA expression in cultured MBECs.
  • Angl also promotes GW3965-induced capillary-like tube formation, artery explant cell migration, and neurite outgrowth in vitro, which in concert indicate that the Angl/Tie2 pathway mediates GW3965-induced brain plasticity after stroke.
  • GW3965 has neurorestorative benefits in stroke treatment.
  • GW3965 treatment starting 1 day after stroke did not decrease lesion volume but did increase synaptic protein expression, axonal growth, and vascular remodeling in the ischemic brain as well as improves functional outcome.
  • Increasing HDL and upregulation of Angl/Tie2 activity appears to contribute to the GW3965-induced brain plasticity after stroke.
  • some embodiments provide methods, systems, and compositions which provide, increase, or promote Angl or Angl signaling activity and provide, , increase, or improve white model remodeling, neurite outgrowth, and/or
  • Some embodiments comprise administration of a composition comprising a pharmaceutically effective amount of one or more of Angl, a promoter of Angl expression, D-4F, HUCBCs, Niacin/Niaspan, and GW3965 (the above referred to convenience only as “Angl- related composition(s)” or “Angl -related composition administration”) to prevent, control, or alleviate neurological conditions, disease, or injuries in subjects needing such treatment.
  • Angl- related composition(s) or “Angl -related composition administration”
  • one may inhibit such illness or injury through Angl -related composition administration for a finite interval of time, thereby limiting the development or course of such condition, disease or injury.
  • Prophylactic Angl -related composition administration of some embodiments may greatly reduce the incidence of damage associated with some forms of illness or injury.
  • Any appropriate routes of Angl -related composition administration known to those of ordinary skill in the art may comprise some embodiments.
  • Angl -related compositions of some embodiments would be administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, patient age, sex, body weight and other factors known to medical practitioners.
  • experience with dose levels in animals is known and dose levels acceptable for safe human use are determinable or scalable in accordance with such information and/or good medical practice.
  • the "pharmaceutically effective amount" for purposes herein is thus determined by such considerations as are known in the art. The amount must be effective to achieve improvement, including but not limited to, decrease in damage or injury, or improvement or elimination of symptoms and other indicators as are selected as appropriate measures by those skilled in the art.
  • Angl-related compositions can be
  • Angl-related compositions can be administered orally, subcutaneously or parenterally including intravenous, intraarterial, intramuscular, intraperitoneal, and intranasal administration as well as intrathecal and infusion techniques, or by local administration or direct inoculation to the site of disease or pathological condition. Implants of the Angl-related compositions may also be useful.
  • the patient being treated is a warm-blooded animal and, in particular, mammals including humans.
  • the pharmaceutically acceptable carriers, diluents, adjuvants and vehicles as well as implant carriers generally refer to inert, non-toxic solid or liquid fillers, diluents or encapsulating material not reacting with the active components of some embodiments.
  • Angl- related compositions may be altered by use of antibodies to cell surface proteins or ligands of known receptors to specifically target tissues of interest.
  • Angl -related composition administration in accordance with some embodiments specifically targets the evolution, expression, or course of associated conditions or pathologies, it is expected that the timing and duration of treatment in humans may approximate those established for animal models in some cases. Similarly, the doses established for achieving desired effects using such compounds in animal models, or for other clinical applications, might be expected to be applicable in this context as well. It is noted that humans are treated generally longer than the experimental animals exemplified herein which treatment has a length proportional to the length of the disease process and drug effectiveness. The doses may be single doses or multiple doses over periods of time. The treatment generally has a length proportional to the length of the disease process and drug effectiveness and the patient species being treated.
  • the pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • the carrier can be a solvent or dispersing medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • Nonaqueous vehicles such as cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, may also be used as solvent systems for such Angl -related composition compositions.
  • various additives which enhance the stability, sterility, and isotonicity of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added.
  • antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example, sugars, sodium chloride, and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. According to some embodiments, however, any vehicle, diluent, or additive used would have to be compatible with the Angl -related compositions.
  • Sterile injectable solutions can be prepared by incorporating Angl -related
  • a pharmacological formulation of some embodiments may be administered to the patient in an injectable formulation containing any compatible carrier, such as various vehicle, adjuvants, additives, and diluents; or the inhibitor(s) utilized in some embodiments may be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres. Many other such implants, delivery systems, and modules are well known to those skilled in the art.
  • the Angl -related compositions may be administered initially by intravenous injection to bring blood levels to a suitable level.
  • the patient's levels are then maintained by an oral dosage form, although other forms of administration, dependent upon the patient's condition and as indicated above, can be used.
  • the quantity to be administered and timing of administration may vary for the patient being treated.
  • compositions may be administered in situ to bring internal levels to a suitable level.
  • the patient's levels are then maintained as appropriate in accordance with good medical practice by appropriate forms of administration, dependent upon the patient's condition .
  • the quantity to be administered and timing of administration may vary for the patient being treated.
  • D-4F generally described as:

Abstract

Certains modes de réalisation de l'invention comprennent des procédés, des systèmes et des compositions pour promouvoir, améliorer et/ou augmenter la re-modélisation de la matière blanche, la croissance de neurite ou la fonction neurologique chez un patient en ayant besoin. Certains modes de réalisation comprennent également l'administration d'une composition comprenant une quantité pharmaceutiquement efficace d'un ou plusieurs éléments d'un groupe comprenant l'Angiopoïétine-1, un promoteur de l'expression d'Angiopoïétine-1, D-4F, HUCBC, Niaspan et GW3965 pour traiter des états, une maladie ou une lésion neurologique(s) chez des mammifères, notamment chez des êtres humains.
PCT/US2014/010755 2013-01-08 2014-01-08 Procédés, systèmes et compositions associés au traitement d'états, d'une maladie ou de lésions neurologiques WO2014110185A1 (fr)

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US20120014921A1 (en) * 2003-06-27 2012-01-19 Advanced Technologies And Regenerative Medicine, Llc Treatment of stroke and other acute neural degenerative disorders via intranasal administration of umbilical cord-derived cells
US20120201787A1 (en) * 2010-12-17 2012-08-09 Abbot Stewart Treatment of spinal cord injury and traumatic brain injury using amnion derived adherent cells

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US20050003998A1 (en) * 2002-08-15 2005-01-06 Goran Bertilsson Therapeutic use of selective LXR modulators
US20120014921A1 (en) * 2003-06-27 2012-01-19 Advanced Technologies And Regenerative Medicine, Llc Treatment of stroke and other acute neural degenerative disorders via intranasal administration of umbilical cord-derived cells
US20120201787A1 (en) * 2010-12-17 2012-08-09 Abbot Stewart Treatment of spinal cord injury and traumatic brain injury using amnion derived adherent cells

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