CN110917194A - Application of rapamycin thiazole derivatives in preparation of anti-Alzheimer's disease drugs - Google Patents
Application of rapamycin thiazole derivatives in preparation of anti-Alzheimer's disease drugs Download PDFInfo
- Publication number
- CN110917194A CN110917194A CN201911082598.2A CN201911082598A CN110917194A CN 110917194 A CN110917194 A CN 110917194A CN 201911082598 A CN201911082598 A CN 201911082598A CN 110917194 A CN110917194 A CN 110917194A
- Authority
- CN
- China
- Prior art keywords
- rapamycin
- fim
- alzheimer
- thiazole derivative
- atoms
- 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
Links
Images
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
- A61K31/435—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
- A61K31/436—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 containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
The invention discloses application of rapamycin thiazole derivatives in preparing anti-Alzheimer disease drugs, and particularly relates to application of a series of rapamycin thiazole derivatives shown in a structural formula (II) in clearing β amyloid and preparing anti-Alzheimer disease drugs, wherein the rapamycin thiazole derivatives have the effect of clearing β amyloid by promoting autophagy of cells, can improve cognitive abilities of dementia mice such as memory, space exploration and the like, and also have the advantages of low cytotoxicity, low immunosuppressive activity and the like, and have wide market application prospect when being applied to preparation of anti-Alzheimer disease drugs.
Description
Technical Field
The invention belongs to the field of medicine research, and particularly relates to application of rapamycin thiazole derivatives in preparation of anti-Alzheimer's disease medicines.
Background
Alzheimer's Disease (AD) is a progressive and fatal neurodegenerative disease, and has the pathological characteristics of extracellular senile plaques formed by β amyloid deposition, nerve fiber tangles formed by Tau hyperphosphorylation, neuron loss with glia cell proliferation and the like, so that no effective therapeutic drug exists at present.
The research shows that the antifungal antibiotic rapamycin (rapamycin, also called sirolimus and sirolimus) can reduce the level and aggregation of β amyloid in the brain of AD mice and improve the cognitive function of mice by inhibiting the activity of mTOR, so that although rapamycin has obvious effect on improving the cognition of mice, rapamycin itself has strong immunosuppressive activity and certain cytotoxicity, a series of adverse reactions can be caused, and thus, a new rapamycin derivative with lower cytotoxicity and immunosuppressive activity than rapamycin is found to have wide application prospect in treating Alzheimer's disease.
Disclosure of Invention
It is an object of the present invention to provide a novel rapamycin derivative having lower cytotoxic and immunosuppressive activity than rapamycin, for use in the treatment of alzheimer's disease.
The invention discovers for the first time that the rapamycin thiazole derivative has the functions of reducing β amyloid and improving the cognitive ability of mice, so the rapamycin thiazole derivative can be used as a raw material source for preparing the anti-Alzheimer disease medicament.
Therefore, the first object of the present invention is to provide the use of rapamycin thiazole derivatives in preparing anti-alzheimer drugs, wherein the structure of the rapamycin thiazole derivatives is shown as the formula (II):
wherein the content of the first and second substances,
x is a single bond or-O (CH)2) n-, wherein n is 2, 3 or 4;
R1is hydrogen, alkyl with 1-10C atoms, cycloalkyl with 3-7C atoms, alkenyl with 2-10C atoms or alkynyl with 2-10C atoms;
R2is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, carboxyl, nitro, cyano, alkyl, alkoxy, N-alkylamino, N-dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxymethyl, alkoxyethyl, alkanoyl, carbamoyl, N-alkylcarbamoyl, N-dialkylcarbamoyl, aminosulfonyl, N-alkylaminosulfonyl, N-dialkylaminosulfonyl or alkylenedioxy having 1 to 3 carbon atoms, wherein the number of carbon atoms of the alkyl group is 1 to 4 and the number of carbon atoms of the alkoxy group is 1 to 4.
The invention also provides an anti-Alzheimer disease drug, which is characterized by comprising an effective amount of rapamycin thiazole derivatives or medicinal salts thereof and a pharmaceutically acceptable carrier.
More preferably:
the invention also provides application of the rapamycin thiazole derivative FIM-X7 in preparing the medicine for resisting Alzheimer's disease, wherein the structure of the rapamycin thiazole derivative FIM-X7 is shown as the formula (I):
the invention also provides the effect of the rapamycin thiazole derivative FIM-X7 shown in the formula (I) in clearing β amyloid activity, and the cytotoxicity and immunosuppressive activity of the compound are tested through apoptosis and half inhibitory concentration IC50, and the result shows that the compound shown in the formula (I) has the characteristics of low cytotoxicity and low immunosuppressive activity compared with rapamycin, and the adverse reaction of a medicament can be obviously reduced.
The invention also provides the function of the rapamycin thiazole derivative FIM-X7 shown in the formula (I) in improving the memory and space exploration cognitive ability of dementia mice.
The invention also provides an anti-Alzheimer disease drug which is characterized by comprising an effective amount of rapamycin thiazole derivative FIM-X7 shown in the formula (I) or medicinal salt thereof and a pharmaceutically acceptable carrier.
Through a mode of combining a cell model and an animal model, the action of β amyloid protein of the rapamycin thiazole derivative FIM-X7 shown in the formula (I) is studied in detail, the improvement of the cognitive ability of mice by the rapamycin thiazole derivative FIM-X7 shown in the formula (I) is verified, and the result shows that the rapamycin thiazole derivative represented by the formula (I) has the action of β amyloid protein removal and the compounds can improve the cognitive ability of the dementia mice such as memory, space exploration and the like, and compared with rapamycin, the rapamycin thiazole derivative FIM-X7 inhibits N2The activity of a-APP695 cell expression A β is equivalent to that of rapamycin, but the a-APP695 cell expression A β has the advantages of lower cytotoxicity, lower immunosuppressive activity and the like, so that the a-APP695 cell expression A β can be applied to preparation of anti-Alzheimer disease drugs and has wide market application prospects.
Rapamycin thiazole derivatives represented by FIM-X7 disclosed in the patent numbers: CN2013107376567, invented name: in Chinese patents of thiazolyl-containing rapamycin derivatives and applications thereof, the thiazolyl-containing rapamycin derivatives can be obtained according to the methods disclosed by the Chinese patents, and can also be obtained by commercial purchase.
Drawings
Figure 1 is a β (P <0.01, P >0.05) that FIM-X7 and rapamycin reduced expression by N2a-APP695 cells.
FIG. 2 is the FIM-X7 and rapamycin vs. N2Comparison of the cell proliferation inhibitory Effect of a-APP695 (P)<0.01)。
FIG. 3 is FIM-X7 with rapamycin induced N2Comparison of apoptotic Effect of a-APP695 cells (. about.P)>0.05，**P<0.01)。
FIG. 4 is a comparison of the inhibitory activity of FIM-X7 on lymphocyte transformation with rapamycin (P < 0.01).
Figure 5 is a comparison of the number of times mice cross the platform, note: compared with the NC group, the method has the advantages that,**P<0.01。
Detailed Description
The following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1: rapamycin thiazole derivative FIM-X7 (hereinafter referred to as FIM-X7) reduces N2a-APP695 cell expresses β amyloid protein
1 materials and principal reagents
Mouse neuroblastoma N stably expressing mutant APP6952a cells (N)2a-APP695) provided by the institute for neurology, medical school of Xiamen university; rapamycin (purity)>99%) produced by Fujiacorii pharmaceutical Co., Ltd, the rapamycin thiazole derivative FIM-X7 (purity)>95%) is synthesized by mTOR inhibitor research institute of microbiological research institute of inventor's Fujian province in laboratories, and has a structure shown in formula (I),
DMSO was purchased from national drug products, Inc.; g418 was purchased from Ameresco; rabbit anti-mTOR, P-mTOR, 4EBP, P-4EBP, APP, P62, LC3B, P-ULK1(757), P70S6K1, P-P70S6K1, and GAPDH were purchased from CST; rabbit anti-IDE and NEP were purchased from Abcam; HRP-labeled goat anti-rabbit IgG secondary antibody was purchased from Bioworld Technology; PVDF membrane and ECL luminescence reagent were purchased from Bio-red; DMEM medium, fetal bovine serum, double antibody, PBS and pancreatin were purchased from Hyclone; OPTI-MEM medium was purchased from Gibco; the Annexin V-FITC/PI double-staining apoptosis detection kit is purchased from Kaikyi biotechnology limited, the BCA protein quantification kit is purchased from Biyuntian biotechnology limited, and the ELISA kit is purchased from Thermifish.
2 method of experiment
2.1 ELISA to determine the Effect of FIM-X7 on the production of β amyloid protein by cells
Subculturing N2a-APP695 cells [ cell culture medium formula: DMEM OPTI-MEM (1:1), 10% FBS, 100. mu.g/ml streptomycin sulfate, 100IU/ml penicillin, and 200. mu.g/ml G418 (geneticin) was prepared by mixing DMEM medium and OPTI-MEM at a volume ratio of 1:1, and then adding FBS, streptomycin sulfate, penicillin, and G418 to give final concentrations: volume fraction 10% FBS, 100. mu.g/ml streptomycin sulfate, 100IU/ml penicillin, 200. mu.g/ml G418]Inoculating cells in a logarithmic growth phase to a 6-well cell culture plate, culturing for 24h at 1 ml/well, adding FIM-X7 DMSO solution and rapamycin DMSO solution diluted by a cell culture medium respectively (namely dissolving FIM-X7 and rapamycin by DMSO respectively and then diluting by the cell culture medium), setting blank control, setting 3 times of repeated tests for each treatment, continuing culturing for 24h, and detecting the contents of A β 40 and A β 42 in a cell culture solution according to an ELISA kit operation method.
2.2 Effect of FIM-X7 on cell proliferation and apoptosis
2.2.1 MTT assay to determine the Effect of FIM-X7 on cell proliferation
N to be in logarithmic growth phase2A-APP695 cells were seeded in 96-well cell culture plates at 100. mu.l/well, 37 ℃, 5% CO2Culturing for 24h, adding FIM-X7 DMSO solution and rapamycin DMSO solution diluted with cell culture medium, setting blank control, setting 3 duplicate wells for each concentration, setting 3 duplicate experiments for each treatment, and continuing culturing for 48 h. Mu.l of MTT (5mg/ml) was added thereto, and the culture was continued for 4 hours, and the OD value was measured at a wavelength of 570 nm. Cell proliferation inhibition (%) of 1- (OD)Test set/ODBlank pairPhoto group) X 100%, calculating IC of test compound on cells50。
2.2.2 flow cytometry to examine the Effect of FIM-X7 on apoptosis
Cell culture and drug treatment are shown in 2.1, cells are treated according to the annexin V-FITC/PI apoptosis kit operation specification, and the apoptosis condition of the cells is detected by a flow cytometer.
2.3 determination of the immunosuppressive Activity of FIM-X7 in the lymphocyte transformation assay (LTT)
Aseptically placing Balb/c mouse spleen in PBS, sieving with 100 mesh sieve, thoroughly blowing, preparing cell suspension, centrifuging at 1500rpm for 5 min, washing spleen lymphocyte with PBS and 1640 complete culture solution for 1 time, and adjusting cell concentration to 1 × 10 with 1640 complete culture solution7One per ml. After the sample to be tested was dissolved in absolute ethanol, the solution was diluted to the desired concentration with 1640 complete culture medium, 50. mu.l of the solution was added to a 96-well cell culture plate, 100. mu.l of each mouse spleen lymphocyte suspension was added, and 50. mu.l of ConA (20. mu.g/ml) was added thereto. Blank control and ConA control were set. After loading, 96-well cell culture plates were incubated at 37 ℃ in 5% CO2The incubator was incubated for 72 hours. 3 replicate wells were set for each concentration and 3 replicate experiments were set for each treatment. 20 μ l of MTT (5mg/ml) was added to each well 4 hours before the termination of the incubation, the incubation was continued for 4 hours, the supernatant was discarded, 150 μ l of dimethyl sulfoxide (DMSO) was added to each well, the light absorption value (OD570) of the sample was measured by a microplate reader, and the inhibition rate I and IC50 of the sample on lymphocyte reaction were calculated:
3 statistical treatment
Data were analyzed using SPSS20 software, single factor analysis of variance was used for the comparisons between groups, a t-test was used for the comparisons between groups, and P <0.05 indicated that the differences were statistically significant.
4 results and discussion
4.1 FIM-X7 inhibits N2a-APP695 cell expresses β amyloid protein
ELISA detection showed (FIG. 1) 10. mu. mol/L F compared to the drug-free blank controlBoth IM-X7 and 10. mu. mol/L rapamycin had N reduction2The effects of A β 40 and A β 42 expressed by a-APP695 cells, the difference being statistically significant (P)<0.01); FIM-X7 inhibits N2The activity of a-APP695 cells expressing A β is equivalent to that of rapamycin, and the difference between the two groups has no statistical significance (P)>0.05)。
4.2 cytotoxic Effect of FIM-X7
To N2The results of the proliferation inhibition assay of a-APP695 cells (FIG. 2) showed that FIM-X7 at a concentration of 50. mu. mol/L was directed against N2The inhibition rate of a-APP695 cell proliferation is only 10%, while rapamycin has N2IC of a-APP695 cells50Is (35 +/-5) mu mol/L; the difference between the two inhibition of cell proliferation is statistically significant (P)<0.01). As can be seen, FIM-X7 is for N2The inhibition activity of a-APP695 cell proliferation is far lower than rapamycin.
FIM-X7 hardly induces N2apoptosis of a-APP695 cells, N induced at 30. mu. mol/L2The difference between the apoptosis number of a-APP695 cells and that of a blank control group has no statistical significance (P)>0.05), significantly less than the same concentration of rapamycin-induced N2a-APP695 apoptosis number (P)<0.01) (fig. 3).
4.3 the lymphocyte transformation inhibitory activity of FIM-X7 was lower than that of rapamycin
The level of in vitro immunosuppression of FIM-X7 was determined using the mouse splenic lymphocyte transformation assay (LTT). The results show (FIG. 4), IC of FIM-X7 on splenic lymphocyte transformation50Is (1.36 +/-0.32) multiplied by 10-6mol/L, the inhibitory activity of lymphocyte transformation is 1/5000 of rapamycin, and the difference is statistically significant (P)<0.01), indicating that FIM-X7 has much lower immunosuppressive activity in vitro than rapamycin.
Example 2: rapamycin thiazole derivative FIM-X7 improves cognitive dysfunction of 5 xFAD mice
1. Animals and reagents
Experimental animals: 5-month-old 5 × FAD mice were provided with littermate C57/BL6, university of Fujian medical laboratory animal center. Reagent: FIM-X7 (purity > 95%) was synthesized by the mTOR inhibitor institute of microbiology, Fujian province; DMSO was purchased from national drug products, Inc.; tween-80 was purchased from Sigma.
2. Animal grouping and administration
The mice are subjected to intraperitoneal injection administration intervention, wherein the administration is performed 1 time every other day for 8 weeks, and the mice are 7 months old after the administration is finished.
NC group: 5-month-old SPF grade littermate C57/BL6 mice, 10 (5 males, 5 females).
Group AD: 5-month-old SPF grade 5 × FAD transgenic mice, 10 (5 males, 5 females).
Rapamycin group: SPF grade 5 x FAD mice, 6 (2 males, 4 females) at 5 months of age. Rapamycin was injected intraperitoneally at a dose of 2.24mg/kg once every other day for 8 weeks.
Low dose FIM-X7 group: SPF grade 5 x FAD mice, 7 (2 males, 5 females) at 5 months of age. The rapamycin derivative FIM-X7 was intraperitoneally administered at a dose of 2.24mg/kg once every other day for 8 weeks.
Medium dose FIM-X7 group: SPF grade 5 x FAD mice, 7 (2 males, 5 females) at 5 months of age. The rapamycin derivative FIM-X7 was intraperitoneally administered at a dose of 5mg/kg once every other day for 8 weeks.
High dose FIM-X7 group: SPF grade 5 x FAD mice, 7 (2 males, 5 females) at 5 months of age. The rapamycin derivative FIM-X7 was injected intraperitoneally at a dose of 10mg/kg once every other day for 8 weeks.
During the administration period, a normal diet was given.
3. Results of the experiment
Compared with the NC group, the escape latency of the AD group mice is obviously prolonged (P <0.01, table 1), the platform crossing frequency is obviously reduced (P <0.01, table 2), and the learning and memory abilities of the AD group mice are proved to be impaired.
The low dose FIM-X7 group and the medium dose FIM-X7 group have shorter escape latency and increased number of platform crossing times compared with the AD group (FIG. 5), which indicates that the drugs in the two dose groups can improve the learning and memory ability of the mice to some extent. Whereas the low dose FIM-X7 group had a closer overall trend towards escape latency to the NC group, more platform crossing times and less dispersion of samples within the group than the medium dose FIM-X7 group (fig. 5); compared with the AD group, the high-dose FIM-X7 group has no reduction in escape latency, and the number of times of platform crossing is increased, but no significant difference exists between the two groups.
TABLE 1 mouse escape latency comparison (mean. + -. standard error)
TABLE 2 comparison of mouse passage through the platform times (mean. + -. standard error)
Note: compared with the NC group, the method has the advantages that,*P<0.01，**P<0.05
in the experiment, the rapamycin thiazole derivative FIM-X7 is given at the doses of 2.24mg/kg and 5mg/kg, so that the escape latency of AD group mice can be shortened to different degrees, and the platform crossing times are increased, wherein the effect of the dose of 2.24mg/kg is more obvious. Therefore, the rapamycin derivative FIM-X7 can improve the spatial learning and memory ability of 5-month-old 5 XFAD mice, possibly has the effect of improving AD, and has better intervention effect at the dose of 2.24 mg/kg.
Claims (4)
1. The rapamycin thiazole derivative has the structure shown in the formula (II):
wherein the content of the first and second substances,
x is a single bond or-O (CH)2) n-, wherein n is 2, 3 or 4;
R1is hydrogen, alkyl with 1-10C atoms, cycloalkyl with 3-7C atoms, alkenyl with 2-10C atoms or alkynyl with 2-10C atoms;
R2is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, carboxyl, nitro, cyano, alkyl, alkaneOxy, N-alkylamino, N-dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxymethyl, alkoxyethyl, alkanoyl, carbamoyl, N-alkylcarbamoyl, N-dialkylcarbamoyl, aminosulfonyl, N-alkylaminosulfonyl, N-dialkylaminosulfonyl or alkylenedioxy having 1 to 3 carbon atoms, wherein the number of carbon atoms in the alkyl group is 1 to 4 and the number of carbon atoms in the alkoxy group is 1 to 4.
2. The use according to claim 1, wherein the rapamycin thiazole derivative FIM-X7 is used for preparing the anti-Alzheimer's disease medicament, and the structure of the rapamycin thiazole derivative FIM-X7 is shown as the formula (I):
3. an anti-alzheimer's disease drug comprising an effective amount of the rapamycin thiazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4. The anti-alzheimer's disease drug according to claim 3, comprising an effective amount of rapamycin thiazole derivative FIM-X7 or a pharmaceutically acceptable salt thereof according to claim 2, and a pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911082598.2A CN110917194A (en) | 2019-11-07 | 2019-11-07 | Application of rapamycin thiazole derivatives in preparation of anti-Alzheimer's disease drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911082598.2A CN110917194A (en) | 2019-11-07 | 2019-11-07 | Application of rapamycin thiazole derivatives in preparation of anti-Alzheimer's disease drugs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110917194A true CN110917194A (en) | 2020-03-27 |
Family
ID=69852543
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911082598.2A Pending CN110917194A (en) | 2019-11-07 | 2019-11-07 | Application of rapamycin thiazole derivatives in preparation of anti-Alzheimer's disease drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110917194A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040010002A1 (en) * | 2000-01-14 | 2004-01-15 | The Trustees Of The University Of Pennsylvania | O-methylated rapamycin derivatives for alleviation and inhibition of lymphoproliferative disorders |
| CN103739616A (en) * | 2013-12-27 | 2014-04-23 | 福建省微生物研究所 | Thiazolyl-containing rapamycin type derivative and application thereof |
| US20170253606A1 (en) * | 2014-06-03 | 2017-09-07 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | A Rapamycin Derivative, and a Preparation Method, Pharmaceutical Composition and Use Thereof |
-
2019
- 2019-11-07 CN CN201911082598.2A patent/CN110917194A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040010002A1 (en) * | 2000-01-14 | 2004-01-15 | The Trustees Of The University Of Pennsylvania | O-methylated rapamycin derivatives for alleviation and inhibition of lymphoproliferative disorders |
| CN103739616A (en) * | 2013-12-27 | 2014-04-23 | 福建省微生物研究所 | Thiazolyl-containing rapamycin type derivative and application thereof |
| US20170253606A1 (en) * | 2014-06-03 | 2017-09-07 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | A Rapamycin Derivative, and a Preparation Method, Pharmaceutical Composition and Use Thereof |
Non-Patent Citations (2)
| Title |
|---|
| ANTONELLA TRAMUTOLA等: "Targeting mTOR to reduce Alzheimer-related cognitive decline: from current hits to future therapies", 《EXPERT REVIEW OF NEUROTHERAPEUTICS》 * |
| LIJUN XIE等: "Design, Synthesis and Biological Evaluation of Novel Rapamycin Benzothiazole Hybrids as mTOR Targeted Anti-cancer Agents", 《CHEM. PHARM. BULL.》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Tavassoly et al. | Quinolinic acid amyloid-like fibrillar assemblies seed α-synuclein aggregation | |
| Lu et al. | TRPV1 sustains microglial metabolic reprogramming in Alzheimer's disease | |
| Zhang et al. | p75 neurotrophin receptor protects primary cultures of human neurons against extracellular amyloid β peptide cytotoxicity | |
| Zhang et al. | Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway | |
| EP3570940B1 (en) | Pridopidine for use in the treatment of fragile x syndrome | |
| JP2015003931A (en) | Therapeutic agents comprising methylphenidate derivatives | |
| CA2839134A1 (en) | Trimethylangelicin as cftr corrector in bronchial epithelial cells | |
| US8563581B2 (en) | Nitroxides for use in treating predisposed or at risk patients | |
| EP2676665A1 (en) | Use of -mangostin in preparation of medicaments for treating alzheimer's disease | |
| Yamamoto et al. | Leptin inhibits amyloid β‐protein fibrillogenesis by decreasing GM1 gangliosides on the neuronal cell surface through PI3K/Akt/mTOR pathway | |
| KR101910153B1 (en) | Levosimendan compounds for preventing or treating tau related disease | |
| JPH10504014A (en) | SSI tyrphostin and pharmaceutical composition | |
| US8383617B2 (en) | Treatment of protein aggregation diseases | |
| US8440893B2 (en) | Therapeutic agent for rheumatoid arthritis | |
| WO2018226230A1 (en) | Compounds and methods for treatment of diamond blackfan anemia | |
| CN110917194A (en) | Application of rapamycin thiazole derivatives in preparation of anti-Alzheimer's disease drugs | |
| EP3197445B1 (en) | Proline or proline derivatives for the treatment of dementia | |
| CA3171783A1 (en) | Deuterated oxophenylarsine compound and use thereof | |
| WO2020165802A1 (en) | Compositions and methods relating to use of agonists of alpha5-containing gabaa receptors | |
| CN114630664A (en) | Treatment and prevention of neuroinflammation or inflammatory brain disorders | |
| WO2020010236A1 (en) | Methods and compositions for the treatment of amyloid-related disorders | |
| Matsumoto et al. | EPI-589, a redox-active neuroprotectant, potently protects cultured cells from oxidative stress and alleviates symptomatic and pathological progression of motor neuron disease in the wobbler mouse | |
| Nishimoto et al. | Streptozotocin induces neurite outgrowth via PI3K-Akt and glycogen synthase kinase 3β in Neuro2a cells | |
| Berkoz | The role of oxidative stress in Alzheimer’s disease | |
| JP2006052192A (en) | Neurite elongation composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |