CN114870018A - 炎症小体nlrp3抑制剂通过抑制神经系统炎症在制备治疗阿尔茨海默症药物中的应用 - Google Patents
炎症小体nlrp3抑制剂通过抑制神经系统炎症在制备治疗阿尔茨海默症药物中的应用 Download PDFInfo
- Publication number
- CN114870018A CN114870018A CN202210514402.8A CN202210514402A CN114870018A CN 114870018 A CN114870018 A CN 114870018A CN 202210514402 A CN202210514402 A CN 202210514402A CN 114870018 A CN114870018 A CN 114870018A
- Authority
- CN
- China
- Prior art keywords
- inflammation
- medicament
- disease
- mice
- nervous system
- 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
- 208000024827 Alzheimer disease Diseases 0.000 title claims abstract description 48
- 239000003814 drug Substances 0.000 title claims abstract description 22
- 206010061218 Inflammation Diseases 0.000 title abstract description 19
- 230000004054 inflammatory process Effects 0.000 title abstract description 19
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 title abstract description 10
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 title abstract description 10
- 210000000653 nervous system Anatomy 0.000 title abstract description 10
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- 230000002401 inhibitory effect Effects 0.000 title abstract description 7
- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000003617 indole-3-acetic acid Substances 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 229940122390 Inflammasome inhibitor Drugs 0.000 claims description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000003623 enhancer Substances 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- 239000003906 humectant Substances 0.000 claims description 3
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 2
- 229920001817 Agar Polymers 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 239000005995 Aluminium silicate Substances 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 230000000274 adsorptive effect Effects 0.000 claims description 2
- 239000008272 agar Substances 0.000 claims description 2
- 229940072056 alginate Drugs 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 235000012211 aluminium silicate Nutrition 0.000 claims description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 229960000541 cetyl alcohol Drugs 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000000796 flavoring agent Substances 0.000 claims description 2
- 235000013355 food flavoring agent Nutrition 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 238000001179 sorption measurement Methods 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 210000005013 brain tissue Anatomy 0.000 abstract description 8
- 210000001130 astrocyte Anatomy 0.000 abstract description 4
- 201000002491 encephalomyelitis Diseases 0.000 abstract description 4
- 210000000274 microglia Anatomy 0.000 abstract description 3
- 230000001575 pathological effect Effects 0.000 abstract description 3
- 206010051288 Central nervous system inflammation Diseases 0.000 abstract description 2
- 210000004556 brain Anatomy 0.000 abstract description 2
- 230000017531 blood circulation Effects 0.000 abstract 1
- 210000004969 inflammatory cell Anatomy 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 40
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 7
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 7
- 102000003777 Interleukin-1 beta Human genes 0.000 description 7
- 108090000193 Interleukin-1 beta Proteins 0.000 description 7
- 230000006399 behavior Effects 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 6
- 230000002757 inflammatory effect Effects 0.000 description 6
- 102000013498 tau Proteins Human genes 0.000 description 5
- 108010026424 tau Proteins Proteins 0.000 description 5
- 102100035904 Caspase-1 Human genes 0.000 description 4
- 108090000426 Caspase-1 Proteins 0.000 description 4
- 102000004889 Interleukin-6 Human genes 0.000 description 4
- 108090001005 Interleukin-6 Proteins 0.000 description 4
- 230000003542 behavioural effect Effects 0.000 description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 3
- QOPBEBWGSGFROG-UHFFFAOYSA-N 2-(1h-indol-2-yl)acetic acid Chemical compound C1=CC=C2NC(CC(=O)O)=CC2=C1 QOPBEBWGSGFROG-UHFFFAOYSA-N 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- GOLXRNDWAUTYKT-UHFFFAOYSA-N 3-(1H-indol-3-yl)propanoic acid Chemical compound C1=CC=C2C(CCC(=O)O)=CNC2=C1 GOLXRNDWAUTYKT-UHFFFAOYSA-N 0.000 description 2
- 238000008157 ELISA kit Methods 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 108010034143 Inflammasomes Proteins 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- -1 indole-3-sulfate Chemical compound 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 238000012549 training Methods 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 241000186604 Lactobacillus reuteri Species 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 102100040653 Tryptophan 2,3-dioxygenase Human genes 0.000 description 1
- 101710136122 Tryptophan 2,3-dioxygenase Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 230000003930 cognitive ability Effects 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000008088 immune pathway Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- 239000003290 indole 3-propionic acid Substances 0.000 description 1
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940001882 lactobacillus reuteri Drugs 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008897 memory decline Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- 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
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- 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
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了炎症小体NLRP3抑制剂吲哚乙酸通过抑制神经系统炎症在制备治疗阿尔茨海默症药物中的应用。本发明发现吲哚乙酸可以有效缓解阿尔茨海默症小鼠中枢神经系统炎症，改善小鼠病理现象。本发明所述炎症小体抑制剂有效抑制神经系统炎症主要是通过血液循环进入大脑后，激活脑组织中小胶质细胞和星形胶质细胞Ahr受体，进一步抑制炎症小体实现阿尔茨海默症的有效治疗。
Description
技术领域
本发明属于药物应用技术领域，尤其是指一种炎症小体NLRP3抑制剂通过抑制神经系统炎症在制备治疗阿尔茨海默症药物中的应用。
背景技术
老年群体的健康状况在社会中备受关注，阿尔茨海默病(Alzheimer disease，AD)是一种神经退行性疾病，主要以β淀粉样蛋白异常沉积和过度磷酸化tau蛋白聚集形成的神经纤维缠结以及神经炎症为主要病理特征，临床表现为记忆力下降、认知判断力缺乏，是最常见的老年痴呆类型，严重影响老年人身体健康和生活质量，而目前尚无特效药。因此如何维持和改善患病老年人的认知能力，提高其晚年的生活质量，已成为当今研究中关注的热点问题。
越来越多的研究表明，肠道微生物代谢物可以通过调节宿主的免疫途径、神经和内分泌系统来影响人体的基本功能，是宿主-微生物交流的关键介质。肠道微生物中一些微生物，如罗伊氏乳杆菌，可将饮食中色氨酸代谢产生多种产物，包括吲哚乙酸。吲哚乙酸作为芳香烃受体的配体，能够有效减轻炎症，抗氧化，维持肠道动态平衡。
2016年有研究表明星型胶质细胞中的I型干扰素信号通过配体激活芳香烃受体和细胞因子信号抑制因子2降低炎症和实验性自身免疫性脑脊髓炎疾病评分。通过补充色氨酸代谢产物吲哚、吲哚-3-硫酸基、吲哚-3-丙酸和吲哚-3-醛或细菌酶色氨酸酶可以减轻中枢神经系统炎症和自身免疫性脑脊髓炎疾病评分。因此通过调节中枢神经系统炎症治疗神经退行性疾病是一种有效、安全的策略。
发明内容
为解决上述技术问题，本发明提供了一种炎症小体NLRP3抑制剂通过抑制神经系统炎症在制备治疗阿尔茨海默症药物中的应用。
本发明的第一个目的在于提供一种炎症小体抑制剂在制备治疗阿尔茨海默症药物中的应用。
所述炎症小体抑制剂可以有效抑制神经系统炎症并治疗阿尔茨海默病。
所述炎症小体抑制剂有效抑制神经系统炎症主要是通过血液循环进入大脑后，激活脑组织中小胶质细胞和星形胶质细胞Ahr受体，进一步抑制炎症小体实现。
所述炎症小体抑制剂可以有效治疗阿尔茨海默病主要表现为能够恢复阿尔茨海默病小鼠行为学及病理特征。
在本发明的一个实施例中，所述炎症小体抑制剂为吲哚乙酸。
在本发明的一个实施例中，所述药物的服用方式为口服。
在本发明的一个实施例中，所述药物的剂型包括片剂、胶囊剂、颗粒剂、滴丸或口服液。
在本发明的一个实施例中，所述药物的剂量为50-400mg/kg/天。
在本发明的一个实施例中，所述药物还包括药学上可接受的药物载体。
在本发明的一个实施例中，所述药物载体包括稀释剂、赋形剂、填充剂、粘合剂、湿润剂、润滑剂、崩解剂、吸收促进剂、表面活性剂、吸附载体以及香味剂中的至少一种。
在本发明的一个实施例中，所述赋形剂包括水，所述填充剂包括淀粉、蔗糖或乳糖中的至少一种；所述粘合剂包括纤维素衍生物、藻酸盐、明胶或聚乙烯吡咯烷酮中的至少一种；所述湿润剂包括甘油；所述崩解剂包括琼脂、碳酸钙或碳酸氢钠中的至少一种；所述吸收促进剂包括季铵化合物；所述表面活性剂包括十六烷醇；所述吸附载体包括高岭土或皂粘土中的至少一种；所述润滑剂包括滑石粉、硬脂酸钙、硬脂酸镁或聚乙二醇中的至少一种。
本发明的第二个目的在于提供一种试剂盒，所述试剂盒包括所述的药物。
本发明的第三个目的在于提供所述的试剂盒在制备治疗阿尔茨海默症药物中的应用。
本发明的上述技术方案相比现有技术具有以下优点：
本发明所述吲哚乙酸作为口服药物治疗阿尔茨海默症有效避免了对机体的物理损伤。
所述吲哚乙酸可通过肠道微生物代谢饮食中色氨酸产生，避免了非机体成分对于机体的毒副作用。
本发明发现口服IAA的AD小鼠，行为学有所改善，具体表现为在水迷宫实验中能够更快找到逃生台。
本发明发现口服IAA的AD小鼠，能够恢复阿尔茨海默病小鼠病理特征，具体表现为β淀粉样蛋白含量与磷酸化的tau蛋白含量下降至与WT鼠水平一致。
本发明发现口服IAA的AD小鼠，神经系统炎症水平下降，具体表现为，在脑脊液中炎症因子IL-1β，TNF-α和IL-6水平都降低至WT鼠水平。
本发明发现体外实验中，IAA能够通过激活脑组织中小胶质细胞BV2和星形胶质细胞MA-C的Ahr受体，通过转录因子NF-κB抑制NLRP3表达、Caspase-1活化和随后的IL-1β分泌，进一步抑制炎症小体。
本发明发现口服IAA的AD小鼠，脑组织中炎症小体表达量下降。
附图说明
为了使本发明的内容更容易被清楚的理解，下面根据本发明的具体实施例并结合附图，对本发明作进一步详细的说明，其中
图1是正常小鼠与AD小鼠血清和脑脊液中吲哚乙酸含量。
图2是AD小鼠口服吲哚乙酸45天后在水迷宫实验中的潜伏时间统计图及路径图。
图3是AD小鼠口服吲哚乙酸45天后，脑脊液中β淀粉样蛋白和过磷酸化的Tau蛋白含量。
图4是AD小鼠口服吲哚乙酸45天后，脑脊液中炎症因子IL-1β，TNF-α和IL-6含量。
图5是AD小鼠口服吲哚乙酸45天后，脑组织中NLRP3、Caspase-1和IL-1β蛋白表达量的WesternBlot结果。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。
实施例1
分别取AD鼠或WT鼠的血清和脑脊液，通过LC-MS测定其中吲哚乙酸含量，实验结果见图1。AD小鼠血清和脑脊液中吲哚乙酸含量均低于WT小鼠水平。
实施例2
小鼠口服吲哚乙酸，操作方式如下：将吲哚乙酸溶于植物油中制成悬浮液，以50mg/kg/天的剂量，每天一次在相同时间对WT鼠或AD鼠进行灌胃。
实施例3
灌胃期间每15天对AD小鼠治疗效果进行水迷宫行为学监测，直至AD小鼠行为学水平恢复至WT鼠水平。具体测试步骤如下：
(1)前三天水迷宫适应性训练，逃生平台高于水面2cm，允许小鼠自由游泳寻找平台。
(2)4-8天定位巡航实验，每天4次，期间逃生平台于水面下1cm，记录找到平台的时间及游泳轨迹。
当AD小鼠行为学有所改善时，主要表现为行为学上与AD鼠有显著差异，与WT鼠无显著差异，具体表现为水迷宫测试中找到平台时间的变化。
在具体实施过程中，AD组的小鼠2分钟时仍未找到逃生台，手动停止计时，而WT组小鼠经前期训练后，能够迅速找到台子。经吲哚乙酸灌胃后的AD鼠在一个月时寻找逃生台的过程有所改善，在45天时均能在2分钟之内找到台子。说明经材料治疗45天后，AD小鼠行为学改善。实验结果见图2。
实施例4
当AD小鼠行为学有所改善时，利用ELISA试剂盒对小鼠脑脊液中β淀粉样蛋白和磷酸化的tau蛋白进行定量。实验结果见图3。
由图可知，AD组小鼠的β淀粉样蛋白含量约为WT鼠的5倍，经吲哚乙酸治疗后的AD鼠，β淀粉样蛋白含量下降。磷酸化的tau蛋白水平变化与β淀粉样蛋白类似。
实施例5
当AD小鼠行为学有所改善时，利用ELISA试剂盒对小鼠脑脊液中炎症因子IL-1β，TNF-α和IL-6进行定量。实验结果见图4。
由图可知，AD组小鼠脑脊液中炎症因子IL-1β，TNF-α和IL-6均高于WT组小鼠。经吲哚乙酸灌胃后的AD鼠，炎症因子水平恢复至WT鼠水平。
实施例6
当AD小鼠行为学有所改善时，利用试剂盒提取小鼠脑组织中蛋白，并用WesternBlot对炎症小体NLRP3相关蛋白进行半定量。实验结果见图2。
结果表明，AD小鼠脑组织中NLRP3、Caspase-1和IL-1β表达量远高于对照组，经吲哚乙酸治疗后，其表达量下降至对照组水平。说明IAA能够抑制NLRP3表达、Caspase-1活化和随后的IL-1β分泌。
显然，上述实施例仅仅是为清楚地说明所作的举例，并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
1.一种炎症小体抑制剂在制备治疗阿尔茨海默症药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述炎症小体抑制剂为吲哚乙酸。
3.根据权利要求1所述的应用，其特征在于，所述药物的服用方式为口服。
4.根据权利要求1所述的应用，其特征在于，所述药物的剂型包括片剂、胶囊剂、颗粒剂、滴丸或口服液。
5.根据权利要求1所述的应用，其特征在于，所述药物的剂量为50-400mg/kg/天。
6.根据权利要求1所述的应用，其特征在于，所述药物还包括药学上可接受的药物载体。
7.根据权利要求6所述的应用，其特征在于，所述药物载体包括稀释剂、赋形剂、填充剂、粘合剂、湿润剂、润滑剂、崩解剂、吸收促进剂、表面活性剂、吸附载体以及香味剂中的至少一种。
8.根据权利要求7所述的应用，其特征在于，所述赋形剂包括水，所述填充剂包括淀粉、蔗糖或乳糖中的至少一种；所述粘合剂包括纤维素衍生物、藻酸盐、明胶或聚乙烯吡咯烷酮中的至少一种；所述湿润剂包括甘油；所述崩解剂包括琼脂、碳酸钙或碳酸氢钠中的至少一种；所述吸收促进剂包括季铵化合物；所述表面活性剂包括十六烷醇；所述吸附载体包括高岭土或皂粘土中的至少一种；所述润滑剂包括滑石粉、硬脂酸钙、硬脂酸镁或聚乙二醇中的至少一种。
9.一种试剂盒，其特征在于，所述试剂盒包括权利要求1中所述的药物。
10.权利要求9所述的试剂盒在制备治疗阿尔茨海默症药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210514402.8A CN114870018A (zh) | 2022-05-12 | 2022-05-12 | 炎症小体nlrp3抑制剂通过抑制神经系统炎症在制备治疗阿尔茨海默症药物中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210514402.8A CN114870018A (zh) | 2022-05-12 | 2022-05-12 | 炎症小体nlrp3抑制剂通过抑制神经系统炎症在制备治疗阿尔茨海默症药物中的应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114870018A true CN114870018A (zh) | 2022-08-09 |
Family
ID=82676423
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210514402.8A Pending CN114870018A (zh) | 2022-05-12 | 2022-05-12 | 炎症小体nlrp3抑制剂通过抑制神经系统炎症在制备治疗阿尔茨海默症药物中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114870018A (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1938018A (zh) * | 2003-10-03 | 2007-03-28 | 维伊林股份有限公司 | 能够提高血清igf－1水平的化合物在制备治疗与降低的igf－1血清水平有关的人和动物的各种疾病状况的治疗组合物中的用途 |
| CN101166721A (zh) * | 2005-03-11 | 2008-04-23 | 奥克萨根有限公司 | 具有pgd2拮抗剂活性的1－乙酸－吲哚衍生物 |
| CN101484420A (zh) * | 2006-07-03 | 2009-07-15 | 比奥维特罗姆上市公司 | 作为5-ht6调节剂的吲哚 |
-
2022
- 2022-05-12 CN CN202210514402.8A patent/CN114870018A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1938018A (zh) * | 2003-10-03 | 2007-03-28 | 维伊林股份有限公司 | 能够提高血清igf－1水平的化合物在制备治疗与降低的igf－1血清水平有关的人和动物的各种疾病状况的治疗组合物中的用途 |
| CN101166721A (zh) * | 2005-03-11 | 2008-04-23 | 奥克萨根有限公司 | 具有pgd2拮抗剂活性的1－乙酸－吲哚衍生物 |
| CN101484420A (zh) * | 2006-07-03 | 2009-07-15 | 比奥维特罗姆上市公司 | 作为5-ht6调节剂的吲哚 |
Non-Patent Citations (2)
| Title |
|---|
| K.V. DILEEP等: ""Inhibition, ADME and structure based modification of IAA and IBA against acetylcholinesterase: an attempt towards new drug development for Alzheimer"s disease"", 《FRONTIERS IN LIFE SCIENCE》 * |
| 师强等: ""靶向NLRP3炎症小体在阿尔茨海默病治疗中的新策略"", 《延安大学学报（医学科学版）》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7250006B2 (ja) | 高投与量バルベナジン製剤ならびにそれに関連する組成物、方法およびキット | |
| RU2140266C1 (ru) | Фармацевтическая композиция с регулируемым выделением на основе одной или нескольких фармацевтически приемлемых солей гамма-гидроксимасляной кислоты и способ ее получения | |
| EP0988028B1 (en) | Use of a composition comprising capsaicin or resiniferatoxin for the treatment of Irritable Bowel Syndrome | |
| US20170348232A1 (en) | Formulations of gaboxadol for treatment of angelman syndrome, fragile x syndrome and fragile x-associated tremor/ataxia syndrome | |
| EP1849462B1 (en) | A method of alleviating signs and symptons of Spasticity | |
| EP3187189A1 (en) | Composition and medicinal product for reducing body weight and body fat, and use of said product | |
| KR20060134041A (ko) | 음식물 섭취 관리 방법 | |
| CA2314433A1 (en) | Use of alpha-glucosidase inhibitors for treating high-risk impaired glucose tolerance | |
| JPH10182471A (ja) | 医薬組成物及び筋緊張低下によって引き起こされる病気で苦しむ患者の治療方法 | |
| ES2635763T3 (es) | Composición de complemento nutricional | |
| US20070264370A1 (en) | Composition and methods for the treatment of joint pain using Angelica gigas Nakai extract and powder as combined with Glucosamine Sulfate, or Chondroitin Sulfate and HCL, or MSM, or aspirin, or Celedrin, and as combinations thereof in powder, pill, capsule, spray, liquid, and gelcap form | |
| CN114870018A (zh) | 炎症小体nlrp3抑制剂通过抑制神经系统炎症在制备治疗阿尔茨海默症药物中的应用 | |
| CN108159017A (zh) | 一种盐酸左氧氟沙星胶囊及其制备方法 | |
| JP2023086766A (ja) | 脆弱ｘ症候群、アンジェルマン症候群又はレット症候群を含む発達障害の軽減又は治療のためのカルバメート化合物の使用 | |
| RU2423981C2 (ru) | Фармацевтическая композиция для лечения болезни паркинсона | |
| Frucht et al. | Parkinsonism-hyperpyrexia syndrome in Parkinson’s disease | |
| JP2021519330A (ja) | ムメフラールを含む認知障害関連疾患の予防又は治療用組成物 | |
| CA2671001A1 (en) | Pharmaceutical composition of memantine | |
| US9433602B2 (en) | Combination and composition for treating obesity | |
| US10675253B2 (en) | Methods of diagnosis and treatment involving nitrite | |
| US5216019A (en) | Pain killer | |
| AU2018278967A1 (en) | Pharmaceutical compositions of donepezil having specific in vitro dissolution profile or pharmacokinetics parameters | |
| CN112843065B (zh) | 一种用于认知障碍的药物及其制备方法 | |
| EP0818198A1 (en) | Potentiation of drug response by increasing serotonin availability | |
| KR20240070564A (ko) | 알츠하이머병 예방 또는 치료용 약학적 조성물 |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220809 |