CN104258371B - WWW tripeptides purposes in preparation treatment Alzheimer disease drug - Google Patents
WWW tripeptides purposes in preparation treatment Alzheimer disease drug Download PDFInfo
- Publication number
- CN104258371B CN104258371B CN201410497265.7A CN201410497265A CN104258371B CN 104258371 B CN104258371 B CN 104258371B CN 201410497265 A CN201410497265 A CN 201410497265A CN 104258371 B CN104258371 B CN 104258371B
- Authority
- CN
- China
- Prior art keywords
- www
- tripeptides
- alzheimer
- disease
- treatment
- 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.)
- Expired - Fee Related
Links
- 208000024827 Alzheimer disease Diseases 0.000 title claims abstract description 42
- 239000003814 drug Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 229940079593 drug Drugs 0.000 title claims abstract description 23
- WVTKBKWTSCPRNU-KYJUHHDHSA-N (+)-Tetrandrine Chemical compound C([C@H]1C=2C=C(C(=CC=2CCN1C)OC)O1)C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@@H]2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-KYJUHHDHSA-N 0.000 claims abstract description 24
- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical group O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 claims abstract description 12
- 230000002265 prevention Effects 0.000 claims abstract description 12
- WVTKBKWTSCPRNU-UHFFFAOYSA-N rac-Tetrandrin Natural products O1C(C(=CC=2CCN3C)OC)=CC=2C3CC(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2CC2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-UHFFFAOYSA-N 0.000 claims abstract description 12
- 241001465754 Metazoa Species 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 239000004005 microsphere Substances 0.000 claims abstract description 6
- 238000002347 injection Methods 0.000 claims abstract description 5
- 239000007924 injection Substances 0.000 claims abstract description 5
- 239000007788 liquid Substances 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 12
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 claims description 11
- 238000009472 formulation Methods 0.000 claims description 3
- 230000000694 effects Effects 0.000 abstract description 21
- 230000008021 deposition Effects 0.000 abstract description 3
- 238000011156 evaluation Methods 0.000 abstract description 3
- 230000010534 mechanism of action Effects 0.000 abstract description 3
- 231100000614 poison Toxicity 0.000 abstract description 3
- 230000007096 poisonous effect Effects 0.000 abstract description 3
- 108010090849 Amyloid beta-Peptides Proteins 0.000 abstract description 2
- 102000013455 Amyloid beta-Peptides Human genes 0.000 abstract description 2
- 238000006384 oligomerization reaction Methods 0.000 abstract description 2
- 238000002648 combination therapy Methods 0.000 abstract 1
- 230000006806 disease prevention Effects 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 230000002195 synergetic effect Effects 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 20
- 238000010175 APPswe/PSEN1dE9 Methods 0.000 description 19
- 238000011830 transgenic mouse model Methods 0.000 description 19
- 238000003304 gavage Methods 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 230000001225 therapeutic effect Effects 0.000 description 14
- 108090000765 processed proteins & peptides Proteins 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000008187 granular material Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 206010039966 Senile dementia Diseases 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 108010060159 Apolipoprotein E4 Proteins 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- 229920001353 Dextrin Polymers 0.000 description 4
- 239000004375 Dextrin Substances 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 238000012347 Morris Water Maze Methods 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 238000001142 circular dichroism spectrum Methods 0.000 description 4
- 239000002131 composite material Substances 0.000 description 4
- 229910052802 copper Inorganic materials 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 235000019425 dextrin Nutrition 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000835 fiber Substances 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000007779 soft material Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 3
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 3
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- DOFAQXCYFQKSHT-SRVKXCTJSA-N Val-Pro-Pro Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DOFAQXCYFQKSHT-SRVKXCTJSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000000151 deposition Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000011812 mixed powder Substances 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000007873 sieving Methods 0.000 description 3
- 238000007619 statistical method Methods 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 3
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 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 description 2
- 208000037259 Amyloid Plaque Diseases 0.000 description 2
- 108010025628 Apolipoproteins E Proteins 0.000 description 2
- 102000013918 Apolipoproteins E Human genes 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 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 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 230000001149 cognitive effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- NUHSROFQTUXZQQ-UHFFFAOYSA-N isopentenyl diphosphate Chemical compound CC(=C)CCO[P@](O)(=O)OP(O)(O)=O NUHSROFQTUXZQQ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 230000002887 neurotoxic effect Effects 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000012549 training Methods 0.000 description 2
- RALAXQOLLAQGTI-UHFFFAOYSA-N 2-[[2-[[2-[[1-(2-amino-4-methylpentanoyl)pyrrolidine-2-carbonyl]amino]-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]butanedioic acid Chemical compound CC(C)CC(N)C(=O)N1CCCC1C(=O)NC(C(=O)NC(CC=1C=CC=CC=1)C(=O)NC(CC(O)=O)C(O)=O)CC1=CC=CC=C1 RALAXQOLLAQGTI-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 1
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000027691 Conduct disease Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 229940123344 GPR antagonist Drugs 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- FQYQMFCIJNWDQZ-CYDGBPFRSA-N Ile-Pro-Pro Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 FQYQMFCIJNWDQZ-CYDGBPFRSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- KRCAKIVDAFTTGJ-ARVREXMNSA-N Trp-Trp-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)N)C(O)=O)=CNC2=C1 KRCAKIVDAFTTGJ-ARVREXMNSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000001467 acupuncture Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229920006125 amorphous polymer Polymers 0.000 description 1
- 108010075875 amyloid beta-protein (16-20) Proteins 0.000 description 1
- 230000006933 amyloid-beta aggregation Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 210000001951 dura mater Anatomy 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000012921 fluorescence analysis Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 235000003969 glutathione Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 108010031424 isoleucyl-prolyl-proline Proteins 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 108010091748 peptide A Proteins 0.000 description 1
- 230000006919 peptide aggregation Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- CIJQGPVMMRXSQW-UHFFFAOYSA-M sodium;2-aminoacetic acid;hydroxide Chemical compound O.[Na+].NCC([O-])=O CIJQGPVMMRXSQW-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- SFIHWLKHBCDNCE-UHFFFAOYSA-N uranyl formate Chemical compound OC=O.OC=O.O=[U]=O SFIHWLKHBCDNCE-UHFFFAOYSA-N 0.000 description 1
- 108010015385 valyl-prolyl-proline Proteins 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention is claimed WWW tripeptides purposes in preparation prevention or treatment Alzheimer disease drug, belongs to field of medicaments. WWW tripeptides animal dosage of the present invention is clear and definite, and tablet, microspheres agent, powdery agent, oral liquid, injection can be made, when WWW tripeptides is used for treating Alzheimer's disease, can individually medication, Alzheimer's disease combination therapies that can also be different from other mechanism of action, when the pharmaceutical composition that wherein WWW tripeptides and tetrandrine, triptolide form is used for the treatment of Alzheimer's disease, poisonous side effect of medicine can not only be reduced, and the effect of Synergistic treatment can be obtained, pharmacological evaluation confirms, WWW tri-Toplink effectively suppresses A β1-42Assemble and prevent A β1-42The phenomenon of the oligomerization of single aggressiveness, significantly inhibits the deposition of amyloid beta, and it is for Alzheimer's disease prevention or treatment determined curative effect, and side effect is little, therefore has wide medical application prospect.
Description
Technical field
The invention belongs to field of medicaments, relate to the new application of a kind of known drug, treat the purposes in Alzheimer disease drug more particularly to WWW tripeptides in preparation.
Background technology
Alzheimer (Alzheimer ' sdisease, AD) be a kind of lose with impermanent memory, persistence cognitive competence goes down and conduct disorder is feature nervous system degenerative disease. Alzheimer have impact on the population that the whole world is huge, brings great misery to the life of people. Now, the definite pathogenesis of AD is still not clear, and it was initially believed that it is common results aging, h and E many factors. A variety of theory is currently also had to want to confirm the definite pathogenesis of AD, wherein the case of the most widely accepted amyloid hypothesis being amyloid beta (A β) peptide to be polymerized and fibril is formed and being biomarker. A β is a kind of small peptide being made up of 38 to 42 amino acid residues, comes from the hydrolysis of amyloid precursor protein (APP). And the brain of AD patient has substantial amounts of A β1-42. By to AD patient's it has been observed that A β gathering in nervous tissue with deposition relevant with the death of neurocyte and cognitive decrease. Therefore, A β is the potential target spot that AD carries out therapeutic intervention. And there is a lot of research to find different medicines with A β for target spot.
Finding different medicines with A β for target spot is hot issue in recent years, the A beta hypothesis fallen ill according to document senile dementia (AD) and related drugs progress (Anhui journal of institutes of education, 2007-5,25th volume the 3rd phase) specifically understand that the interference A β medicine being formed and depositing and the medicine that senile plaque is formed that stops being target spot with A β can play a role in multiple approach: (1) can reduce the synthesis of A β precursor protein, stops the synthesis of APP in the level of transcription and translation;(2) reduce the generation of A β, regulate the activity of cerebral tissue a, beta-secretase; (3) due to the premise that A beta peptide aggregation is its neurotoxic effect, this process relates to the A β conversion by a-screw-β-lamellar structure, and this process skin section special with molecule is relevant; (4) inflammatory reaction that antagonism A β participates in. Even if proposing much new synthetic molecules as suppressing A β1-42The potential drug built up, but the mechanism of action of these molecules not yet illustrates completely. Chinese patent CN101346396B discloses g protein coupled receptor antagonist and the application thereof of prevention and treatment Alzheimer's disease, and this antagonist produces toxin, has serious side effect, DeGrain, is unfavorable for large-scale popularization and application.
Uncertain along with drug research result, the progress for the peptides mortifier of A β starts to receive much concern, and a lot of polypeptide fragments is believed to be attached to the polymeric central hydrophibic core of A β thus preventing the deposition of A β. Multiple small peptide is also proved to be effective molecule for the treatment of AD, for instance as the glutathion of antioxidant. There is also evidence, WMDF and Ac-AVVIA is effective in cure to AD. Additionally, research shows that the Development process of AD is had stronger rejection characteristic by the polypeptide of such as KLVFF and LPFFD and peptide quasi-molecule. There are a kind of two tetradecapeptides, it is possible to anti-cytotoxicity relevant for AD widely, be exposed in the environment of A β including in test in vitro, show cell death activity.
Tang Dou hospital of The Fourth Military Medical University Neurology Department has delivered one section about A β20-29Small peptide blocks ApoE/A β and combines and reduce A β1-42Thioflavin-T (Th-T) fluorescence analysis and transmission electron microscope method is utilized to confirm the A β of synthetic disclosed in fibrosis and neurovirulent effect effect (ChinJClinNeurosci2009.17 (1) .1 ~ 6) thereof20-29Small peptide no cytotoxicity effect, it is possible to be combined with ApoE4 competitively, thus blocking A β1-42Be combined with ApoE4, reduce ApoE4 to A β1-42Fibrotic facilitation and neurotoxic effect thereof, illustrate A β20-29Small peptide can become suppression A β1-42The novel blocker that/ApoE4 combines, prevents Therapeutic Method new for AD from providing effective experiment basis for exploring, but its effect is still further studied.
Tripeptides is to form through three aminoacid dehydrating condensations, it is beneficial to body absorption, borderline hypertension is had certain therapeutical effect by the advantage having no side effect, tripeptides ILE-PRO-PRO IPP (IPP) and VAL-PRO-PRO VPP (VPP). Different types of tripeptides has different drug actions. Trp-Trp-tryptophan (Trp-Trp-Trp, be called for short WWW tripeptides) tripeptides is degradable and be prone to the advantage absorbed in mammal body, is beneficial to the performance of medicine.
Summary of the invention
Medicine in order to solve to exist in prior art treatment Alzheimer's disease is indefinite, DeGrain, and the defect that poisonous side effect of medicine is big it is an object of the invention to provide prevention and the medicine for the treatment of Alzheimer's disease. From the foregoing, A β20-29Small peptide blocks ApoE/A β and combines and reduce A β1-42Fibrosis and neurovirulent effect effect thereof, therefore the present invention relates to a kind of medicinal usage of WWW tripeptides, and namely WWW tripeptides is for preparing the purposes in prevention or treatment senile dementia. Medicine provided by the present invention is used for determined curative effect during treatment or the prevention of Alzheimer's disease, and poisonous side effect of medicine is little, has medical application prospect widely.
An object of the present invention is to provide WWW tripeptides and treats and prevents the application in Alzheimer disease drug in preparation. Inventor through investigative test find, WWW tripeptides have significantly suppress amyloid beta deposition effect, WWW tripeptides be by with A β1-42It is combined into complex to stablize A β1-42Alpha-helix, helical structure and suppression beta sheet structure formation, thus remaining stable for A β1-42Conformation, thus suppressing A β1-42Gathering, owing to there is very close relationship between generation and the progress of the gathering of A β and the formation of senile plaque and Alzheimer's disease, it can thus be anticipated that WWW tripeptides can improve the state of an illness of patient for prevention or the treatment of Alzheimer's disease or delay disease to play a positive role in the present invention. Test examples 6 of the present invention and test examples 7 confirm that WWW tripeptides is to A β1-42Caused rat alzheimer ' disease model and D-galactose induced mice Alzheimer's disease model have well treatment or preventive effect. The WWW tripeptides of the present invention is oral formulations, and its animal dosage is 100mg/kg d ~ 500mg/kg d, it is preferred to 50mg/kg d ~ 500mg/kg d, more preferably 100mg/kg d ~ 500mg/kg d, more preferably 100mg/kg d ~ 300mg/kg d.
The two of the purpose of the present invention are to provide a kind of pharmaceutical composition containing WWW tripeptides and treat and prevent the application in Alzheimer disease drug in preparation, the pharmaceutical composition of the present invention comprises WWW tripeptides, tetrandrine and/or triptolide, WWW tripeptides in described pharmaceutical composition: tetrandrine: the weight ratio of triptolide is (1-500): (0.1-5): (0.1-5).
The three of the purpose of the present invention are openly contained WWW tripeptides and are capable of the pharmaceutical preparation of said medicine purposes. In above-described medicinal usage, inventor has been prepared into making tablet, microspheres agent, powdery agent, oral liquid and injection by test. Wherein tablet contains two or more following adjuvant: starch, dextrin, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline Cellulose, hydroxypropyl cellulose, starch slurry lactose, mannitol, micropowder silica gel, cross-linking sodium carboxymethyl cellulose and crospolyvinylpyrrolidone; Described microspheres agent is containing, for example lower adjuvant: gelatin, sodium sulfate, formalin. Described WWW tripeptides is beneficial in mammal body and degrades and be prone to absorb, being conducive to the performance of drug effect, and the content containing WWW tripeptides in the oral formulations of described WWW tripeptides medicine in each preparation unit is 0.1mg-200mg.
Compared with prior art, it is an advantage of the current invention that:
(1) WWW tripeptides in mammal body degradable and be prone to absorb, be conducive to the performance of drug effect;
(2) WWW tripeptides and A β1-42In conjunction with peptide-A β1-42Stable composite, and WWW tri-Toplink stablizes A β1-42Alpha-helix, helical structure and suppression beta sheet structure formation, can effectively suppress A β1-42Gathering and prevent A β1-42The phenomenon of the oligomerization of single aggressiveness;
(3) WWW tripeptides and other mechanism of action when senile dementia is played the drug combination of therapeutical effect, its mechanism of drug action is complementary, itself and tetrandrine and triptolide coupling can play the synergism to senile dementia prevention or treatment, it is possible to improve motion function and the therapeutic effect of patients of senile dementia.
Accompanying drawing explanation
Fig. 1 is WWW tripeptides and A β1-42Thioflavin T result of the test schematic diagram:
Fig. 2 is WWW tripeptides and A β1-42Circular dichroism spectra result of the test schematic diagram:
Fig. 3 is WWW tripeptides and A β1-42'sTransmission electron microscope(TEM) result of the test schematic diagram.
Detailed description of the invention
Specific embodiment is adopted to further illustrate present disclosure below.
Herein below is in conjunction with concrete preferred implementation further description made for the present invention, it is impossible to assert that specific embodiment of the invention is confined to these explanations. For general technical staff of the technical field of the invention, without departing from the inventive concept of the premise, it is also possible to make some simple deduction or replace, protection scope of the present invention all should be considered as belonging to.
The thioflavin T test of the WWW tripeptides of experimental example 1, a kind of prevention or treatment Alzheimer's disease:
By A β1-42Be dissolved in PH7.4, concentration be 0.01mol/L phosphate buffer in be made into the mixed solution of 50 μm of ol/L, A β in this mixed solution1-42Be 50 μm of ol/L with the initial concentration of peptide, until ultimate density when being 2.5 μm of ol/L, is placed on 37 DEG C and hatches 48h, be subsequently added into ThT(5 μm of ol/L and be dissolved in 50mmol/L glycine-NaOH solution, PH8.50) detect the fluorescence of 450nm and 485nm. Each sample is measured 3 times, records fluorescence intensity.
Shown in Fig. 1, embodiment 1 result shows: thioflavin T can promptly with A β1-42Polymer fiber combine, inspiring a new wavelength is the light of 450nm, and shows as the light that wavelength is 482nm and be remarkably reinforced, and WWW tripeptides and A β1-42WWW tripeptides-A the β co-cultured1-42The sulphur production intensity of complex can reduce, and this fluorescent technique can be used for detecting WWW tripeptides to A β1-42Polymerization or the regulating power decomposed. As it is shown in figure 1, compared to resveratrol, the concentration of WWW tripeptides is that 2.5 μm of ol/L show A β1-42The better inhibition of polymer, it was shown that WWW tripeptides is A β1-42Polymeric mortifier.
The circular dichroism spectra test of the WWW tripeptides of experimental example 2, a kind of prevention or treatment Alzheimer's disease:
By the A β that concentration is 50 μm of ol/L1-42It is dissolved in phosphate buffered solution, and adds, at experimental group, the WWW tripeptides that concentration is 50 μm of ol/L, hatch 48h at then placing 37 DEG C, A β in this mixed solution1-42It is 5 μm of ol/L with the ultimate density of WWW tripeptides, uses the container ware of 1mm thickness, by A β1-42Monomer and WWW tripeptides-A β1-42Composite sample prevents detection structure in circular dichroism spectrometer respectively, and spectrum is at 25 DEG C, and wavelength is 190-260nm, is recorded during ripple width 0.5nm.
Shown in Fig. 2, embodiment 2 result shows: circular dichroism spectra shows that in WWW tripeptides-A beta composite, β-pleated sheet structure can reduce, as in figure 2 it is shown, circular dichroism spectra detection A β1-42Find near 217nm, have a blanking bar time independent, it was shown that there is beta sheet structure, find that when detecting WWW tripeptides-A beta composite the dark fringe near 217nm significantly alleviates, then show that WWW tripeptides can reduce the formation of beta sheet structure, thus suppressing A β1-42The polymerization of monomer.
Transmission electron microscope (TEM) test of the WWW tripeptides of experimental example 3, a kind of prevention or treatment Alzheimer's disease:
With phosphate buffer (PBS, pH7.4) by A β1-42Sample is dissolved into the concentration of 1mg/ml, it is then placed within WWW tripeptides experimental group and blank group that concentration is 25 μm of ol/L, until the ultimate density of mixed solution hatches 48h when being 25 μm of ol/L altogether, by the sample point sample of 5 μ l in the copper mesh of 300 hole Formvar-carbon, add the uranyl formate dyeing 1min of 1%, put and dry in atmosphere, then be placed in electricity Microscopic observation, detect A β1-42With WWW tripeptides-A β1-42The structure of complex.
Shown in Fig. 3, embodiment 3 result shows: as shown in the Electronic Speculum figure of Fig. 3, from A β1-42Monomer, it is observed that the A β of the long wire of high density in figure1-42Fiber, fibril aggregation becomes parallel pencil, crosses one another again between bundle and bundle; But, from WWW tripeptides-A β1-42Complex figure only sees a small amount of linear fiber and amorphous polymer, short A β1-42Fibre bundle cross-links mutually at random, thus defining irregular polymer; Illustrate that WWW tripeptides can suppress A β1-42The polymerization of monomer.
Prepared by embodiment 4, WWW tripeptides tablet
Preparation technology: weigh the WWW tripeptides of recipe quantity, starch, dextrin and low-substituted hydroxypropyl cellulose mix homogeneously. Separately take 60% ethanol of Sq, be incorporated in mixed-powder, soft material processed after mix homogeneously, granulated by 16 mesh sieves, less than 60 DEG C dry. Carry out granulate with 18 mesh sieves after completing after drying, sift out the fine powder in dry granular, the magnesium stearate mixing with sieving, then it is mixed evenly with dry granule again, tabletting, to obtain final product.
Prepared by embodiment 5, WWW tripeptides microspheres agent
Preparation technology: WWW tripeptides is dissolved in 5% gelatin and forms suspension and emulsion, it is acid with vinegar acid for adjusting pH value, it is subsequently added into 60% appropriate sodium sulfate, heat to 50 DEG C of mixings to be formed and condense capsule, it is cooled to 15 DEG C, regulate with alkali and add appropriate 37% formalin when pH value is alkalescence and formed and solidify capsule, be washed to formaldehydeless microspheres agent.
Prepared by embodiment 6, WWW tripeptides tablet
Preparation technology: weigh recipe quantity, WWW tripeptides, tetrandrine, starch, dextrin and low-substituted hydroxypropyl cellulose mix homogeneously. Separately take 60% ethanol of Sq, be incorporated in mixed-powder, soft material processed after mix homogeneously, granulated by 16 mesh sieves, less than 60 DEG C dry. Carry out granulate with 18 mesh sieves after completing after drying, sift out the fine powder in dry granular, the magnesium stearate mixing with sieving, then it is mixed evenly with dry granule again, tabletting, to obtain final product.
Prepared by embodiment 7, WWW tripeptides tablet
Preparation technology: weigh recipe quantity, WWW tripeptides, triptolide, starch, dextrin and low-substituted hydroxypropyl cellulose mix homogeneously. Separately take 60% ethanol of Sq, be incorporated in mixed-powder, soft material processed after mix homogeneously, granulated by 16 mesh sieves, less than 60 DEG C dry. Carry out granulate with 18 mesh sieves after completing after drying, sift out the fine powder in dry granular, the magnesium stearate mixing with sieving, then it is mixed evenly with dry granule again, tabletting, to obtain final product.
Prepared by embodiment 8, WWW tripeptides tablet
Preparation technology: each adjuvant in prescription is crossed 100 mesh sieves, weigh WWW tripeptides, after tetrandrine, triptolide mix homogeneously with lactose, mannitol, it is separately added into the micropowder silica gel of recipe quantity, microcrystalline Cellulose, crospolyvinylpyrrolidone and cross-linking sodium carboxymethyl cellulose, mix homogeneously again, adds 60% alcoholic solution soft material, 18 mesh sieve granules, wet granular dries in 60 DEG C, 16 mesh sieve granulate, adds magnesium stearate mix homogeneously, tabletting, to obtain final product.
Embodiment 9, WWW tripeptides of the present invention are to A β1-42The therapeutical effect of induced mice Alzheimer's disease model
1 material and method
1.1 experiment materials
Laboratory animal is mice, 8 weeks ages of Mus, and body weight 35-40g is provided by Nanjing Experimental Animal Center, A β1-42Purchased from American Sigma company, WWW tripeptides is provided by the synthesis of Shanghai Qiang Yao company, and Morris water maze is purchased from Shanghai Ji Liang company.
The foundation of 1.2 mice Alzheimer's disease models and evaluation
1.2.1 intracerebral ventricle injection A β1-42The preparation of solution: by A β1-42Being dissolved in physiological saline solution, making A β concentration is 10mmol/L, puts to hatch 3 days in 37 DEG C of calorstats and carries out aging.
1.2.2 the making of animal model: raise under standard environment, be randomly divided into 2 groups: matched group and model group, often group 12. 2 groups there was no significant difference on Mus age and body weight. Animal gives after adaptability feeds 1 week, by mice with 2% pentobarbital sodium intraperitoneal anesthesia (40～50mg/kg weight), it is fixed on stereo brain orienting instrument, cut off head hair, skin is cut after iodine tincture disinfection, select right side tricorn for injection target area with reference to " mouse brain stereotaxic atlas ", in bregma 1.0mm backward, 1.6mm place is opened by center line, bore with three edged needle and open skull, expose cerebral dura mater, then with microsyringe with the speed of 12 μm/s from brain surface vertical inserting needle 4.0mm, by 10mmol/LA β1-42Solution 5 μ l is slowly injected into, and slowly removes pin, sew up the incision after let the acupuncture needle remain at a certain point 2min. Matched group injects equal-volume physiological saline solution.
1.2.3Morris water maze behavioristics measures: 2 groups of mices proceeded by the test of Morris water maze respectively at postoperative 10th day. Test program is orientation navigation test: lasting 5 days, first 2 days is the training adaptation phase, latter 3 days record achievements, if mice finds platform in 1min, records its actual escape latency; If not finding platform in 1min yet, then being drawn upper mounting plate by experimenter and stop 20S, escape latency is recorded as 1min.
1.2.4 the evaluation of animal model
Be can be seen that by following table, the escape latency of model group started matched group from the 1st of experimental record the day and is just obviously prolonged (P < 0.05 or P < 0.01), and model group escape latency between 3 days and matched group escape latency no significant difference between 3 days, show to adopt the Alzheimer's disease type that the method is set up reliably accurate, it is possible to for the evaluating drug effect of Alzheimer's disease medicine.
2 animal models and packet administration
According to above-mentioned modeling method modeling, and matched group, normal group are set, often group 10, raise under standard environment. Each group administering mode is as described below:
Normal group: gavage gives the normal saline of same volume;
Matched group: gavage gives the normal saline of same volume;
Model group: gavage gives the normal saline of same volume;
Experimental group 1: gavage gives the WWW tripeptides 200mg/kg/d of embodiment 4 preparation;
Experimental group 2: gavage gives the WWW tripeptides 250mg/kg/d of embodiment 4 preparation;
Experimental group 3: gavage gives the WWW tripeptides 300mg/kg/d of embodiment 4 preparation;
Experimental group 4: gavage gives the WWW tripeptides 250mg/kg/d+ tetrandrine 28mg/kg/d of embodiment 6 preparation;
Experimental group 5: gavage gives the WWW tripeptides 250mg/kg/d+ triptolide 5.6mg/kg/d of embodiment 7 preparation;
Experimental group 6: gavage gives the WWW tripeptides 250mg/kg/d+ tetrandrine 28mg/kg/d+ triptolide 5.6mg/kg/d of embodiment 8 preparation;
Above-mentioned administration group is administered after 10 days after modeling, within 11st day, it is recorded as the 1st day, every day is administered once, observe drinking water for animals and diet situation every day, respectively at administration the 1st day, it is administered the 5th day, is administered the 10th day, it is administered the 15th day, is administered the escape latency measuring mice for 20 days with Morris water maze behavioristics assay method. Mice is put to death after having measured for the last time. Respectively group mice Morris water maze behavioristics measurement result is as shown in the table.
The each administration group of table 1 is to A β1-42The therapeutic effect (escape latency, unit S) of induced mice Alzheimer's disease model
Compared with model group, * P < 0.05, * * P < 0.01;
As can be seen from Table 1: each administration group escape latency of the 1st day there was no significant difference, but along with the prolongation of administration time, the escape latency difference of each administration group mice strengthens, and wherein WWW tripeptides each administration group is respectively provided with positive therapeutical effect. It is embodied in:
1) the mice escape latency of each treatment group of WWW tripeptides has significant difference compared with model group, all significantly shorten the escape latency of mice, its drug treatment is after 15 days, and the mice escape latency of each treatment group has significant difference compared with model group. WWW tripeptides is to A β1-42Induced mice Alzheimer's disease model has significant therapeutic effect;
2) the mice escape latency of WWW tripeptides each treatment group is variant, the effect of the table 1 known experimental group of data 2 be best, and this shows that the WWW tripeptides of variable concentrations is to A β1-42Induced mice Alzheimer's disease model has diversity, and wherein the WWW tripeptides of 250mg/kg/d is to A β1-42The therapeutic effect of induced mice Alzheimer's disease model is best;
3) each treatment group of compound recipe has significant difference compared with single medicine group, and this shows that experimental group 4 of the present invention, experimental group 5 and experimental group 6 combination exist significant synergism, is obviously enhanced, accelerates the therapeutic process of Alzheimer's disease on medication effect.
Embodiment 10, the WWW tripeptides of the present invention therapeutical effect to the Alzheimer's disease of APP/PS1 bi-transgenic mice
1 material
WWW tripeptides is provided by the synthesis of Shanghai Qiang Yao company, and APP/PS1 bi-transgenic mice is provided by Nanjing Experimental Animal Center, and keeping away dark auto testing instrument is Chengdu TME Technology Co., Ltd.'s product.
2 experimental techniques
The foundation of 2.1 experimental grouies: take APP/PS1 bi-transgenic mice and be randomly divided into following drug treatment group and often organize 10 mices. Each therapeutic component does not give following medicine:
Normal group: gavage gives the normal saline of same volume;
Matched group: gavage gives the normal saline of same volume;
Model group: gavage gives the normal saline of same volume;
Experimental group 1: gavage gives the WWW tripeptides 200mg/kg/d of embodiment 4 preparation;
Experimental group 2: gavage gives the WWW tripeptides 250mg/kg/d of embodiment 4 preparation;
Experimental group 3: gavage gives the WWW tripeptides 300mg/kg/d of embodiment 4 preparation;
Experimental group 4: gavage gives the WWW tripeptides 250mg/kg/d+ tetrandrine 28mg/kg/d of embodiment 6 preparation;
Experimental group 5: gavage gives the WWW tripeptides 250mg/kg/d+ triptolide 5.6mg/kg/d of embodiment 7 preparation;
Experimental group 6: gavage gives the WWW tripeptides 250mg/kg/d+ tetrandrine 28mg/kg/d+ triptolide 5.6mg/kg/d of embodiment 8 preparation;
The detection of 2.2 step-through test behavioristicss
Keeping away active box dark two Room clearly of dark auto testing instrument, have a hole between two Room, bottom passes to copper grid. Before formal experiment, each group of APP/PS1 bi-transgenic mice is trained, APP/PS1 bi-transgenic mice head is carried Fang Renming room, hole. first adapt to environment 2min, then give darkroom copper grid logical 36V electric current, APP/PS1 bi-transgenic mice is subject to electric shock and namely runs away to bright room after entering darkroom, copper grid continue the 5min that is energized, and this is training process. Carrying out the test of memory of APP/PS1 bi-transgenic mice after 24h, record APP/PS1 bi-transgenic mice first time enters the time (keeping away dark incubation period) in darkroom, if being still introduced into darkroom in APP/PS1 bi-transgenic mice 5min. Its incubation period is counted as 300s.
3 statistical methods
Experimental data represents with ± s, carries out statistical analysis with SPSS11.5 software kit, adopts ANOVA and LSD ' Sposthoctest to carry out statistical analysis, indicates significant difference with P < 0.05.
4 experimental results
WWW tripeptides is as shown in table 2 on the impact of APP/PS1 bi-transgenic mice step-through test.
APP/PS1 bi-transgenic mice is kept away dark preclinical impact (± s) by table 2WWW tripeptides
Compared with normal group, ##P < 0.01; Compared with model group, * P < 0.05, * * P < 0.01;
As can be seen from Table 2, WWW tripeptides treatment group is kept away relative to APP/PS1 bi-transgenic mice and is significantly extended dark incubation period (P < 0.01), and APP/PS1 bi-transgenic mice is had significant prevention and therapeutic effect by prompting WWW tripeptides. It is embodied in:
1) the APP/PS1 bi-transgenic mice of WWW tripeptides each treatment group is kept away and is had significant difference compared with model group dark incubation period, all significantly shortens APP/PS1 bi-transgenic mice and keeps away dark incubation period, there is significant difference. WWW tripeptides is to A β1-42The Alzheimer's disease of caused APP/PS1 bi-transgenic mice has significant therapeutic effect;
2) the APP/PS1 bi-transgenic mice escape latency of WWW tripeptides each treatment group is variant, it is best by the effect of the table 2 known experimental group of data 2, this shows that the Alzheimer's disease of APP/PS1 bi-transgenic mice is had diversity by the WWW tripeptides of variable concentrations, and wherein the WWW tripeptides of 250mg/kg/d is best to the therapeutic effect of the Alzheimer's disease of APP/PS1 bi-transgenic mice;
3) each treatment group of compound recipe has significant difference compared with single medicine group, and this shows that experimental group 4 of the present invention, experimental group 5 and experimental group 6 combination exist significant synergism, is obviously enhanced, accelerates the therapeutic process of Alzheimer's disease on medication effect.
Showing in the embodiment of the present invention 9 or embodiment 10 that WWW tripeptides acts on the mechanism of Alzheimer's disease and acts on the medicine of Alzheimer's disease with other drug and do not conflict, it can be used in combination, and can obtain the synergism in treatment.
Claims (10)
1.WWW tripeptides purposes in preparation prevention or treatment Alzheimer disease drug.
2. medicinal usage as claimed in claim 1, it is characterised in that the animal dosage of WWW tripeptides is 1mg/kg d ~ 500mg/kg d.
3. medicinal usage as claimed in claim 1, it is characterised in that the animal dosage of WWW tripeptides is 50mg/kg d ~ 500mg/kg d.
4. medicinal usage as claimed in claim 1, it is characterised in that the animal dosage of WWW tripeptides is 100mg/kg d ~ 500mg/kg d.
5. medicinal usage as claimed in claim 2, it is characterised in that described animal dosage is 100mg/kg d ~ 300mg/kg d.
6. the medicinal usage as described in as arbitrary in claim 2-3, it is characterised in that described WWW tripeptides makes tablet, microspheres agent, powdery agent, oral liquid, injection.
7. the medicinal usage as described in as arbitrary in claim 1-4, it is characterised in that in the oral formulations of described medicine, in each preparation unit, content containing WWW tripeptides is 0.1mg-200mg.
8. the pharmaceutical composition containing WWW tripeptides, it is characterised in that it contains tetrandrine.
9. the pharmaceutical composition containing WWW tripeptides as claimed in claim 8, it is characterised in that it is possibly together with triptolide.
10. the pharmaceutical composition containing WWW tripeptides as claimed in claim 9, it is characterised in that WWW tripeptides in described pharmaceutical composition: tetrandrine: the weight ratio of triptolide is (1-500): (0.1-5): (0.1-5).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410497265.7A CN104258371B (en) | 2014-09-25 | 2014-09-25 | WWW tripeptides purposes in preparation treatment Alzheimer disease drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410497265.7A CN104258371B (en) | 2014-09-25 | 2014-09-25 | WWW tripeptides purposes in preparation treatment Alzheimer disease drug |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104258371A CN104258371A (en) | 2015-01-07 |
| CN104258371B true CN104258371B (en) | 2016-06-15 |
Family
ID=52150028
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410497265.7A Expired - Fee Related CN104258371B (en) | 2014-09-25 | 2014-09-25 | WWW tripeptides purposes in preparation treatment Alzheimer disease drug |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104258371B (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2002102868A (en) * | 1999-08-09 | 2004-01-27 | Трипеп Аб (Se) | Protein polymerization inhibitors and methods for their use |
| CN1112181C (en) * | 2000-05-26 | 2003-06-25 | 北京大学 | Application of tripterygium plant extract in preventing and curing diseases in nervous system |
| CN1328280C (en) * | 2002-11-28 | 2007-07-25 | 中国科学院上海药物研究所 | Tetrandrine and tetrandrine compound, synthesis and uses thereof |
| WO2005024057A1 (en) * | 2003-09-10 | 2005-03-17 | Galapagos Genomics N.V. | Method of identifying a compound that changes the amyloid-beta precursor protein processing in a cell |
| WO2005075505A1 (en) * | 2004-02-04 | 2005-08-18 | Postech Foundation | Peptides that antagonize fpr class receptor mediated signaling |
-
2014
- 2014-09-25 CN CN201410497265.7A patent/CN104258371B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN104258371A (en) | 2015-01-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Tang et al. | A novel drug candidate for Alzheimer's disease treatment: gx-50 derived from Zanthoxylum bungeanum | |
| JP5906267B2 (en) | Dried plant tissue and plant tissue extract for improving central nervous degenerative diseases accompanied by learning / memory disorders and movement disorders, and pharmaceuticals and foods containing them | |
| IL272596B1 (en) | Pridopidine for use in treating als | |
| CN111655669A (en) | Compositions and methods for treating neurological disorders including motor neuron diseases | |
| DE212018000131U1 (en) | Nano-drugs with delayed release against a neurodegenerative disease | |
| WO2019006734A1 (en) | Use of (+)-2-borneol in preparation of drug for promoting upregulation of expression of sphingosine kinase-1 and/or bdnf | |
| León-Moreno et al. | Kinematic changes in a mouse model of penetrating hippocampal injury and their recovery after intranasal administration of endometrial mesenchymal stem cell-derived extracellular vesicles | |
| CN114028406A (en) | Pharmaceutical composition for preventing, treating or delaying alzheimer's disease or dementia | |
| CN104622930A (en) | Application of babao (Chinese character) pill in treatment of senile dementia and pharmaceutical composition of babao pill | |
| US20220105106A1 (en) | Compositions and methods relating to use of agonists of alpha5-containing gabaa receptors | |
| CN104258371B (en) | WWW tripeptides purposes in preparation treatment Alzheimer disease drug | |
| CN104274817B (en) | WRW tripeptides purposes in preparation treatment Alzheimer disease drug | |
| CN104324359B (en) | RRY tripeptides purposes in preparation treatment Alzheimer disease drug | |
| CN103690581B (en) | A kind of pharmaceutical composition for the treatment of senile dementia | |
| CN104248750B (en) | The purposes of FWW tripeptides in preparation treatment Alzheimer disease drug | |
| DE60216142T2 (en) | Tropan derivatives having a dopamine reuptake inhibitory activity for the treatment of ischemic disorders | |
| CN104258372B (en) | Application of RGD tripeptides in preparation of medicines for treating Alzheimer disease | |
| EP4035669A1 (en) | Preparation of drug for treating alzheimer's disease | |
| CN102727484A (en) | Use of silymarin in preparations of drugs for treatment of Alzheimer's disease | |
| CN104306954A (en) | Use of WRY tripeptide in preparation of drug for treating Alzheimer's disease | |
| CN103520147A (en) | Application of puerarin or medicinal composition containing puerarin in preparation of medicament with effect of preventing or treating senile dementia | |
| CN109528719B (en) | Application of vinpocetine in preparation of medicine for preventing and/or treating altitude disease caused by acute altitude advancement | |
| ES2935705T3 (en) | A ligand of the GABA A receptor | |
| WO2019114676A1 (en) | New medical use of persimmon leaf extract and of preparation of persimmon leaf extract | |
| Faso | Effects of water crude leaf extract of Moringa oleifera Lam (Moringaceae) on normotensive rat blood pressure and isolated duodenum |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160615 Termination date: 20210925 |