CN114617914A - 一种防治神经退行性疾病的新型药物 - Google Patents
一种防治神经退行性疾病的新型药物 Download PDFInfo
- Publication number
- CN114617914A CN114617914A CN202011457961.7A CN202011457961A CN114617914A CN 114617914 A CN114617914 A CN 114617914A CN 202011457961 A CN202011457961 A CN 202011457961A CN 114617914 A CN114617914 A CN 114617914A
- Authority
- CN
- China
- Prior art keywords
- lithocarpus litseifolius
- extract
- lithocarpus
- disease
- litseifolius
- 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
- 239000003814 drug Substances 0.000 title claims abstract description 15
- 230000004770 neurodegeneration Effects 0.000 title claims abstract description 12
- 208000015122 neurodegenerative disease Diseases 0.000 title claims abstract description 12
- 241001365741 Lithocarpus litseifolius Species 0.000 claims abstract description 54
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 49
- 208000037259 Amyloid Plaque Diseases 0.000 claims abstract description 18
- 201000004810 Vascular dementia Diseases 0.000 claims abstract description 11
- 230000008021 deposition Effects 0.000 claims abstract description 8
- 230000036541 health Effects 0.000 claims abstract description 7
- 210000001320 hippocampus Anatomy 0.000 claims abstract description 7
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 7
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
- 210000002966 serum Anatomy 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- 239000000284 extract Substances 0.000 claims description 28
- 235000013616 tea Nutrition 0.000 claims description 11
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 claims description 9
- 230000004900 autophagic degradation Effects 0.000 claims description 9
- 229930003944 flavone Natural products 0.000 claims description 9
- 150000002212 flavone derivatives Chemical class 0.000 claims description 9
- 235000011949 flavones Nutrition 0.000 claims description 9
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 claims description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- 210000004027 cell Anatomy 0.000 claims description 8
- 230000002829 reductive effect Effects 0.000 claims description 8
- 206010012289 Dementia Diseases 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 6
- 230000004083 survival effect Effects 0.000 claims description 6
- 210000002865 immune cell Anatomy 0.000 claims description 5
- 230000005971 DNA damage repair Effects 0.000 claims description 4
- 239000004471 Glycine Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 238000001704 evaporation Methods 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
- 239000000203 mixture Substances 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 239000011347 resin Substances 0.000 claims description 4
- 229920005989 resin Polymers 0.000 claims description 4
- 238000002791 soaking Methods 0.000 claims description 4
- 230000004913 activation Effects 0.000 claims description 3
- 239000006210 lotion Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 230000001737 promoting effect Effects 0.000 claims description 3
- 229910002012 Aerosil® Inorganic materials 0.000 claims 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 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 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
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 239000000443 aerosol Substances 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 235000013361 beverage Nutrition 0.000 claims description 2
- 230000008827 biological function Effects 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 235000013373 food additive Nutrition 0.000 claims description 2
- 239000002778 food additive Substances 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 235000001727 glucose Nutrition 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000000832 lactitol Substances 0.000 claims description 2
- 235000010448 lactitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 claims description 2
- 229960003451 lactitol Drugs 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000865 liniment Substances 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 239000004033 plastic Substances 0.000 claims description 2
- 229920003023 plastic Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims 2
- 238000000746 purification Methods 0.000 claims 2
- -1 plasters Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 7
- 238000010175 APPswe/PSEN1dE9 Methods 0.000 description 10
- 206010039966 Senile dementia Diseases 0.000 description 10
- 241001633106 Lithocarpus Species 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 244000269722 Thea sinensis Species 0.000 description 8
- 238000011830 transgenic mouse model Methods 0.000 description 8
- 241000699660 Mus musculus Species 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 102000004889 Interleukin-6 Human genes 0.000 description 4
- 108090001005 Interleukin-6 Proteins 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 4
- 238000009825 accumulation Methods 0.000 description 4
- 235000009508 confectionery Nutrition 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 4
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 4
- 229960002930 sirolimus Drugs 0.000 description 4
- YFGHCGITMMYXAQ-UHFFFAOYSA-N 2-[(diphenylmethyl)sulfinyl]acetamide Chemical compound C=1C=CC=CC=1C(S(=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000219428 Fagaceae Species 0.000 description 3
- 102000003777 Interleukin-1 beta Human genes 0.000 description 3
- 108090000193 Interleukin-1 beta Proteins 0.000 description 3
- 102000008135 Mechanistic Target of Rapamycin Complex 1 Human genes 0.000 description 3
- 108010035196 Mechanistic Target of Rapamycin Complex 1 Proteins 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004958 brain cell Anatomy 0.000 description 3
- 210000005013 brain tissue Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229960001165 modafinil Drugs 0.000 description 3
- 230000003950 pathogenic mechanism Effects 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- AKCRNFFTGXBONI-UHFFFAOYSA-N torin 1 Chemical compound C1CN(C(=O)CC)CCN1C1=CC=C(N2C(C=CC3=C2C2=CC(=CC=C2N=C3)C=2C=C3C=CC=CC3=NC=2)=O)C=C1C(F)(F)F AKCRNFFTGXBONI-UHFFFAOYSA-N 0.000 description 3
- 238000002137 ultrasound extraction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 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 2
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 2
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 2
- 102000003952 Caspase 3 Human genes 0.000 description 2
- 108090000397 Caspase 3 Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- 101001074727 Homo sapiens Ribonucleoside-diphosphate reductase large subunit Proteins 0.000 description 2
- 101000575639 Homo sapiens Ribonucleoside-diphosphate reductase subunit M2 Proteins 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 102000019305 Microtubule associated protein 1A Human genes 0.000 description 2
- 108050006673 Microtubule associated protein 1A Proteins 0.000 description 2
- 102000004866 Microtubule-associated protein 1B Human genes 0.000 description 2
- 108090001040 Microtubule-associated protein 1B Proteins 0.000 description 2
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 2
- 102100036320 Ribonucleoside-diphosphate reductase large subunit Human genes 0.000 description 2
- 102100026006 Ribonucleoside-diphosphate reductase subunit M2 Human genes 0.000 description 2
- 102100024908 Ribosomal protein S6 kinase beta-1 Human genes 0.000 description 2
- 101710108924 Ribosomal protein S6 kinase beta-1 Proteins 0.000 description 2
- 244000228451 Stevia rebaudiana Species 0.000 description 2
- 235000006092 Stevia rebaudiana Nutrition 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000003920 cognitive function Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 150000002338 glycosides Chemical class 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 229940123729 mTOR kinase inhibitor Drugs 0.000 description 2
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000003959 neuroinflammation Effects 0.000 description 2
- 231100000915 pathological change Toxicity 0.000 description 2
- 230000036285 pathological change Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 208000006888 Agnosia Diseases 0.000 description 1
- 241001047040 Agnosia Species 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010070246 Executive dysfunction Diseases 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 1
- 102100034533 Histone H2AX Human genes 0.000 description 1
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- 101001067891 Homo sapiens Histone H2AX Proteins 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 241000579722 Kocuria Species 0.000 description 1
- 102000009308 Mechanistic Target of Rapamycin Complex 2 Human genes 0.000 description 1
- 108010034057 Mechanistic Target of Rapamycin Complex 2 Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- HOKKHZGPKSLGJE-UHFFFAOYSA-N N-methyl-D-aspartic acid Natural products CNC(C(O)=O)CC(O)=O HOKKHZGPKSLGJE-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 206010062519 Poor quality sleep Diseases 0.000 description 1
- 108010041388 Ribonucleotide Reductases Proteins 0.000 description 1
- 102000000505 Ribonucleotide Reductases Human genes 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 108020000411 Toll-like receptor Proteins 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000003930 cognitive ability Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 239000002475 cognitive enhancer Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229940100601 interleukin-6 Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 1
- 230000003962 neuroinflammatory response Effects 0.000 description 1
- 230000007171 neuropathology Effects 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 230000003976 synaptic dysfunction Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 238000011820 transgenic animal model Methods 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/49—Fagaceae (Beech family), e.g. oak or chestnut
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Botany (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medical Informatics (AREA)
- Biotechnology (AREA)
- Alternative & Traditional Medicine (AREA)
- Microbiology (AREA)
- Polymers & Plastics (AREA)
- Hospice & Palliative Care (AREA)
- Food Science & Technology (AREA)
- Nutrition Science (AREA)
- Psychiatry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
本发明提供了木姜叶柯在制备预防或治疗神经退行性疾病例如阿尔茨海默病或血管性痴呆药物或保健品中的应用。其中，所述木姜叶柯能够1)抑制皮层和海马中老年斑(Senile Plaques,简称SP)沉积；和2)抑制血清内炎症因子表达。
Description
技术领域
本发明涉及分子生物学领域，具体涉及一种植物提取物在防治老年性痴呆中的用途。
背景技术
阿尔茨海默症(Alzheimer's disease，简称AD)是一种进展性和致命性的神经退行性疾病，主要表现为认知功能下降及日常生活能力逐渐下降，是老年性痴呆最常见的病因，全世界约有4680万患者。迄今虽无中国范围的AD流行病学现况数据；但文献显示2010年中国65至69岁人群的AD现患率为2.6％(0.0–28.2％)、95至99岁人群的现患率为60.5％(39.7-81.3％)，2010年中国AD患者数估计为569万人(385-753万)，AD的标准化死亡比中位数为1.94:1(四分位间距1.74-2.45)。由于AD的患病率不断升高、持续时间较长、护理治疗费用较高等特性，预期AD在未来数十年内将为一个持续的重大的公共卫生问题。
目前最有影响力的AD致病机制假说是淀粉样蛋白假说，该假说认为Amyloidβ(简称Aβ)肽在脑组织中的蓄积是AD的主要驱动因素：AD的标志性病理学特征是细胞外淀粉样斑块(老年斑)在脑内的沉积，这些淀粉样斑块主要由Aβ肽组成。体内、外证据均提示，Aβ肽的可溶性寡聚体具有神经毒性，被认为是AD的致病因素。Aβ在脑内的蓄积和积聚会激发病理生理学事件的级联效应，包括突触功能障碍、形成神经原纤维缠结、神经元丢失、神经递质缺乏和痴呆等。另外，大量神经病理学、临床流行病学及动物模型等研究证实神经炎症是AD重要的神经生物特征，因此神经炎症也是AD治疗药物研究的重要靶点之一。其次，新的研究认为自噬的缺陷也可能会导致包括阿尔茨海默氏病在内的许多神经退行性疾病。
对于确诊的AD痴呆，已批准药物有：1)抑制脑内的乙酰胆碱酶活性的donepezil
galantamine
以及rivastigmine
2)抗N甲基D天冬氨酸受体的memantine
等。这些药物虽可以暂时缓解或改善患者的认知和精神症状等，但均无法阻止或逆转病情进展，疗效也差强人意。
木姜叶柯(学名：Lithocarpus litseifolius(Hance)Chun)，也称为多穗柯或多穗石柯(Lithocarpus polystachyrus Rehd或Lithocarpus polystachyaw(wall.)Rehd)，别名溆浦瑶茶、甜茶、甜叶子树、胖稠、甜味茶、大叶稠子、苷茶等，系壳斗科石柯属常绿乔木。以野生状态分布于我国长江以南各省区海拔500米至2500米以上的低山密林中，尤以江西、广西、湖南、安徽等省资源丰富。木姜叶柯的化学成分主要为黄酮类和三萜类，其中二氢查尔酮类是其甜味的主要来源，现代研究初步表表明，木姜叶柯具有较广的生物活性，如降血糖、抗氧化、抗过敏和抗微生物，且安全无毒。
因此，研究与开发防治老年痴呆天然安全的药物或保健食品成为当今重要的研究课题。木姜叶柯的提取物是否可以用于防治老年性痴呆，从病理病因上阻止或逆转病情进展，本发明旨在解决该问题。
发明内容
本发明人的研究发现木姜叶柯能明显改善阿尔茨海默症模型动物全身炎症症状，可以有效改善大脑海马区老年斑的沉积，并高效抑制哺乳动物雷帕霉素靶蛋白复合体(mammalian target of rapamycin complex 1，mTORC1)通路，促进自噬标志分子微管结合蛋白1A/1B轻链3I型(microtubule-associated protein 1A/1B-light chain 3I，LC 3I)到LC 3II转化，从而大大强化细胞清理代谢废物机能，使得细胞获得“再生”，对包括阿尔茨海默症为主的老年性痴呆症均有确切的疗效。
本发明公开了木姜叶柯在制备预防或治疗神经退行性疾病诸如老年性痴呆的药物或保健品中的应用。
在一个实施例中，木姜叶柯为一种木姜叶柯提取物或包含木姜叶柯提取物的组合物。
在一个实施例中，所述木姜叶柯的提取物的制备方法为：
使用乙醇浸泡木姜叶柯的叶子，采用超声波辅助提取，提取后的乙醇溶液用旋转蒸发器减压蒸发乙醇，得到木姜叶柯的提取物；使用树脂纯化木姜叶柯的提取物。所述木姜叶柯的提取物为木姜叶柯黄酮。
在一个具体实施例中，所述木姜叶柯的干燥至恒重的叶经过粉粹，过40-100目筛诸如60目筛后，用50％至95％诸如70％乙醇浸泡12-36小时，诸如24小时，然后采用超声波辅助提取方法提取木姜叶柯黄酮。其中，优选地，粉碎的叶子过40、50、60、70、80、90、或100目筛；浸泡粉碎叶的乙醇浓度优选为50％至95％，例如50％、60％、70％、80％、90％、95％；浸泡的时间优选12、16、20、24、28、32、或36小时。
在一个具体实施例中，浸泡粉碎的叶的乙醇浓度70％、粉碎的叶和乙醇的固液重量比1:20-1:50，例如1:20、1:25、1:30、1:35、1:40、1:45、1:50，优选为1:35；超声波辅助提取的超声功率540W，超声提取10-30分钟，优选为15分钟。
使用旋转蒸发器减压蒸发提取后的乙醇，得到木姜叶柯黄酮。木姜叶柯黄酮用AB-8树脂纯化，工艺条件为：吸附流速为0.2-1.0mL/分钟，优选为0.5mL/分钟；洗脱乙醇浓度为30％至90％诸如90％，洗脱体积为1.0-3.0BV，优选为1.875BV(床体积)，洗脱剂流速为0.5-2.0mL/分钟，优选为1mL/分钟。
如前述的神经退行性疾病选自阿尔茨海默病、血管性痴呆、和阿尔茨海默病和血管性痴呆并存的混合性痴呆中的至少一种。
优选地，老年性痴呆为阿尔茨海默病。
如前任意所述药品的剂型包括但不限于以下组中的至少一种：丸剂、散剂、颗粒剂、片剂、煎膏剂、贴膏剂、滴丸剂、胶囊剂、糖浆剂、合剂、酒剂、酊剂、茶剂、搽剂、洗剂、涂膜剂、膏药、气雾剂、喷雾剂、注射剂、露剂等。
其中，所述药品还包括药学上可接受的载体或辅料，所述辅料包括但不限于以下组中的至少一种：淀粉、糊精、乳糖、微晶纤维素、羟丙甲基纤维素、聚乙二醇、硬脂酸镁、微粉硅胶、木糖醇、乳糖醇、葡萄糖、甘氨酸、甘露醇、甘氨酸等。
如前任意所述保健品包括片剂、胶囊剂、口服液、液体饮料、保健茶、和食品添加剂中的至少一种。
在一个具体实施例中，所述木姜叶柯能够具有以下生物学功能的一种以上：
1)抑制皮层和海马中老年斑(Senile Plaques,简称SP)沉积；
2)抑制血清内炎症因子表达；
3)抑制mTORC1的激活；
4)促进细胞自噬；
5)维持免疫细胞的存活和促进DNA损伤修复。
发明有益效果
与现有技术相比，本发明的有益效果在于本发明首次公开木姜叶柯提取物在制备治疗阿尔茨海默症药物及保健品中的用途。采用相关药理学实验进行木姜叶柯提取物防治阿尔茨海默症的药效学评价，分别从改善全身炎症症状、抑制Aβ的沉积、促进细胞自噬，以及帮助细胞损伤修复等多方面，阐明该提取物多途径、多靶点治疗阿尔茨海默病的用途。因此，木姜叶柯提取物在治疗阿尔茨海默症中具有广泛的应用背景，可应用于制备抗阿尔茨海默症药物和保健品。
附图说明
图1示出木姜叶柯提取物对APP/PS1双转基因小鼠皮层和海马中老年斑(SP)的影响。
图2示出木姜叶柯提取物对APP/PS1双转基因小鼠血清内炎症因子的影响。
图3示出木姜叶柯提取物对mTORC1的抑制作用。
图4示出木姜叶柯提取物可以促进细胞自噬。
图5示出穗柯提取物可以维持免疫细胞的存活和促进DNA损伤修复。
具体实施方式
下面将通过具体描述，对本发明作进一步的说明。
除非另有限定，本文中所使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解相同的含义。
本申请中，单数形式“一个”、“该”包括复数对象，除非上下文另外清楚规定。
定义
如本文所用的术语“老年性痴呆”、“老年痴呆”可互换，是指一种进行性发展的神经系统退行性疾病。临床上以记忆障碍、失语、失用、失认、视空间技能损害、执行功能障碍以及人格和行为改变等为代表症状，老年性痴呆包括阿尔茨海默病、血管性痴呆(又称老年人血管性痴呆)、阿尔茨海默病和血管性痴呆并存的混合性痴呆等中的一种以上。阿尔茨海默病致病机制假说是淀粉样蛋白假说，该假说认为Amyloidβ(简称Aβ)肽在脑组织中的蓄积是AD的主要驱动因素：AD的标志性病理学特征是细胞外淀粉样斑块(老年斑)在脑内的沉积，这些淀粉样斑块主要由Aβ肽组成。血管性痴呆中，致病机理主要是由于血管的病变阻碍了血流，脑细胞无法得到充足的氧气与营养，由此便会导致脑细胞的死亡与认知功能受损，出现痴呆的症状。研究证明，在血管性痴呆进程中，神经炎症反应的起着很重要的作用。脑细胞缺氧导致了内皮细胞功能障碍，从而增加了血脑屏障渗透性，这导致了包括纤维蛋白原在内的血浆蛋白的外渗进入大脑。纤维蛋白原激活了CD11b和Toll样受体，导致活性氧的产生，促炎细胞因子的产生，和小神经胶质细胞、星形胶质细胞等的活化。炎症反过来又加剧了血脑屏障的瓦解，并诱导内皮细胞粘附分子的表达，导致白细胞和血小板粘附和微血管闭塞，从而加重了血管性痴呆的症状。
如本文所用的术语“木姜叶柯”学名为Lithocarpus litseifolius(Hance)Chun，又称为“溆浦瑶茶”或“多穗石柯”、“多穗柯”(拉丁名为Lithocarpus polystachyus(Wall.)或“Lithocarpus polystachyaw(wall.)Rehd”Rehd.、)，是指壳斗科柯属植物，，别名甜茶、甜叶子树、胖稠、甜味茶、大叶稠子、苷茶、多穗柯等，系壳斗科石柯属常绿乔木。
如本文所用的术语“木姜叶柯提取物”是指从木姜叶柯中经过提取获得的活性物质诸如黄酮。其中木姜叶柯提取物可以具有防治神经退行性疾病诸如老年性痴呆的功能。
实施例
通过以下实施例进一步说明本发明。提供实施例仅用于说明目的，并且不应被解释为以任何方式限制本发明的范围或内容。
实施例1：木姜叶柯提取物(ONC008)的提取方法
将干燥至恒重的木姜叶柯叶粉粹过60目铜筛后用70％乙醇浸泡24小时,然后采用超声波辅助提取方法提取木姜叶柯黄酮，具体参数为：乙醇浓度70％、固液比1:35、超声功率540W、超声提取15分钟，最后用旋转蒸发器减压蒸发提取后的乙醇，得到木姜叶柯黄酮。木姜叶柯黄酮用AB-8树脂纯化，工艺条件为：吸附流速为0.5mL/分钟，洗脱乙醇浓度为90％，洗脱体积为1.875BV(床体积)，洗脱剂流速为1mL/分钟。
实施例2：在体研究证明ONC008对APP/PS1双转基因痴呆小鼠具有治疗作用
1材料
1.1实验动物
2月龄APP/PS1双转基因小鼠8只，雄性，体重25±2g，SPF级。APP/PS1双转基因小鼠能够很好地模拟AD的病理变化，是目前国际上公认的AD转基因动物模型，因此被广泛地应用于AD相关的研究。
1.2实验药物及试剂
通过实施例1制备得到的木姜叶柯提取物(编号为ONC008)的粉末，用温蒸馏水溶解；肿瘤坏死因子-α(Tumor necrosis factor alpha，简称TNF-α)抗体(#3707，Cellsignaling Technology)、白细胞介素1族(Interleukin 1beta，简称IL-1β)抗体(sc-32294，Santa Cruz Biotechnology)、白细胞介素6族(IL-6)抗体(ab6672，Abcam)和Aβ抗体(6E10，Biolegend)。
1.3主要仪器
Nikon A1R共聚焦显微镜，NIS-Elements计算机彩色图像处理系统，徕卡冰冻组织切片机，Fuji图像分析系统。
2方法
2.1分组与给药
按体重一致原则，随机将APP/PS1双转基因小鼠分为对照组和ONC008给药组，每组4只。模型组给以每日400mg/kg的ONC008，对照组给以等体积蒸馏水。各组小鼠给药8个月，至10月龄时处死提取组织样品。
2.2组织样品处理
提取血液和脑组织。从血液中提取血清并检测其中的细胞因子TNF-α、IL-1β和IL-6。一个脑半球用于提取蛋白样本，对另一半球进行多聚甲醛固定及冰冻切片和免疫组化染色。
2.3统计学处理
所得数据以均数±标准差表示，采用统计软件SigmaPlot12.5进行统计分析，组间数据比较用学生t检验，以P＜0.05为差异有显著性意义。
3实验结果
尽管认知能力的减退包括记忆力障碍是阿尔茨海默症的临床表现之一，但这并不意味着能够改善记忆力的药物就能治疗阿尔茨海默症。例如，现有技术中的相反教导，觉醒促进剂莫达非尼(Modafinil)作为一种认知增强剂被广泛使用。但是莫达非尼在临床测试中并不能改善阿尔茨海默症病人的病症(参见Rea R，et al.Apathy in Alzheimer'sdisease:any effective treatment.Scientific World Journal,2014:421385)。然而，本发明是首次揭示了多穗柯甜茶提取物可以阻止或逆转病情进展，具有确切的疗效。
3.1ONC008对APP/PS1双转基因小鼠中老年斑的影响结果显示，与对照组比较，模型组小鼠皮层中老年斑数量和所占面积没有明显变化，模型组小鼠海马中老年斑数量没有明显变化，但所占脑区面积比显著减少，说明ONC008可减少APP/PS1双转基因小鼠海马中老年斑沉积(参见表1和图1)。
表1 ONC008对APP/PS1双转基因小鼠皮层和海马中老年斑(SP)的影响
3.2 ONC008对APP/PS1双转基因小鼠血清内炎症因子的影响结果显示，与对照组比较，TNF-α、IL-1β、IL-6的蛋白表达水平，均显著性降低，证明ONC008具有抗炎症作用(参见图2)。
实施例3：体外研究证明ONC008可激活细胞自噬从而促进细胞代谢废物的排除。
1.实验方法
分别给人上皮细胞系MCF-10A以1mg/mL的ONC008、100nM雷帕霉素(rapamycin)、10nM mTOR激酶抑制剂Torin1、或DMSO作为对照。MCF-10A经过处理5或12小时后，提取细胞总蛋白并利用免疫印迹法分别检测其中pS6(磷酸化位点S235/6)、pS6K1(磷酸化位点T389)和pAKT(磷酸化位点S473)，或自噬标志分子LC3，其中以GAPDH为上样对照。
2.实验结果
2.1结果如图3所示雷帕霉素抑制了pS6和pS6K1/2，却激活了Akt，证明雷帕霉素抑制了mTORC1，同时激活了S6K1/2-IRS-PI3K负反馈通路。mTOR激酶抑制剂Torin1抑制了pS6、pS6K1/2和pAKT，证明Torin1同时抑制了mTORC1和mTORC2。而ONC008减少了pS6和pS6K1/2，但是没有改变pAKT，证明ONC008抑制了mTORC1和S6K1/2。
2.2如图4结果显示ONC008可以将LC3I转换为LC3II，表明ONC008可以促进细胞自噬。
实施例4：ONC008可以维持免疫细胞的存活
1.实验方法
通过磁性分拣法用CD34分选磁珠从人类脐带血细胞中提纯造血干细胞/祖细胞并进行培养，并加入4μg/mLONC008或对照纯水分别处理72小时。提取细胞总蛋白并利用免疫印迹法检测其中p-NFκB-65、LC3、裂解的caspase 3、ribonucleotide reductase subunits1和2(RRM1 and RRM2)、p-S6K1、pS6、和γH2AX，其中以GAPDH为上样对照。
2.实验结果
2.1如图5左所示，ONC008可以促进LC3I转换为LC3II，并减少了细胞凋亡标志分子裂解的caspase 3，提示ONC008可以通过维持免疫细胞的存活来增强免疫力。
2.2如图5右所示，ONC008增加了在DNA修复过程中起到重要作用的RRM1和RRM2的表达，提示ONC008可以促进DNA损伤修复，从而提高细胞的存活率。
通过引用并入
本文引用的每个专利文献和科学文献的全部公开内容通过引用并入本文用于所有目的。
等效
本发明可以在不脱离其基本特征的情况下以其他具体形式实施。因此，前述实施例被认为是说明性的，而不是对本文所述的本发明的限制。本发明的范围由所附权利要求书而不是由前述说明书表示，并且意在将落入权利要求书的等同物的含义和范围内的所有改变包括在其中。
Claims (12)
1.木姜叶柯在制备预防或治疗神经退行性疾病的药物或保健品中的应用。
2.如权利要求1所述的应用，其中，木姜叶柯为一种木姜叶柯的提取物或包含木姜叶柯的提取物的组合物。
3.如权利要求2所述的应用，其中，所述木姜叶柯的提取物的制备方法为：
使用乙醇浸泡粉粹的木姜叶柯的叶，采用超声波辅助提取，提取后的乙醇溶液用旋转蒸发器减压蒸发乙醇，得到木姜叶柯的提取物；使用树脂纯化木姜叶柯的提取物。
4.如权利要求3所述的应用，其中，所述木姜叶柯的提取物为木姜叶柯黄酮。
5.如权利要求2所述的应用，其中，所述浸泡木姜叶柯的乙醇浓度为50％至95％，所述纯化步骤中洗脱液乙醇浓度为30％至90％。
6.如权利要求5所述的应用，其中所述浸泡木姜叶柯的乙醇浓度为70％，所述纯化步骤中洗脱液乙醇浓度为90％。
7.如权利要求1所述的应用，其中，神经退行性疾病选自阿尔茨海默病、血管性痴呆、和阿尔茨海默病和血管性痴呆并存的混合性痴呆中的至少一种。
8.如权利要求7所述的应用，其中，神经退行性疾病为阿尔茨海默病。
9.如权利要求1至8任一项所述的应用，其中，所述药品的剂型选自丸剂、散剂、颗粒剂、片剂、煎膏剂、贴膏剂、滴丸剂、胶囊剂、糖浆剂、合剂、酒剂、酊剂、茶剂、搽剂、洗剂、涂膜剂、膏药、气雾剂、喷雾剂、注射剂、和露剂等的至少一种。
10.如权利要求9所述的应用，其中，所述药品还包括药学上可接受的载体或辅料，所述辅料选自淀粉、糊精、乳糖、微晶纤维素、羟丙甲基纤维素、聚乙二醇、硬脂酸镁、微粉硅胶、木糖醇、乳糖醇、葡萄糖、甘氨酸、甘露醇、和甘氨酸等的至少一种。
11.如权利要求1至8任一项所述的应用，其中，所述保健品选自片剂、胶囊剂、口服液、液体饮料、保健茶、和食品添加剂的至少一种。
12.如权利要求1至8任一项所述的应用，其中，所述木姜叶柯能够具有以下生物学功能的至少一种：
1)抑制皮层和海马中老年斑(SP)沉积；
2)抑制血清内炎症因子表达；
3)抑制mTORC1的激活；
4)促进细胞自噬；
5)维持免疫细胞的存活和促进DNA损伤修复。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011457961.7A CN114617914A (zh) | 2020-12-10 | 2020-12-10 | 一种防治神经退行性疾病的新型药物 |
| PCT/CN2021/136809 WO2022121986A1 (zh) | 2020-12-10 | 2021-12-09 | 一种防治神经退行性疾病的新型药物 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011457961.7A CN114617914A (zh) | 2020-12-10 | 2020-12-10 | 一种防治神经退行性疾病的新型药物 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114617914A true CN114617914A (zh) | 2022-06-14 |
Family
ID=81894998
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011457961.7A Pending CN114617914A (zh) | 2020-12-10 | 2020-12-10 | 一种防治神经退行性疾病的新型药物 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN114617914A (zh) |
| WO (1) | WO2022121986A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114931591A (zh) * | 2022-04-28 | 2022-08-23 | 西南医科大学 | 木芙蓉叶提取物在治疗神经退行性疾病药物中的应用 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115474640A (zh) * | 2022-09-30 | 2022-12-16 | 良甜生物医药科技江苏有限公司 | 一种功能性木姜叶柯茶饮及其制备方法 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101904882A (zh) * | 2010-07-28 | 2010-12-08 | 广西壮族自治区中医药研究院 | 一种木姜叶柯总黄酮的制备方法 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101874824B (zh) * | 2009-05-01 | 2015-07-15 | 常州高新技术产业开发区三维工业技术研究所有限公司 | 一种含三叶苷的活性提取物及其用途 |
| CN102845577A (zh) * | 2012-09-24 | 2013-01-02 | 程小榕 | 野生甜茶叶和野生葛根处复方制成的灵茶 |
| CN103961395A (zh) * | 2014-05-21 | 2014-08-06 | 吕健军 | 一种植物提取物组合物及其用于调控血糖的方法 |
| CN104431063A (zh) * | 2014-11-13 | 2015-03-25 | 董珉 | 防治心脑血管疾病的甜茶功能饮品及其制备方法 |
| CN105037569B (zh) * | 2015-05-19 | 2017-11-03 | 湘潭大学 | 一种甜叶悬钩子水溶性多糖用于保护肝脏及激活乙醛脱氢酶的应用 |
-
2020
- 2020-12-10 CN CN202011457961.7A patent/CN114617914A/zh active Pending
-
2021
- 2021-12-09 WO PCT/CN2021/136809 patent/WO2022121986A1/zh active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101904882A (zh) * | 2010-07-28 | 2010-12-08 | 广西壮族自治区中医药研究院 | 一种木姜叶柯总黄酮的制备方法 |
Non-Patent Citations (3)
| Title |
|---|
| 于凡等: "别样茶预防轻度认知障碍的可行性探讨", 《中华中医药杂志》 * |
| 雷鸣等: "多穗石柯化学成分及药理作用研究进展", 《中药药理与临床》 * |
| 马琮鉴等: "根皮苷药理作用研究进展", 《医药导报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114931591A (zh) * | 2022-04-28 | 2022-08-23 | 西南医科大学 | 木芙蓉叶提取物在治疗神经退行性疾病药物中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2022121986A1 (zh) | 2022-06-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5712207B2 (ja) | 脳疾患及び状態の予防及び治療のための組成物及び方法 | |
| Wu et al. | New insights into the role and mechanisms of ginsenoside Rg1 in the management of Alzheimer’s disease | |
| KR20180100234A (ko) | 호두 올리고펩타이드 분말 및 그의 제조방법과 용도 | |
| Guan et al. | Puerarin ameliorates retinal ganglion cell damage induced by retinal ischemia/reperfusion through inhibiting the activation of TLR4/NLRP3 inflammasome | |
| JP2009534321A (ja) | 漢方薬組成物ならびにこれらの調製方法および使用 | |
| CN114617914A (zh) | 一种防治神经退行性疾病的新型药物 | |
| CN109414427A (zh) | 包含基于萘醌的化合物作为活性成分的用于预防或改善作为与抗癌药物治疗相关的副作用的疲劳、恶病质、疼痛、认知衰退和造血干细胞减少的组合物 | |
| CN103857400B (zh) | 玫瑰红景天提取物和分离的化合物及其在治疗神经变性疾病中的应用 | |
| KR101449469B1 (ko) | 홍삼추출물에 의한 망막 재생을 통한 눈 기능 저하 및 황반 변성 질환의 예방 및 치료용 조성물 | |
| KR102278102B1 (ko) | 엑소좀을 유효성분으로 포함하는 급성 간질환의 예방 또는 치료용 조성물 | |
| Chhabra et al. | Matrine exerts its neuroprotective effects by modulating multiple neuronal pathways | |
| US8940788B2 (en) | Anti-angiogenic composition containing macrolactin A and a derivative thereof as active ingredients | |
| KR20190098052A (ko) | 지방줄기세포 유래의 엑소좀을 유효성분으로 포함하는 조성물의 궤양성 대장염의 개선 용도 | |
| Wang et al. | Grape seed extract attenuates demyelination in experimental autoimmune encephalomyelitis mice by inhibiting inflammatory response of immune cells | |
| KR20190051150A (ko) | 장수풍뎅이 유충의 추출물을 함유하는 항알레르기성 조성물 | |
| KR101539573B1 (ko) | 진세노사이드 화합물 K (compound K)에 의한 망막 재생을 통한 눈 기능 저하 및 황반 변성 질환의 예방 및 치료용 조성물 | |
| US20190142886A1 (en) | Ecklonia cava extract and a pharmaceutical composition for preventing or treating vascular diseases comprising the same as an active ingredient | |
| EP3235502A2 (en) | Composition containing poria cocos bark extract for preventing, improving or treating neurodegenerative disorders | |
| KR20210119974A (ko) | 뇌 내 염증의 억제 또는 경감제 | |
| KR20170040177A (ko) | 톱니모자반 추출물을 유효성분으로 포함하는 항치매용 조성물 | |
| Korivi et al. | New strategies from natural materials to fight against diet-induced metabolic disorders (Part-II) | |
| CN114642707A (zh) | 含有灯盏细辛、人参、麦冬、五味子的药物组合物 | |
| KR101972070B1 (ko) | 장수말벌의 일벌로부터 분리된 봉독을 함유하는 통풍의 예방 또는 치료용 조성물 | |
| CN110638854A (zh) | 一种胸腺路径预防或/和治疗阿尔兹海默症的药物或保健食品 | |
| CN109662986A (zh) | 一种柿叶提取物及其制剂的新医药用途 |
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 |