CN105412074A - 槲皮素在制备预防及治疗与ApoE蛋白水平有关疾病的药物中的应用 - Google Patents

槲皮素在制备预防及治疗与ApoE蛋白水平有关疾病的药物中的应用 Download PDF

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CN105412074A
CN105412074A CN201510988203.0A CN201510988203A CN105412074A CN 105412074 A CN105412074 A CN 105412074A CN 201510988203 A CN201510988203 A CN 201510988203A CN 105412074 A CN105412074 A CN 105412074A
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庄江兴
卜国军
许华曦
章喜林
胡进
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Abstract

槲皮素在制备预防及治疗与ApoE蛋白水平有关疾病的药物中的应用，涉及槲皮素。槲皮素可增加ApoE蛋白水平，减少AD小鼠模型大脑皮层中不溶性Aβ水平及总Aβ水平，减少AD小鼠模型大脑皮层中Aβ斑块数量；可作为治疗AD药物的新的化合物；可增加永生化星形胶质细胞和原代星形胶质细胞胞外ApoE水平；可抑制细胞外ApoE蛋白降解；可增加AD小鼠模型的大脑皮层中apoE蛋白水平，减少大脑皮层中不溶性Aβ水平和总Aβ水平；可减少AD小鼠模型的大脑皮层中Aβ斑块数量。槲皮素可在制备治疗ApoE蛋白水平降低引起的疾病药物中的应用，疾病包括但不限于ApoE蛋白水平降低引起的机能障碍疾病、阿尔茨海默病。

Description

槲皮素在制备预防及治疗与ApoE蛋白水平有关疾病的药物中的应用
技术领域
本发明涉及槲皮素，尤其是涉及槲皮素在制备预防及治疗与ApoE蛋白水平有关疾病的药物中的应用。
背景技术
阿尔茨海默病(alzheimersdisease，AD)是一种与年龄密切相关的神经退行性疾病,主要病理特征为脑神经细胞外出现β-淀粉样蛋白(Aβ)聚集的老年斑和脑神经细胞内Tau蛋白异常聚集形成的神经纤维缠结。大量证据表明，Aβ在大脑中的积累、沉积是AD发病早期重要特征和发病机制。Aβ的积累、聚集和沉积在AD发病过程中起着重要作用，大脑中过量的Aβ会引起神经炎症和神经毒性从而引发AD。因此，促进Aβ从大脑中清除，减少Aβ在大脑中积累是治疗AD的有效途径。载脂蛋白E(apolipoproteinE，ApoE)是一种与胆固醇类物质运输相关的血浆蛋白，能结合血液中的脂肪和细胞表面受体，在生物体内起着十分重要的作用。ApoE是一种多态性蛋白，与多种疾病相关。其中，ApoE的基因型多态性与AD的发病风险高度相关,并且ApoE在Aβ代谢过程中起重要作用。增加AD大脑内ApoE水平可以促进大脑Aβ清除，提高胆固醇的运输，维持突触可塑性和减弱神经炎症反应，这些因素与AD发病密切相关。在AD患者中，ApoE在血浆及脑脊液中的表达水平往往低于正常人。因此，通过提高ApoE的水平促进Aβ代谢、提高胆固醇的运输、维持突触可塑性和减弱神经炎症反应可能预防或推迟AD的发生和发展。最近研究发现RXRs的激动剂bexarotene和LXRs激动剂TO901317能提高大脑中ApoE的水平，促进Aβ42的清除，缓和AD小鼠的认知和记忆缺陷[13-15]。另外，Pioglitazone(一种PPARγ的激动剂)，也可以增加ApoE表达，减少淀粉样斑的形成，改善AD小鼠记忆[9]。这些研究表明，提高ApoE的表达水平与脂化程度可以有效促进Aβ清除，减少AD模型小鼠淀粉样斑形成并改善小鼠AD相关症状，对以ApoE作为AD治疗靶点具有重要的指导意义。
实验中所用ApoE3或apoE4基因替换星形胶质细胞系(immortalizedastrocytes)来源于人类ApoE3或apoE4基因替换小鼠Apoe基因的转基因小鼠[16]。AD转基因小鼠模型为表达5种家族性AD突变基因(3xAPP[K670N/M671L(Swedish)+I716V(Florida)+V717I(London)and2xPS1[M146L+L286V]])的转基因小鼠模型[17]。实验中分别用TBS缓冲液(Tris-HCl),TBSX缓冲液(包含1％TritonX-100)和GDN-HCl(含5M盐酸胍缓冲液)分别提取TBS可溶性，TBSX缓冲液可溶和不溶性(GDN-HCl中可溶)Aβ[18]。
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[9]Mandrekar-Colucci,S.,Karlo,J.C.,Landreth,G.E.,2012.Mechanismsunderlyingtherapidperoxisomeproliferator-activatedreceptor-gamma-mediatedamyloidclearanceandreversalofcognitivedeficitsinamurinemodelofAlzheimer'sdisease.JNeurosci32,10117-10128.
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[12]Cruchaga,C.,Kauwe,J.S.,Nowotny,P.,Bales,K.,Pickering,E.H.,Mayo,K.,Bertelsen,S.,Hinrichs,A.,Alzheimer'sDiseaseNeuroimaging,I.,Fagan,A.M.,Holtzman,D.M.,Morris,J.C.,Goate,A.M.,2012.CerebrospinalfluidAPOElevels:anendophenotypeforgeneticstudiesforAlzheimer'sdisease.HumMolGenet21,4558-4571.
[13]Cramer,P.E.,Cirrito,J.R.,Wesson,D.W.,Lee,C.Y.,Karlo,J.C.,Zinn,A.E.,Casali,B.T.,Restivo,J.L.,Goebel,W.D.,James,M.J.,Brunden,K.R.,Wilson,D.A.,Landreth,G.E.,2012.ApoE-directedtherapeuticsrapidlyclearbeta-amyloidandreversedeficitsinADmousemodels.Science335,1503-1506.
[14]iddell,D.R.,Zhou,H.,Comery,T.A.,Kouranova,E.,Lo,C.F.,Warwick,H.K.,Ring,R.H.,Kirksey,Y.,Aschmies,S.,Xu,J.,Kubek,K.,Hirst,W.D.,Gonzales,C.,Chen,Y.,Murphy,E.,Leonard,S.,Vasylyev,D.,Oganesian,A.,Martone,R.L.,Pangalos,M.N.,Reinhart,P.H.,Jacobsen,J.S.,2007.TheLXRagonistTO901317selectivelylowershippocampalAbeta42andimprovesmemoryintheTg2576mousemodelofAlzheimer'sdisease.MolCellNeurosci34,621-628.
[15]Vanmierlo,T.,Rutten,K.,Dederen,J.,Bloks,V.W.,vanVark-vanderZee,L.C.,Kuipers,F.,Kiliaan,A.,Blokland,A.,Sijbrands,E.J.,Steinbusch,H.,Prickaerts,J.,Lutjohann,D.,Mulder,M.,2011.LiverXreceptoractivationrestoresmemoryinagedADmicewithoutreducingamyloid.NeurobiolAging32,1262-1272.
[16]Morikawa,M.,Fryer,J.D.,Sullivan,P.M.,Christopher,E.A.,Wahrle,S.E.,DeMattos,R.B.,O'Dell,M.A.,Fagan,A.M.,Lashuel,H.A.,Walz,T.,Asai,K.,Holtzman,D.M.,2005.Productionandcharacterizationofastrocyte-derivedhumanapolipoproteinEisoformsfromimmortalizedastrocytesandtheirinteractionswithamyloid-beta.NeurobiolDis19,66-76.
[17]Oakley,H.,Cole,S.L.,Logan,S.,Maus,E.,Shao,P.,Craft,J.,Guillozet-Bongaarts,A.,Ohno,M.,Disterhoft,J.,VanEldik,L.,Berry,R.,Vassar,R.,2006.Intraneuronalbeta-amyloidaggregates,neurodegeneration,andneuronlossintransgenicmicewithfivefamilialAlzheimer'sdiseasemutations:potentialfactorsinamyloidplaqueformation.JNeurosci26,10129-10140.
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发明内容
本发明的目的在于提供槲皮素在制备预防及治疗与ApoE蛋白水平有关疾病的药物中的应用。
大量实验发现，槲皮素可增加ApoE蛋白水平，减少AD小鼠模型大脑皮层中不溶性Aβ水平及总Aβ水平，减少AD小鼠模型大脑皮层中Aβ斑块数量。可作为治疗AD药物的新的化合物。
1)槲皮素增加永生化星形胶质细胞(immortalizedastrocytes)和原代星形胶质细胞(primaryastrocytes)胞外ApoE水平。
2)槲皮素可抑制细胞外ApoE蛋白降解。
3)槲皮素可增加AD小鼠模型的大脑皮层中apoE蛋白水平，减少大脑皮层中不溶性Aβ(包括Aβ40和Aβ42)水平和总Aβ水平。
4)槲皮素可减少AD小鼠模型的大脑皮层中Aβ斑块数量。
槲皮素可通过增加ApoE蛋白的稳定性从而增加ApoE蛋白水平，在AD小鼠模型中槲皮素可显著降低不溶性Aβ水平及Aβ斑块的数量。
由此可见，槲皮素可在制备治疗ApoE蛋白水平降低引起的疾病药物中的应用，所述疾病包括但不限于ApoE蛋白水平降低引起的机能障碍疾病、阿尔茨海默病(alzheimersdisease，AD)。
附图说明
图1为槲皮素增加永生化星形胶质细胞及原代星形胶质细胞胞外ApoE水平。n.s.,无显著意义；*,p<0.05；**,p<0.01；***,p<0.001。Ctrl,空白对照；Que,槲皮素；Bex,bexarotene。
图2为槲皮素抑制ApoE蛋白降解实验。*,p＜0.05；**,p＜0.01；***,p＜0.001。Ctrl,空白对照；Que,槲皮素；Bex,bexarotene。
图3为槲皮素可增加AD小鼠模型大脑皮层中apoE蛋白水平，减少大脑皮层中不溶性Aβ(包括Aβ40和Aβ42)水平及总Aβ水平。n.s.表示无显著性意义；*,p<0.05；**,p<0.01；***,p<0.001。n＝8～9。Ctrl,空白对照；Que,槲皮素；Bex,bexarotene。
图4为槲皮素可减少阿尔茨海默病转基因小鼠模型(5xFAD)大脑皮层中Aβ斑块数量。n.s.表示无显著性意义；*,p<0.05；**,p<0.01；***,p<0.001，n＝8～9。Ctrl,玉米油；Que,槲皮素；Bex,bexarotene.
具体实施方式
以下实施例将结合附图对本发明作进一步的说明。
图1给出槲皮素增加永生化星形胶质细胞及原代星形胶质细胞胞外ApoE水平。我们用槲皮素(10μM)及bexarotene((1μM，阳性对照组)分别处理永生化星形胶质细胞及原代星形胶质细胞，然后用Westernblot分析和定量永生化星形胶质细胞(A,C,D)及原代星形胶质细胞(B,F,G)胞内外ApoE蛋白水平。同时我们采用qRT-PCR技术检测永生化星形胶质细胞(E)及原代星形胶质细胞(H)的mRNA水平。结果发现槲皮素增加永生化星形胶质细胞及原代星形胶质细胞胞外ApoE水平，但不提高mRNA转录水平。用one-wayANOVAwithTukey’sposthocanalysis方法分析，n.s.,无显著意义；*,p<0.05；**,p<0.01；***,p<0.001。Ctrl,空白对照；Que,槲皮素；Bex,bexarotene。
图2给出槲皮素抑制ApoE蛋白降解实验。我们收集了APOE3和APOE4基因替换永生化星形胶质细胞培养液(内含有分泌到胞外的ApoE蛋白)，分别与槲皮素和bexarotene共同孵育，每间隔6小时取样分别用Westernblot(A,B,C)和ELISA(D,E)定量ApoE蛋白水平。我们发现了槲皮素能有效抑制ApoE蛋白的降解。用two-wayANOVAwithBonferroni’sposthocanalysis方法分析，*,p＜0.05；**,p＜0.01；***,p＜0.001。Ctrl,空白对照；Que,槲皮素；Bex,bexarotene.
图3给出槲皮素可增加AD小鼠模型大脑皮层中apoE蛋白水平，减少大脑皮层中不溶性Aβ(包括Aβ40和Aβ42)水平及总Aβ水平。分别用槲皮素及bexarotene(阳性对照组)灌胃2个月大5xFAD小鼠10天，取小鼠大脑皮层。用Westernblot和qRT-PCR法分别定量大脑皮层中ApoE蛋白水平，我们发现了槲皮素增加大脑皮层中ApoE蛋白水平。同时分别用TBS缓冲液(Tris-HCl),TBSX缓冲液(包含1％TritonX-100)和GDN-HCl(含5M盐酸胍缓冲液)分别提取TBS可溶性，TBSX缓冲液可溶和不溶性(GDN-HCl中可溶)Aβ,用ELISA定量，结果表明，灌胃给药能显著降低大小鼠大脑皮层中不溶性Aβ40(F)和Aβ42(I)水平，因大脑皮层中TBS可溶性，TBSX缓冲液可溶Aβ40(D,E)和Aβ42(G,H)远少于不溶性Aβ40和Aβ42水平，因此，槲皮素也同时降低了大脑皮层中的总Aβ40和Aβ42水平。用one-wayANOVAwithTukey’sposthocanalysis方法分析，n.s.表示无显著性意义；*,p<0.05；**,p<0.01；***,p<0.001。n＝8–9。Ctrl,空白对照；Que,槲皮素；Bex,bexarotene。
图4给出槲皮素可减少阿尔茨海默病转基因小鼠模型(5xFAD)大脑皮层中Aβ斑块数量。将2个月大的小鼠用槲皮素灌胃10天，取脑切片，用MOAB-2抗体做免疫组化分析。结果表明槲皮素可显著减少5xFAD小鼠大脑皮层中Aβ斑块数量，即减轻AD小鼠病理特征。用one-wayANOVAwithTukey’sposthocanalysis方法分析，n.s.表示无显著性意义；*,p<0.05；**,p<0.01；***,p<0.001，n＝8–9。Ctrl,玉米油；Que,槲皮素；Bex,bexarotene。

Claims (2)

1.槲皮素在制备预防及治疗与ApoE蛋白水平有关疾病的药物中的应用。
2.如权利要求1所述应用，其特征在于所述疾病包括但不限于ApoE蛋白水平降低引起的机能障碍疾病、阿尔茨海默病。
CN201510988203.0A 2015-12-24 2015-12-24 槲皮素在制备预防及治疗与ApoE蛋白水平有关疾病的药物中的应用 Pending CN105412074A (zh)

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CN101104612A (zh) * 2006-07-11 2008-01-16 中国科学院上海药物研究所 银杏叶标准提取物中的黄酮醇类β-分泌酶抑制剂、及其提取方法和用途

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CN108785684A (zh) * 2018-06-07 2018-11-13 暨南大学 一种槲皮素修饰的纳米硫及其制备方法与在抗阿尔兹海默症药物中的应用
CN108785684B (zh) * 2018-06-07 2020-06-16 暨南大学 一种槲皮素修饰的纳米硫及其制备方法与在抗阿尔兹海默症药物中的应用

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