CN108743599A - 一种化合物在减少蛋白聚积治疗老年痴呆方面的应用 - Google Patents
一种化合物在减少蛋白聚积治疗老年痴呆方面的应用 Download PDFInfo
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Abstract
本发明公开了金丝桃苷在拮抗β淀粉样蛋白聚积、改善认知记忆能力和减少老年斑方面的应用。阿尔茨海默症(Alzheimer’s disease,AD)是一种以神经细胞纤维缠结、β淀粉样蛋白(Aβ)斑块沉积和认知功能下降为病理特征的神经退行性疾病，其中Aβ蛋白胞外毒性聚积被认为是AD发病的主要环节之一。本发明发现金丝桃苷及其同分异构体异槲皮素能够显著抑制β淀粉样蛋白1‑42单体聚积形成纤维，并抑制β二级结构的形成，提高AD小鼠的空间记忆学习能力并能明显清除APP/PS1双转基因AD模型小鼠大脑组织中的淀粉样斑块，这说明金丝桃苷能够应用于阿尔茨海默症的治疗和相关药物研发。
Description
技术领域
本发明属于药物技术领域，具体地，涉及金丝桃苷以拮抗β淀粉样蛋白1-42(Aβ42)的聚积为靶点，制备治疗阿尔茨海默症的药物中的应用。
背景技术
阿尔茨海默症(Alzheimer’sdisease，AD)又称早老性痴呆，临床表现为精神运动异常、语言障碍、认知及记忆能力减退，是一种常见的发生在老年人群进行性神经功能衰退疾病。根据《2009年世界阿尔茨海默症报告》报道，到2050年为止，患该病的人数将激增至1.5亿[1]。
关于AD的发病机制目前最为被广泛接受的是以β淀粉样蛋白的寡聚体和纤维性沉淀形成为标志的Aβ学说[2]。在正常生理下，由β淀粉样前体蛋白(betaamyloidprecursorprotein，APP)经β和γ剪切酶水解而来的Aβ的生成和降解处于平衡状态。病理条件下，APP代谢出现异常，Aβ生成急剧增多，由于不能被及时清除而积聚在脑内，毒性寡聚体的形成使神经细胞纤维缠结、星形胶质细胞和小胶质细胞增生并释放炎症因子(如TNF-α、IL-6、IL-2)引起级联反应，反过来又会加强Aβ的生成[3]，引发神经退行性疾病。因此，清除大脑中Aβ的累积成为了治疗该疾病的一条重要途径[4]。
目前临床上尚无治疗AD的特异性药物出现。现有治疗AD的药物如：胆碱酯酶抑制剂盐酸多奈哌齐、非甾体抗炎药物阿司匹林、钙拮抗剂尼莫地平等只能减缓AD发病进程，改善症状，无法阻止病情发展。基于Aβ假说，设计β分泌酶和γ分泌酶抑制剂来减少Aβ的生成，但减少分泌酶的本身伴随较大的副作用；免疫治疗，Aβ抗体、多肽等设计本身对于抗体和多肽如何通过血脑屏障在大脑中有效积累和毒副作用对于治疗阿尔茨海默症又是一个挑战。
流行病学研究发现，一些水果、蔬菜和中草药的天然活性成分可以降低AD发病的风险率[5]。姜黄素能够抑制Aβ蛋白的体外累积并能清除AD鼠大脑内老年斑的形减少Aβ寡聚物的毒性作用[6]。另发现葡萄籽提取物的主要多酚成分白藜芦醇等也能够抑制Tg2576Aβ累积水平，改善其记忆功能损伤[7]。这些证据都表明，抑制Aβ聚积和减少其毒性的小分子化合物的开发能够成为具有前途的AD治疗研究方向。
金丝桃苷(英文名Hyperoside，化学名2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxychromen-4-one，分子式C21H20O12)金丝桃苷，又名槲皮素-3-O-β-D-吡喃半乳糖苷。属于黄酮醇苷类化合物。苷元为槲皮素，糖基为吡喃半乳糖，由槲皮素的3位O原子以β糖苷键与糖基相连。金丝桃苷分布广泛，具有抗炎、解痉、利尿、止咳、降压、降低胆固醇、蛋白同化、局部和中枢镇疼以及对心、脑血管的保护作用等多种生理活性，是一种重要的天然产物，而对拮抗Aβ蛋白聚积为靶点来治疗AD方面的应用未见任何报道。本发明以AD淀粉样蛋白假说为基础通过体内和体外实验对金丝桃苷在AD治疗方面的作用进行了系统性的研究。
参考文献
1.WorldAlzheimer’sReport2009.MartinPrince.JimJacksonetal.2009
2.HardyJ,SelkoeDJ.TheamyloidhypothesisofAlzheimer’sdisease:progressandproblemson theroadtotherapeutics.Science.2002:297:353-356
3.MehlhornG,HolbornM,etal.Inductionofcytokinesinglialcellssurroundingcortical beta-amyloidplaquesintransgenicTg2576micewithAlzheimerpathology,IntJDevNeurosci.200018(4-5):423-31
4.WangJ,HoL,etal.(2006a)ModerateconsumptionofCabernetSauvignonattenuateAbeta neuropathologyinamousemodelofAlzheimer’sdisease.FASEBJ20:2313-2320
5.AssuncaoM,SantosMarquesMJ,etal.Greenteaavertsage-dependentdeclineofhippoca-mpalsignalingsystensrelatedtoantioxidantdefensesandsurvival.FreeRadicBiolMed.2010.48:831-838
6.VenusSinghMithu,BidyutSarkar,etal.Curcuminaltersthesaltbridge-contain-ingturnregion inamyloidbeta1-42aggregates.JBC.2014.289(16):11122-11131
7.LiuP,kEMPERLJ,etal.GrapeseedpolyphenolicextractspecificallydecreasesAβ56inthe brainsofTg2576mice.JAlzheimerDis.2011.26(4):657-66
发明内容
1、金丝桃苷在拮抗Aβ蛋白1-42聚积治疗阿尔茨海默症方面的应用
2、金丝桃苷在制备治疗大脑中Aβ淀粉样蛋白沉积症的药物中的应用
3、与现有技术相比，本发明的有益效果在于：本发明以AD淀粉样蛋白的假说为基础，从体外和体内两个方面进行实验对金丝桃苷在AD治疗方面的作用进行了系统性的研究。证实金丝桃苷能够对Aβ蛋白的二级结构、单体的聚合、寡聚体的神经毒性、纤维结构的形成，对阿尔茨海默症APP/PS1双转基因AD小鼠B6C3-Tg的Aβ淀粉样蛋白沉积的形成具有明显的抑制作用，并能显著改善AD小鼠学习记忆能力。
4、本发明使用APP/PS1双转基因小鼠作为金丝桃苷对老年痴呆疗效的动物模型，通过灌胃给药方式长期喂养，并测定金丝桃苷对AD小鼠大脑中Aβ蛋白老年斑的清除效果和其学习记忆功能方面的改善效果。
附图说明：
图1为金丝桃苷抑制Aβ42单体聚集的硫磺素T实验(ThT)和抑制Aβ42寡聚体介导的神经毒性损伤的MTT实验结果
图2为金丝桃苷抑制Aβ42单体形成纤维结构的透射电镜检测结果(TEM)
图3为圆二色光谱检测金丝桃苷抑制Aβ42单体β折叠形成的结果(CD)
图4为金丝桃苷对已形成的Aβ纤维结构的解聚(左ThT,右TEM)
图5为水迷宫实验检测金丝桃苷对APP/PS1转基因小鼠的记忆能力的改善(MorrisWater Maze)
图6为水迷宫实验检测金丝桃苷对APP/PS1转基因小鼠的记忆能力的改善(YMaze)
图7为硫磺素S染色检测金丝桃苷对APP/PS1转基因小鼠大脑老年斑的清除结果(ThS)
图8为刚果红染色检测金丝桃苷对APP/PS1转基因小鼠大脑老年斑的清除结果(CongoRed)
具体实施方式：
下面结合附图，用本发明的实施例来进一步说明本发明的实质内容，但并不以此来限定本发明。对于本发明所属技术领域普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演和替换，都应当视为属于本发明的保护范围。
实施例1金丝桃苷抑制Aβ42单体聚集的硫磺素T实验(ThT)和抑制Aβ42寡聚体介导的神经毒性损伤的MTT实验
蛋白Aβ蛋白由南京淘普生物有限公司合成提供，纯度大于95％。化合物金丝桃苷及其异构体异槲皮素(Isoquercetin)由上海源叶生物公司提供。Aβ单体粉末储存于-80℃，首次取出使用时室温静置30分钟，然后六氟异丙醇(HFIP)稀释至1.0mg/ml，静置至少2小时，超声30分钟破坏已存在的多聚体结构，低温静置干燥后，立即贮藏在-20℃。硫代硫磺素T(ThioflavinT)采购与Sigma(货号T3516-5g)。称取0.032g的ThT粉末溶解于20ml20mMTris-HCl(pH7.4)溶液中即得5mMThT母液，使用时稀释至5uM。
使用时，HFIP处理过的Aβ蛋白和化合物金丝桃苷分别用100ul溶解，PBS缓冲液(100nM磷酸盐，10mMNaCl，pH7.4)稀释，混合液中Aβ终浓度为20uM，单体药物浓度为0uMControl对照组和10uM(Low)、20uM(Middle)、40uM(High)实验组，每个样品总体系30ul。将配好的混合液37℃慢摇孵育，24小时后，加入270ul5uMThT，通过荧光分析测试仪检测，激发波长Ex＝430nm，发射波长Em＝480nm测其荧光值，每个样品测试5次，取平均值。
用上述方法，检测的各组荧光强度结果见附图1，左下。可以看出，与不加药的Control对照组相比，加入金丝桃苷化合物的实验组荧光强度明显下降并呈浓度依赖性，与抑制Aβ蛋白聚集作用的阳性药物姜黄素(curcumin)的结果相近，其他几种金丝桃苷结构类似化合物效果不及金丝桃苷，检测结果表明化合物金丝桃苷能够明显抑制Aβ蛋白单体的有效聚集，可用于预防和治疗阿尔茨海默症，另外，金丝桃苷的异构体异槲皮素与其对Aβ聚积的抑制效果相近。
Aβ42寡聚体介导的神经毒性损伤实验所用细胞为人神经瘤母细胞SH-SY5Y，10％FBS的DMEM培养基37℃孵育培养。Aβ蛋白不加药物的对照组与加入药物的实验组母液37℃慢摇培养过夜，转入含有SH-SY5Y的96孔细胞培养板中，Aβ蛋白终浓度为1uM，药物终浓度为0.25uM，0.5uM，1uM和2uM，每个浓度设置三个平行孔，作用时间3小时，MTT法490nm波长测试5次分析细胞增殖情况。
用上述方法，检测的各组吸光值结果见附图2，右下。可以看出，与未加药物的对照组相比，加入金丝桃苷化合物的实验组吸光值明显上升，药物金丝桃苷明显抑制Aβ蛋白聚集形成寡聚体介导的神经细胞毒性反应，低浓度时效果强于阳对照姜黄素，而另一组胆碱酯酶抑制剂类药物安理申(盐酸多奈哌齐，HCl-done)则对Aβ蛋白的聚集导致的细胞毒性不起作用，金丝桃苷的异构体异槲皮素与其对Aβ寡聚体毒性的抑制效果相近。检测结果表明化合物金丝桃苷能够明显抑制Aβ蛋白单体聚集介导的神经细胞毒性作用，可用于预防和治疗阿尔茨海默症。
实施例2金丝桃苷与Aβ蛋白透射电镜实验(Transmissionelectronmicroscopy，TEM)
前处理如实施例1处理方式，然后，37℃孵育24小时的Aβ蛋白样品取5ul滴在300目碳膜铜网表面，空气干燥，经2％(w/v)磷钨酸钠盐负染30秒，室温静置4小时左右，使用JEM-100CXII透射电镜系统(JEOLinc.,Tokyo,Japan)检测拍照，加速电压80kV。
观察结果见附图2。与未加药对照组相比，加入金丝桃苷化合物的实验组(HPY)Aβ蛋白形成纤维密度、长度和宽度明显下降并呈浓度依赖性，而另一组胆碱酯酶抑制剂类药物安理申(盐酸多奈哌齐)则对Aβ蛋白的纤维形成的抑制不起作用，金丝桃苷的异构体异槲皮素(ISO)与其对Aβ纤维结构的抑制效果相近。检测结果表明化合物金丝桃苷能够明显抑制Aβ蛋白单体形成纤维结构，可用于预防和治疗阿尔茨海默症。
实施例3金丝桃苷与Aβ蛋白圆二色光谱实验(CD)
Aβ单体与药物混合，Aβ终浓度20uM，药物终浓度分别为0uM、10uM、20uM和40uM，37℃慢摇孵育12小时后，使用J-810光谱仪(Jasco，Japan)检测。波长范围为190-250nm，分辨率为0.5nm，谱宽2nm，扫描速度100nm/min，响应时间1s，测定温度为常温。溶液加入到光程为0.1mm的石英比色皿中进行测定，每个实验重复三次。将每次所得扫描曲线减去缓冲液曲线后作为实验结果，每个实验重复三次，并给出平均值。
利用仪器生产厂商提供的软件Jascow32数据分析发现(附图3)，Aβ蛋白单体主要形成β折叠结构，与对照组不加金丝桃苷相比，加入金丝桃苷后能明显减少β折叠结构的形成，且浓度依赖，而另一组胆碱酯酶抑制剂类药物安理申(盐酸多奈哌齐)则对Aβ蛋白的单体β折叠结构的形成不起作用，金丝桃苷的异构体异槲皮素与其对Aβ二级结构的抑制效果相近。表明化合物金丝桃苷能够明显抑制Aβ蛋白单体二级β折叠结构的形成，可用于预防和治疗阿尔茨海默症。
实施例4金丝桃苷对已形成的Aβ纤维结构的解聚
前处理如实施例1和2，不同的是，Aβ42蛋白首先37℃48小时孵育后再加入药物作用，每6小时取样-20℃保存，待48小时后，统一进行ThT和TEM检测。
用上述方法，检测的各组荧光强度结果见附图4，上；TEM结果见附图4，下。可以看出与不加药的Control对照组相比，加入金丝桃苷化合物的实验组(HYP)荧光强度基本保持不变，而且48小时作用后的TEM结果发现金丝桃苷并不能对已形成的Aβ纤维进行解聚作用，同样地，异槲皮素(ISO)对已形成的Aβ纤维进行解聚作用没有明显变化。
实施例5金丝桃苷对APP/PS1转基因小鼠的行为学实验
本发明实验使用的野生型(WT)和带有APP/PS1双转基因小鼠购于南京大学模式动物研究所，并严格按照供应商提供的PCR方法对小鼠基因进行鉴定。将8月龄APP/PS1转基因鼠分别设为金丝桃苷给药组(低浓度组HYPL,高浓度组HYPH)、异槲皮素给药组(低浓度组ISO L,高浓度组ISOH)、安理申给药组、生理盐水为对照组1，WT野生型小鼠为对照组2，本实验室发现的养血清脑药物治疗组(YX)为阳对照组3，持续灌胃给药2个月。
Y迷宫实验设置三条外观相同的黑色条形长臂，呈Y字形结合，三条长臂记号为A、B、C，小鼠从A臂放入，自由行动过程中若从另一长臂折返则记为错误，例如ABA、BCB等，发生错误时，则以该臂为起点重新计算，如ABACBABCBA。每只小鼠实验时长8分钟，实验完毕时，清理Y迷宫并用酒精消毒，干燥后进行下一只小鼠实验。
Morris水迷宫实验，小鼠水迷宫训练阶段两天(不记录数据)，将小鼠面向池壁分别从4个入水点(象限)分别放入水池，平台隐藏在水下1cm处，水温保持23℃，训练持续2分钟，若小鼠在2分钟内未能找到平台，则将其用工具引导至隐藏平台上并停留20秒，然后进行下一次训练。实验阶段从第三天开始，实验连续进行6天，每只小鼠每天实验1次，实验时，将小鼠面向池壁从4个入水点(象限)分别放入水池，记录小鼠从入水到找到并停留在水下隐藏平台所需时间，作为潜伏期。第八天移走平台，每只小鼠从原平台所在位置最远端下水，自由游泳2分钟，动物在目标象限(平台所在区域)游泳的时间、穿越平台的次数及路径等主要参数将被微型摄像机跟踪记录并分析。
Morris水迷宫实验结果发现，金丝桃苷治疗后，AD小鼠找到平台的潜伏期明显下降，相比于野生小鼠(WT)和AD灌胃生理盐水组(Control)，训练实验从第三天开始，金丝桃苷治疗AD鼠后的潜伏期逐渐下降(图5左下)，撤掉平台后，小鼠进行定位航行实验，结果发现金丝桃苷治疗组AD小鼠穿越虚拟平台的次数有非常明显的改善(图5右下)，效果与阳对照药物养血清脑接近，而相比而言，安理申药物组对AD鼠症状的改善效果有限,异槲皮素与金丝桃苷的作用效果相近。综合以上行为学结果可以看出，金丝桃苷能够显著提高AD小鼠的学习和记忆能力，表明金丝桃苷可应用于阿尔茨海默症预防和治疗药物的研发。
Y迷宫实验结果统计见附图6，野生小鼠(WT)正确率为82％左右，灌胃生理盐水的AD鼠Y迷宫实验正确率只有约58％，金丝桃苷治疗2个月后后，AD小鼠的Y迷正确率明显上升，效果略由于养血清脑药物治疗组，好于安理申治疗组，说明金丝桃苷及其同分异构体异槲皮素能够改善AD鼠认知记忆能力，具备成为阿尔茨海默症预防和治疗药物的潜力。
实施例6金丝桃苷对APP/PS1转基因小鼠大脑组织作用的病理实验
10月龄AD小鼠0.4％戊巴比妥钠麻醉后，通过灌注心房取血，4％多聚甲醛心脏灌流进行全身固定，取脑组织称重，半脑放入4％多聚甲醛溶液中用于做组织病理，另半装入冻存管-80℃保存用于生化分析。4％多聚甲醛固定的脑组织腊块包埋后切片，通过硫磺素S、刚果红对大脑皮层和海马区沉积斑块进行染色。病理图像通过数字显微镜和荧光显微镜获得并进行定量分析。
脑组织硫磺素S染色和刚果红染色结果如图7、图8所示，金丝桃苷治疗组无论是皮层区还是海马区，其染色的Aβ沉积斑块数量相比于只灌胃生理盐水的对照组AD小鼠来说，均呈现出明显的减少，且具有统计意义，效果略优于阳对照养血清脑药物治疗组，而安理申药物组则对AD鼠脑组织斑块沉积并没有显著的改变，另异槲皮素的老年斑清除效果与金丝桃苷相近，表明金丝桃苷能够抑制Aβ蛋白在脑组织内的沉积，可用于于阿尔茨海默症预防和治疗药物的研发。
Claims (8)
1.一种化合物金丝桃苷在拮抗β淀粉样蛋白1-42聚积治疗老年痴呆方面的应用。
2.权利1所述的老年痴呆，特指阿尔茨海默症，英文名为Alzheimer’s disease。
3.化合物金丝桃苷在阿尔茨海默症相关药物研发中的应用。
4.化合物金丝桃苷在抑制Aβ1-42单体聚积形成寡聚体介导的神经细胞毒性损伤作用方面的阿尔茨海默症治疗及药物研发。
5.化合物金丝桃苷在抑制Aβ1-42单体β折叠形成、抑制Aβ1-42单体聚积形成寡聚体和纤维方面的阿尔茨海默症治疗及药物研发。
6.化合物金丝桃苷在抑制Aβ蛋白聚积形成老年斑的阿尔茨海默症方面的治疗效应和相关药物研发。
7.化合物金丝桃苷在改善认知记忆能力障碍的阿尔茨海默症治疗效应及相关药物研发。
8.化合物金丝桃苷及其类似物在阿尔茨海默症治疗和药物研发应用中的分子结构基础,金丝桃苷的分子结构在阿尔茨海默症治疗作用和药物研发中的作用。金丝桃苷化学名为Hyperoside，又名Hyperin；482-36-0；Quercetin 3-galactoside；Quercetin-3-O-galactoside；Hyperosid，国际化合物标识InChI＝1S/C21H20O12/c22-6-13-15(27)17(29)18(30)21(32-13)33-20-16(28)14-11(26)4-8(23)5-12(14)31-19(20)7-1-2-9(24)10(25)3-7/h1-5,13,15,17-18,21-27,29-30H,6H2/t13-,15+,17+,18-,21+/m1/s1，分子量464.379g/mol，分子式C21H20O12。同时，具有金丝桃苷类似结构的化合物分子在阿尔茨海默症的治疗和药物研发中的应用。对于金丝桃苷分子糖苷上的羟基进行变化形成的异构体异槲皮素，或者对金丝桃苷上的其他羟基基团进行简单的替换或对其增减基团-CH2-带来的结构的改变所形成的类似化合物。
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| CN119157893A (zh) * | 2024-11-22 | 2024-12-20 | 山东第一医科大学(山东省医学科学院) | 金丝桃苷在制备防治脑衰老药物中的应用 |
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