天麻素、黄芪总皂苷和芍药苷对阿尔茨海默病模型小鼠脑内β-淀粉样多肽表达的影响及其机制  

Effect and mechanism of traditional Chinese herbs against Aβexpression in brain tissues of mice with Alzheimer′s disease

作　　者：周楠楠[1] 朱燃[1] 赵雪梅[1] 梁平[1] 

机构地区：[1]中国医学科学院基础医学研究所北京协和医学院基础学院病理学系,100005

出　　处：《中华病理学杂志》2016年第11期780-785,共6页Chinese Journal of Pathology

基　　金：国家“十二五”科技重大专项“重大新药创制”项目（2012ZX09103301-051）

摘　　要：目的：观察天麻素、黄芪总皂苷和芍药苷3种中药成分对5XFAD阿尔茨海默病（ AD）模型小鼠脑内β-淀粉样多肽（ Aβ）斑块及学习记忆和认知能力的影响。方法1.5个月龄5XFAD AD模型小鼠70只分为天麻素高、低剂量组（天麻素-H、天麻素-L），黄芪总皂苷高、低剂量组（黄芪总皂苷-H、黄芪总皂苷-L）及芍药苷高、低剂量组（芍药苷-H、芍药苷-L），阳性对照组，每组10只；另取同窝阴性小鼠10只作为阴性对照组。药物干预4个月后，观察各组小鼠行为学变化及脑部病理学变化情况，并用模型细胞探讨其相关的作用机制。结果与阳性对照组相比，在行为学水迷宫试验中，天麻素-H、黄芪总皂苷-H和芍药苷-H组隐形平台寻找时间分别缩短，平台撤后在原目标象限停留时间分别延长（ P＜0.01）；在病理形态学检测中，天麻素-H、黄芪总皂苷-H和芍药苷-H组海马区Aβ斑块阳性面积分别降低70.1％、62.4％和57.6％（ P＜0.01），皮层区Aβ斑块阳性面积分别降低81.0％、69.6％和66.6％（ P＜0.01）；各干预组小鼠行为学改善和脑部Aβ斑块减少呈药物剂量依赖性；各干预组小鼠脑匀浆中及模型细胞培养上清液中Aβ水平均有降低；分泌酶表达结果显示，天麻素降低模型细胞β分泌酶基因转录水平达32.9％（ P＜0.01），降低β分泌酶蛋白表达水平达47.9％（ P＜0.01），黄芪总皂苷和芍药苷对β分泌酶在转录和蛋白表达水平无影响。结论天麻素、黄芪总皂苷和芍药苷均可明显改善5XFAD模型小鼠的学习认知及记忆能力，且均可明显抑制小鼠脑内Aβ斑块及脑组织中Aβ多肽，其中天麻素-H作用效果最好；天麻素抑制Aβ斑块可能与抑制β分泌酶进而减少Aβ的产生有关，而黄芪总皂苷和芍药苷未观察到对β分泌酶的影响。Objective To investigate the effects of gastrodin, astragaloside and paeoniflorin from three types of traditional Chinese herbs against on β-amyloid plaques and memory ability in 5XFAD Alzheimer′s disease （ AD） transgenic mice.Methods Seventy 5XFAD mice were randomly divided into seven groups, namely gastrodin-high and gastrodin-low dose groups （GAS-H, GAS-L）, astragaloside-high and astragaloside-low dose groups （ AST-H, AST-L） , and paeoniflorin-high and paeoniflorin-low dose groups （ PAE-H, PAE-L） , and positive control group.Negative control groups were also established.After being treated for four months, 5XFAD mice were evaluated for memory ability and Aβplaques, and the mechanism were was explored by utilizing cell model （ over-expression Aβand β-secretase ） .Results Gastrodin, astragaloside and paeoniflorin enhanced the learning and memory ability of 5XFAD mice, and reduced Aβin the cerebral homogenate and Aβplaques in brain.Compared with the untreated transgenic positive group, Aβplaques was reduced in hippocampus and cortex in the GAS-H group by 70.1% and 81.0%, in the＆amp;nbsp;AST-H group by 62.4% and 69.6%, and in the PAE-H group by 57.6% and 66.6% （ P 〈0.01 ） , respectively.Aβwas reduced in the cerebral homogenate of all groups.The effects were dose-dependent.In vitro study suggested a dose-dependent effect of gastrodin, astragaloside and paeoniflorin in reducing Aβin cell models.Gastrodin suppressed BACE mRNA level by 32.9%（ P〈0.01 ） , and suppressed β-secretase protein level by 47.9% （ P〈0.01 ） .Conclusions Three types of Chinese herbs can inhibit β-amyloid plaques in brain of AD.Gastrodin reduced Aβproduction and accumulation by inhibiting β-secretase.Astragaloside and paeoniflorin have no demonstrable effects against β-secretase.

关 键 词：阿尔茨海默病 淀粉样Β蛋白前体 天麻属 黄芪 芍药属 大脑皮质 海马 

分 类 号：R749.16[医药卫生—神经病学与精神病学]