美金刚激活NGF/TrkA信号通路改善APP/PS1转基因小鼠学习记忆障碍  

Memantine improves cognitive deficits by activiating NGF/TrkA signaling in APP/PS1 transgenic mice

作　　者：姚维范[1] 刘明妍[1] 钟欣[1] 杨时伦 杜可[1] 毛瑞琨 魏敏杰[1] 

机构地区：[1]中国医科大学药学院药理学教研室,辽宁沈阳110122

出　　处：《中国药理学通报》2016年第4期473-480,共8页Chinese Pharmacological Bulletin

基　　金：国家科技部"重大新药创制"科技重大专项子课题(No2013ZX09103001-003);国家自然科学基金资助项目(No81501098);辽宁省教育厅科学研究一般项目(NoL2012279);辽宁省科学技术计划项目(No2013225079)

摘　　要：目的考察NGF/TrkA信号通路在美金刚(memantine,MEM)改善APP/PS1转基因小鼠的学习记忆障碍中的作用及其相关机制。方法以Morris水迷宫、被动避暗试验及自主活动试验观察动物行为学变化,免疫组化检测小鼠脑内Aβ1-42表达水平,ELISA法及比色法考察其脑内ChAT及AChE活性,并用Western blot法检测小鼠海马NGF的水平及其特异性受体TrkA下游ERK通路相关蛋白的表达水平。结果 MEM明显改善APP/PS1转基因小鼠的学习记忆障碍,并明显降低其脑内Aβ1-42蛋白沉积。MEM可上调NGF表达水平,继而激活NGF-TrkA通路,明显增加TrkA、c-raf、ERK1/2及其下游效应蛋白CREB的磷酸化水平;同时,增强其脑内ACh生成酶ChAT并降低其水解酶AChE活性。结论 MEM可能通过增加NGF的表达,激活TrkA信号通路,降低APP/PS1转基因小鼠脑内Aβ1-42蛋白沉积,从而改善其学习记忆障碍。Aims To study the role of NGF / TrkA signaling pathway in Memantine( MEM) improving APP /PS1 transgenic mice cognitive deficits and to explore its possible mechanisms. Methods Cognitive performance was assessed by Morris water maze( MWM),passive avoidance test( PAT) and locomotivity test. Aβ1-42 protein levels were determined by immunohistochemistry. The activities of AChE and ChAT were also examined by ELISA and colorimetry. Western blot was used to detect the expression levels of NGF and its receptor TrkA and the downstream ERK pathway. Results MEM treatment significantly ameliorated the cognitive deficits,dramatically reduced the Aβ1-42 overexpression. MEM increased the activity of choline acetyltransferase( ChAT),while decreased that of acetylcholine esterase( AChE). Moreover,MEM activiated NGF signaling by increasing the phosphorylation of TrkA following the increased phosphorylation of c-Raf,ERK1 /2 and downstream effector CREB after MEM treatment.Conclusion MEM treatment may activate the NGF /TrkA signaling in APP / PS1 mice to reduce amyloidosis and cognitive deficits.

关 键 词：美金刚 NGF TRKA 学习记忆障碍 阿尔茨海默病 AΒ 

分 类 号：R-332[医药卫生] R322.81