培哚普利通过调控脑锌代谢改善APP/PS1转基因小鼠认知功能

 目的 探讨培哚普利对APP/PS1转基因小鼠认知功能和大脑皮层锌、铁、锰、铜、镁、钙水平，以及锌转运体家族成员（ZnT1、ZnT2、ZnT3、ZnT4、ZnT5、ZnT6、ZnT7） mRNA表达水平的影响。方法 10只APP/PS1转基因小鼠随机分为对照组和培哚普利治疗组（各5只）。应用水迷宫实验检测小鼠认知功能；应用电感耦合等离子体质谱（inductively coupled plasma mass spectrometry，ICP-MS）检测小鼠大脑皮层6种金属微量元素的含量；应用real-time PCR检测小鼠大脑皮层锌转运体家族成员mRNA表达水平。结果 培哚普利降低了APP/PS1转基因小鼠逃避潜伏期，增加了小鼠穿越平台次数；培哚普利增加了APP/PS1转基因小鼠大脑皮层锌水平，而铁、锰、铜、镁、钙水平在培哚普利应用前后未见显著性差异；培哚普利降低了锌转运体家族成员中ZnT1的mRNA表达水平，而ZnT2、ZnT3、ZnT4、ZnT5、ZnT6、ZnT7 的表达水平在培哚普利应用前后未见显著性差异。结论 培哚普利可以通过下调大脑皮层ZnT1表达，调控脑锌代谢，进而改善APP/PS1转基因小鼠认知功能，提示调控脑内锌稳态是培哚普利改善阿尔茨海默病（Alzheimer's disease，AD）认知水平的重要机制之一。

The ameliorating effects of perindopril on cognitive function of APP/PS1 transgenic mouse via zinc regulation in cerebral cortex

Objective To investigate the effects of perindopril on cognitive function,concentrations of Zn,Fe,Mn,Cu,Mg,Ca and mRNA levels of ZnT1,ZnT2,ZnT3,ZnT4,ZnT5,ZnT6 and ZnT7 in cerebral cortex of APP/PS1 transgenic mouse. Methods Ten APP/PS1 transgenic mice were randmly divided into control group and perindopril treatment group (n=5 in each group).Morris water maze test was used to analyze cognitive function of the mouse.Inductively coupled plasma mass spectrometry (ICP-MS) was used to analyze concentrations of 6 metal elements in cerebral cortex of the mouse.Real-time PCR were used to analyze mRNA expressions of 7 ZnTs. Results The escape latency of the mice treated with perindopril was significantly lower than the controls.The mice treated with perindopril traveled across the target platform significantly more often than the controls.Perindopril significantly increased the concentration of Zn in the cerebral cortex,whereas there was no significant changes in the concentrations of Fe,Mn,Cu,Mg and Ca before and after the administration of perindopril.Perindopril down-regulated the mRNA expression of ZnT1 in the cerebral cortex.There was no significant changes in ZnT2,ZnT3,ZnT4,ZnT5,ZnT6 and ZnT7 mRNAexpressions between the mouse treated with and without perindopril. Conclusions The decreased expression of ZnT1 and increased concentrations of Zn in cerebral cortex of APP/PS1 transgenic mouse suggested the function of perindopril on brain Zn homeostasis,which may play a key role in the ameliorating effects of perindopril on cognitive function of Alzheimer's disease (AD).