阿戈美拉汀缓解APP/PS1转基因小鼠焦虑及抑郁样行为的机制  

Mechanism of agomelatine alleviating anxiety-and depression-like behaviors in APP/PS1 transgenic mice

作　　者：李甜 任俞桦 高艳萍 苏强 Li Tian;Ren Yuhua;Gao Yanping;Su Qiang(Department of Physiology,School of Basic Medicine/Key Laboratory of Cellular Physiology,Ministry of Education/Shanxi Key Laboratory of Cell Physiology,Shanxi Medical University,Taiyuan 030001,Shanxi Province,China;Department of Medical Laboratory,Fenyang College of Shanxi Medical University,Fenyang 032200,Shanxi Province,China)

机构地区：[1]山西医科大学基础医学院生理学系,细胞生理学教育部重点实验室,细胞生理学山西省重点实验室,山西省太原市030001 [2]山西医科大学汾阳学院医学检验系,山西省汾阳市032200

出　　处：《中国组织工程研究》2025年第6期1176-1182,共7页Chinese Journal of Tissue Engineering Research

基　　金：国家自然科学基金委员会青年科学基金项目(82301631),项目负责人:李甜;山西省科技厅山西省基础研究自然科学研究青年项目(20210302124086),项目负责人:李甜。

摘　　要：背景:阿戈美拉汀在临床上用于治疗焦虑、抑郁等相关精神行为异常。前期研究证实,阿戈美拉汀能够有效缓解阿尔茨海默病模型小鼠的认知行为、海马突触可塑性及脑病理特征,然而阿戈美拉汀能否改善阿尔茨海默病模型小鼠的焦虑和抑郁样行为仍不清楚。目的:探究阿戈美拉汀对APP/PS1(阿尔茨海默病)转基因小鼠焦虑和抑郁样行为的改善效应及分子机制。方法:①将18只APP/PS1转基因小鼠随机分为模型对照组(n=9)、模型干预组(n=9),将18只野生型小鼠随机分为对照组(n=9)、干预组(n=9),模型干预组与干预组小鼠腹腔注射阿戈美拉汀10 mg/(kg·d),连续注射31 d后进行高架十字迷宫、强迫游泳行为学实验与海马组织mRNA测序。②取小鼠海马神经元细胞株(HT22)、脑微血管内皮细胞株(bEnd.3),分别分4组培养:空白组不加入任何药物,药物组加入20µmol/L阿戈美拉汀,模型组加入10µmol/Lβ-淀粉样蛋白1-42,实验组加入10µmol/Lβ-淀粉样蛋白1-42+20µmol/L阿戈美拉汀,培养24 h后,免疫印迹检测HT22细胞S416p-tau和S9p-GSK3β的蛋白表达,免疫印迹检测bEnd.3细胞低密度脂蛋白受体相关蛋白1、糖基化终产物受体的蛋白表达。结果与结论:①在高架十字迷宫实验中,模型对照组小鼠的探索开放臂时间与开放臂进入次数均少于对照组(P<0.05),模型干预组小鼠的探索开放臂时间与开放臂进入次数均多于模型对照组(P<0.05);在强迫游泳测试中,模型对照组小鼠的不动时间长于对照组(P<0.05),模型干预组小鼠的不动时间短于模型对照组(P<0.05);海马组织mRNA测序显示,阿戈美拉汀可以增强APP/PS1小鼠海马区低密度脂蛋白受体相关蛋白1的表达。②免疫印迹检测显示,模型组HT22细胞S416p-tau蛋白表达高于空白组(P<0.05),实验组HT22细胞S416p-tau蛋白表达低于模型组(P<0.05),药物组HT22细胞S9p-GSK3β蛋白表达高于空白组(P<0.05),实验组HT22�BACKGROUND:Agomelatine is a clinically proven treatment for neuropsychiatric symptoms,such as anxiety and depression.Furthermore,our previous study has demonstrated that agomelatine ameliorates cognitive behaviors,hippocampal synaptic plasticity,and brain pathology in a mouse model of Alzheimer’s disease.However,it remains unclear whether agomelatine can improve anxiety and depression-like behaviors in Alzheimer’s disease model mice.OBJECTIVE:To investigate the improving effects of agomelatine on anxiety-and depression-like behaviors in APP/PS1 transgenic mice and its underlying molecular mechanisms.METHODS:(1)Eighteen APP/PS1 transgenic mice were randomly divided into model control group(n=9)and model intervention group(n=9).Another wildtype mice were randomized into control group(n=9)and intervention group(n=9).Model intervention group and intervention group were intraperitoneally injected with 10 mg/kg agomelatine per day for 31 continuous days.Behavioral experiments,including the elevated cross maze and forced swimming tests,and mRNA sequencing of the hippocampus were then performed.(2)Mouse hippocampal neuronal cell lines(HT22)and brain microvascular endothelial cell lines(bEnd.3)were cultured and divided into four groups:blank group without any drug,drug group with 20μmol/L agomelatine,model group with 10μmol/Lβ-amyloid 1-42,and experimental group with 10μmol/Lβ-amyloid 1-42+20μmol/L agomelatine.After 24 hours of incubation,protein expression of S416p-tau and S9p-GSK3β in HT22 cells was detected by immunoblotting,and protein expression of low-density lipoprotein receptor-related protein 1 and glycosylation end-product receptor in bEnd.3 cells was detected by immunoblotting.RESULTS AND CONCLUSION:In the elevated plus maze test,the time spent in the open arms(P<0.01)and the entries into open arms(P<0.05)in the mice of model control group were evidently lower than those in the control group,whereas those were obviously increased in the model intervention group compared with the model control group(P

关 键 词：阿尔茨海默病 阿戈美拉汀 APP/PS1转基因小鼠 焦虑 抑郁 

分 类 号：R453.9[医药卫生—治疗学] R362[医药卫生—临床医学] R749.16