PRE-084通过调节神经元MAM改善1型糖尿病小鼠的学习记忆障碍  

PRE-084 ameliorated learning and memory impairment in T1DM via regulating neuronal MAM

作　　者：何姝璿 蒋世秋 胡娟 檀佳璐 杜梦宇 王强[1] 李岩松 HE Shuxuan;JIANG Shiqiu;HU Juan;TAN Jialu;DU Mengyu;WANG Qiang;LI Yansong(Department of Anesthesiology&Center for Brain Science,The First Affiliated Hospital of Xi’an Jiaotong University,Xi’an 710061,China)

机构地区：[1]西安交通大学第一附属医院麻醉手术部&脑科学研究中心,陕西西安710061

出　　处：《西安交通大学学报（医学版）》2023年第6期866-872,共7页Journal of Xi’an Jiaotong University（Medical Sciences）

基　　金：陕西省自然科学基金青年项目(No.2022JQ-819);国家自然科学基金项目(No.82274290)。

摘　　要：目的糖尿病小鼠可表现出学习记忆功能障碍,探究Sigma-1受体激动剂PRE-084对1型糖尿病小鼠海马区神经元及认知损伤的影响。方法将20只8~10周龄链脲佐菌素诱导的1型糖尿病小鼠和20只对照小鼠随机分为4组(CON+Vehicle、CON+PRE-084、T1DM+Vehicle和T1DM+PRE-084组);分别用添加PRE-084及对照溶剂的高糖培养基培养小鼠原代神经元。监测并记录各组小鼠的体质量、饮食饮水量及空腹血糖水平,利用新物体识别实验检测小鼠的学习记忆能力,透射电镜检测小鼠海马CA1区神经元MAM结构的变化,生化试剂盒检测小鼠海马区ATP、活性氧(ROS)的表达水平;利用CCK8和细胞ROS试剂盒检测原代神经元的细胞活力和ROS水平。结果PRE-084可降低糖尿病小鼠体质量、饮食饮水量和血糖。PRE-084明显缓解1型糖尿病小鼠的学习记忆障碍,改善糖尿病小鼠海马CA1区神经元MAM结构的变化,升高糖尿病小鼠海马区ATP的水平,降低糖尿病小鼠海马区及高糖条件下神经元中ROS表达水平。结论Sigma-1受体激动剂PRE-084改善1型糖尿病小鼠学习记忆障碍可能与海马区神经元MAM结构变化、ATP产量增加及ROS生成减少相关。Objective Diabetic mice could show learning and memory dysfunction,and we aimed to investigate the effect of Sigma-1 receptor agonist,PRE-084,on neurons and cognitive impairment in mice with type 1 diabetes(T1DM).Methods Twenty mice with T1DM induced by streptozocin,aged 8-10 weeks,and 20 control mice(CON)were randomly divided into four groups(CON+Vehicle,CON+PRE-084,T1DM+Vehicle and T1DM+PRE-084).Mouse primary neurons were cultured in high glucose medium with PRE-084 and control solvent,respectively.The body weight,food and water intake,and fasting blood glucose level of mice in each group were detected and recorded.The learning and memory abilities of mice were detected by new object recognition experiment.The mitochondria-associated endoplasmic reticulum membrane(MAM)structure of neurons in hippocampal CA1 area of mice was detected by transmission electron microscope.And the expression levels of ATP and reactive oxygen species(ROS)in hippocampus of mice were detected by biochemical kit.Cell viability and ROS level of primary neurons were detected by CCK8 and cellular ROS kit.Results PRE-084 reduced the increase of body weight,food and water intake,and blood glucose caused by diabetes.PRE-084 significantly ameliorated the learning and memory impairment of the mice with T1DM,improved the changes of MAM structure in neurons of hippocampal CA1 area of diabetic mice,increased the level of ATP in hippocampus of diabetic mice,and decreased the increase of ROS expression in diabetic hippocampus and neurons under high glucose conditions.Conclusion Sigma-1 receptor agonist,PRE-084,could improve learning and memory impairment in the mice with T1DM,which might be related to the structural changes of MAM,the increase of ATP production,and the decrease of ROS production in hippocampal neurons.

关 键 词：PRE-084 Sigma-1受体 神经元 1型糖尿病 学习记忆 MAM ROS 

分 类 号：R741.05[医药卫生—神经病学与精神病学]