基于线粒体氧化呼吸链相关调节基因探讨二甲双胍对皮质酮致小鼠抑郁样行为的作用  

Effect of metformin on corticosterone-induced depression-like behavior in mice involves genes of the mitochondrial respiratory chain

作　　者：李俊[1,2] 余冬 王木兰 冯育林[1,2] 杜力军[2,3] 龚琴 LI Jun;YU Dong;WANG Mulan;FENG Yulin;DU Lijun;GONG Qin(Jiangxi University of Chinese Medicine,Nanchang 330006,China.;National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine,Nanchang 330006.;School of Life Sciences Tsinghua University,Beijing 100084)

机构地区：[1]江西中医药大学,南昌330006 [2]江西中医药大学中药固体制剂制造技术国家工程研究中心,南昌330006 [3]清华大学生命科学学院,北京100084

出　　处：《中国比较医学杂志》2023年第8期95-104,共10页Chinese Journal of Comparative Medicine

基　　金：江西省科技创新平台组建(20202BCD44004)。

摘　　要：目的二甲双胍(metformin,Met)是临床常用的降血糖药,对能量代谢的调控是其药理作用主要机制之一。本文基于线粒体氧化呼吸链相关调控基因对二甲双胍的抗抑郁作用进行探索,以从能量代谢角度探讨其抗抑郁作用相关机制。方法ICR小鼠皮下注射皮质酮(corticosterone,CORT,20 mg/kg)连续3周复制小鼠抑郁模型,注射一周后,二甲双胍(200、100、50 mg/kg)灌胃给药2周,给药期间测量小鼠糖水偏好率;给药结束后进行旷场试验,记录小鼠进入旷场中央区的次数和停留时间,在周边区域的跨格数;qPCR和Western blot检测海马组织中线粒体呼吸链相关基因Nduf(NADH dehydrogenase ubiquinone)和Mrp(mitochondrial ribosomal protein)mRNA表达,以及神经营养因子BDNF(brain-derived neurotrophic factor)、环磷酸腺苷反应元件蛋白CREB(cAMP response element-binding protein)和神经突触后受体AMPAR(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor)、NMDAR(N-methyl-d-aspartic acid receptor)mRNA或蛋白表达情况。此外,还观察了二甲双胍(连续灌胃给药1周)对正常小鼠的作用。结果二甲双胍不影响正常和模型小鼠的体重;提高正常和模型小鼠的糖水偏好性;增加正常和模型小鼠进入旷场中央区域的次数,增加模型小鼠在外周区域的活动距离;二甲双胍上调正常和模型小鼠海马组织中Nduf、Mrp的大部分亚型的mRNA表达(除Ndufa8、Ndufa13);增强正常小鼠海马中Creb、Ampar、Nmdar mRNA表达和BDNF、CREB、AMPAR、NMDAR蛋白表达,拮抗模型小鼠中Bdnf、Creb mRNA和BDNF、CREB蛋白表达的下调。结论二甲双胍可以改善CORT所致小鼠抑郁样行为,其机制与调节海马组织中线粒体氧化呼吸链、神经可塑性相关的基因或蛋白表达有关。Objective Metformin(Met)is a commonly used hypoglycemic drug in clinical practice.Regulation of energy metabolism is one of the main mechanisms of its pharmacological action.In this study,we investigated the antidepressive effect of metformin on the basis of mitochondrial oxidative respiratory chain-related genes and explored the related mechanism of its antidepressive effect from the perspective of energy metabolism.Methods ICR mice were injected subcutaneously with corticosterone(20 mg/kg)for 3 weeks to induce a mouse model of depression-like behaviors.One week after injection,metformin(200,100 and 50 mg/kg)was administered by gavage for 2 weeks.During administration,the preference rate of sucrose was measured.At the end of administration,an open field test was conducted,and the times and duration of mice traveling in the central area and the distance traveled in the peripheral area were recorded.qPCR and Western blot were used to detect the mRNA and protein expression of mitochondrial respiratory chain related genes NADH dehydrogenase ubiquinone(Nduf),mitochondrial ribosomal protein(Mrp),brain-derived neurotrophic factor(BDNF),cAMP response element-binding protein(CREB),and postsynaptic receptorα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPAR),and N-methyl-d-aspartic acid receptor(NMDAR)in the hippocampus.The effects of metformin(administration for 1 week)on normal mice were also observed.Results Metformin did not affect the weight of normal or model mice.The sucrose preference rate was enhanced after metformin administration in normal and model mice.In the open field test,metformin increased the number of entrances to the central area in normal and model mice,and increased the distance traveled in the peripheral area in model mice.Additionally,metformin upregulated the mRNA expression of most Nduf subtypes(except for Ndufa8 and Ndufa13)and Mrp,the mRNA expression of Creb,Ampar,Nmdar and protein expression of BDNF,CREB,AMPAR,NMDAR in the hippocampus of normal mice,while antagonizing downreg

关 键 词：小鼠 皮质酮 抑郁 二甲双胍 能量代谢 线粒体 

分 类 号：R-33[医药卫生]