锌剂预处理对丙咪嗪抗抑郁药效的增强作用及其机制  

Enhancing effect of zinc pretreatment on antidepressant effect of imipramine and its mechanism

作　　者：吴少华 余敏玲 任麟祥 危智盛[1] WU Shaohua;YU Minling;REN Linxiang;WEI Zhisheng(Department of Neurology,The First Affiliated Hospital of Guangdong Pharmaceutical University,Guangzhou 510080,China)

机构地区：[1]广东药科大学附属第一医院神经内科,广州510080

出　　处：《山东医药》2024年第20期25-29,共5页Shandong Medical Journal

基　　金：广东省自然科学基金面上项目(2021A1515011695)。

摘　　要：目的 观察锌剂预处理对丙咪嗪抗抑郁药效的增强作用,并探讨相关机制。方法 将SD大鼠随机分为模型组、锌组、丙咪嗪组、锌+丙咪嗪组、锌+H89+丙咪嗪组及对照组。模型组、锌组、丙咪嗪组、锌+丙咪嗪组、锌+H89+丙咪嗪组采用电击箱构建习得性无助抑郁模型;对照组大鼠同样放于电箱中,但不给予电击。造模结束后,模型组腹腔注射生理盐水;锌组腹腔注射葡萄糖酸锌连续3 d;丙咪嗪组腹腔注射丙咪嗪、单次给药;锌+丙咪嗪组腹腔注射葡萄糖酸锌连续3 d,第4天给予丙咪嗪;锌+H89+丙咪嗪组腹腔注射葡萄糖酸锌连续3 d,在第1天锌剂给药后注射H89[蛋白激酶A(PKA)抑制剂]注射液,在第4天给予丙咪嗪;对照组腹腔注射生理盐水。大鼠给药结束24 h后进行电击穿梭逃避试验及强迫游泳行为学测试评价抑郁样行为,采集外侧缰核(LHb)检测细胞色素氧化酶及星形胶质细胞中的内向整流钾通道4.1(Kir4.1)蛋白。结果 锌组、丙咪嗪组、锌+H89+丙咪嗪组和模型组强迫游泳不动时间和逃避失败次数高于对照组;锌+丙咪嗪组强迫游泳不动时间和逃避失败次数低于模型组、锌组、丙咪嗪组及锌+H89+丙咪嗪组(P均<0.01)。锌组、丙咪嗪组、锌+H89+丙咪嗪组和模型组LHb中细胞色素氧化酶表达及Kir4.1阳性星形胶质细胞数高于对照组,锌组、丙咪嗪组、锌+丙咪嗪组细胞色素氧化酶表达及Kir4.1阳性星形胶质细胞数低于模型组,锌+丙咪嗪组细胞色素氧化酶表达及Kir4.1阳性星形胶质细胞数低于锌组、丙咪嗪组(P均<0.01)。结论 锌剂预处理可增强丙咪嗪的抗抑郁药效,其作用机制可能与调控Kir4.1表达、抑制LHb簇状放电有关,这一作用可被PKA抑制剂H89所阻断。Objective To investigate the enhancing effect of zinc pretreatment on antidepressant effect of imipra-mine and to explore the underlying mechanism.Methods SD rats were randomly divided into the model group,zinc group,imipramine group,zinc+imipramine group,zinc+H89+imipramine group,and control group.In the model group,zinc group,imipramine group,zinc+imipramine group,zinc+H89+imipramine group,we constructed the learned helplessness depression models by using the electric box;the rats in the control group were also placed in the elec-tric box,but no electric shock was given.After modeling,rats in the model group were intraperitoneally injected with nor-mal saline;rats in the zinc group were intraperitoneally injected with zinc gluconate for 3 consecutive days;rats in the imipramine group were intraperitoneally injected with imipramine as a single dose;rats in the zinc+imipramine group were intraperitoneally injected with zinc gluconate for 3 consecutive days and were given imipramine on the 4th day;rats in the zinc+H89+imipramine group were intraperitoneally injected with zinc gluconate for 3 consecutive days,and were in-jected with H89[protein kinase A(PKA)inhibitor]injection after zinc administration on the first day and were given imip-ramine on the 4th day;rats in the normal control group were injected with normal saline.Depressive behaviors were as-sessed 24 h after the last administration using the shock shuttle-escape test and forced swimming test.Subsequently,the lateral habenular(LHb)was collected to evaluate the expression of cytochrome oxidase and Kir4.1 protein in astrocytes.Results In the forced swimming test,the zinc group,imipramine group,zinc+H89+imipramine group,and LH model group exhibited significantly longer immobility time compared with the control group.Similarly,in the shock shuttle-es-cape test,these groups showed more failure escape time compared with the control group.Notably,the zinc+imipramine group displayed significantly shorter immobility time and fewer failures in both tests compared

关 键 词：锌剂 丙咪嗪 抗抑郁药物 外侧缰核 

分 类 号：R749.4[医药卫生—神经病学与精神病学]