瑞替加滨对慢性应激所致的大鼠抑郁样症状的改善作用及机制研究  

The ameliorating effect of retigabine on chronic stress-induced depression-like symptoms in rats and its mechanism

作　　者：冯楚钰 任建辉 祝曙光[3] 覃翠颖 郭继全 臧林泉 FENG Chu-yu;REN Jian-hui;ZHU Shu-guang;QIN Cui-ying;GUO Ji-quan;ZANG Lin-quan(Department of Pharmacology,School of Pharmacy,Guangdong Pharmaceutical University,Guangzhou 511436,China;Huadu Maternal and Child Health Care Center,Guangzhou 510800,China;The First Affiliated Hospital of Guangdong Pharmaceutical University,Guangzhou 510080,China;Guangdong Provincial People’s Hospital,Guangzhou 510020,China)

机构地区：[1]广东药科大学药学院药理系,广州511436 [2]广州市花都区妇幼保健院,广州510800 [3]广东药科大学附属第一医院,广州510080 [4]广东省人民医院,广州510020

出　　处：《中国新药杂志》2021年第15期1407-1412,共6页Chinese Journal of New Drugs

基　　金：2018年广东省研究生示范课程建设资助项目(2018SFKC25);广东药科大学创新强校其他类资助项目(2017QTLXXM27)。

摘　　要：目的:研究瑞替加滨(retigabine,RTG)对慢性应激诱导的大鼠抑郁样症状的改善作用,并初步探究可能的分子机制。方法:将32只SD大鼠随机分为正常组、模型组、RTG高剂量组(4 mg·kg^(-1))和RTG低剂量组(2 mg·kg^(-1))。采用长期反复低温水浸束缚方法,建立大鼠慢性应激模型。利用旷场实验、强迫游泳实验和糖水偏好实验评估大鼠的抑郁样症状;通过HE染色法和尼氏(Nissl)染色法检测大鼠海马的组织病理形态变化;采用Western Blot法检测大鼠海马中脑源性神经营养因子(brain derived neurotrophic factor,BDNF)、突触素(synaptophysin,SYP)、葡萄糖调节蛋白78(glucose regulated protein 78,GRP78)、C/EBP同源蛋白(C/EBP homologous protein,CHOP)、B淋巴细胞瘤-2(B-cell lymphoma-2,Bcl-2)、Bcl-2相关X蛋白(Bcl-2 associated X protein,Bax)和半胱氨酸蛋白酶-3(Caspase-3)的蛋白水平。结果:在慢性应激大鼠模型中,RTG给药显著上调旷场实验中的总运动距离、平均运动速度以及在中央区域停留的时间,升高大鼠的糖水偏好程度和缩短强迫游泳静止不动时间;明显改善海马组织病理性损伤;显著增加BDNF,SYP,GRP78和Bcl-2的蛋白表达,并减少CHOP,Bax和Caspase-3的蛋白表达。结论:RTG对长期反复低温水浸束缚诱导的大鼠抑郁样症状及海马结构病理学损伤均具有保护作用,该作用与缓解海马神经细胞内质网应激、减少细胞凋亡和改善神经可塑性有关。Objective:To study the ameliorating effect of retigabine(RTG)on chronic stress-induced depression-like symptoms in rats,and to explore the possible molecular mechanism.Methods:32 SD rats were randomly divided into control group,model group,RTG high dose(4 mg·kg^(-1))and RTG low dose(2 mg·kg^(-1))groups.Long-term repeated low-temperature water immersion restraint method was used to establish the rat chronic stress model.Open field test,forced swimming test and sucrose preference test were conducted to evaluate the degree of depression-like symptoms of rats.The histopathological changes in hippocampus of rats were detected by HE staining and Nissl staining.The levels of brain derived neurotrophic factor(BDNF),synaptophysin(SYP),glucose regulated protein 78(GRP78),C/EBP homologous protein(CHOP),B-cell lymphoma-2(Bcl-2),Bcl-2 associated X protein(Bax)and Caspase-3 protein in hippocampus were determined by using Western Blot analysis.Results:In the chronic stress rat model,RTG markedly increased the total distance of movement,average movement speed,and stationary time in the central area in the open field experiment.RTG significantly increased the sucrose consumption ratio of rats and shortened the immobility time of forced swimming.In addition,RTG effectively improved the tissue lesion of hippocampus,markedly increased the protein expression of BDNF,SYP,GRP78 and Bcl-2 and decreased that of CHOP,Bax and Caspase-3.Conclusion:RTG has protective effect on depression-like symptoms and hippocampal structural pathological damage in rats induced by long-term repeated low-temperature water immersion.Its mechanism may be attributed to alleviating the endoplasmic reticulum stress of hippocampal nerve cells,reducing cell apoptosis,and improving neuroplasticity.

关 键 词：瑞替加滨 慢性应激 抑郁症 内质网应激 细胞凋亡 神经可塑性 

分 类 号：R965[医药卫生—药理学]