艾地苯醌对帕金森病模型小鼠的神经保护作用及机制  

Neuroprotective effect and mechanism of idebenone on Parkinson's disease model

作　　者：何培坤 段青蕊 高玉元[1] 聂坤[1] 郭曼莉 王丽娟[1,2] 王丽敏 HE Peikun;DUAN Qingrui;GAO Yuyuan;NIE Kun;GUO Manli;WANG Lijuan;WANG Limin(不详;Department of Neurology,Guangdong Provincial People s Hospital,Guangdong Academy of Medical Sciences,Guangdong Neuroscience Institute,Guangzhou 510080,China;School of Medicine,South China University of Technology,Guangzhou 510006,China)

机构地区：[1]广东省人民医院(广东省医学科学研究院)神经科,510080 [2]华南理工大学医学院,510006

出　　处：《中国神经免疫学和神经病学杂志》2022年第1期31-35,共5页Chinese Journal of Neuroimmunology and Neurology

基　　金：国家自然科学基金资助项目(81974195);广东省重点领域研发计划项目(2018B030337001);广东省自然科学基金资助项目(2018A030313427);广东省科技计划项目(2020A0505140006);广东省基础与应用基础研究基金项目(2019A1515110061);广州市科技计划项目(202102080054);中华国际医学交流基金会中华神经病学专项基金-创新思维研究基金资助项目(CIMF-Z-2016-20-1801)。

摘　　要：目的探讨艾地苯醌(idebenone)对1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的帕金森病(PD)模型小鼠的神经保护作用及其可能的机制。方法将48只雄性C57/BL6小鼠随机分为正常对照组、PD模型组、艾地苯醌低剂量组以及高剂量组,每组12只。按体重30 mg/kg给予小鼠腹腔注射MPTP(连续5 d)建立PD模型。PD造模前5 d分别按体重100、200 mg/kg给予艾地苯醌低剂量组及高剂量组小鼠艾地苯醌灌胃干预,连续11 d。采用爬杆实验和倒挂实验检测小鼠的运动能力;采用免疫组化法检测各组小鼠黑质区酪氨酸羟化酶阳性(TH+)细胞数;采用Western blot检测各组小鼠脑组织B淋巴细胞瘤-2(Bcl-2)、与Bcl-2相关的促凋亡调节因子X(Bax)、半胱氨酸天冬氨酸蛋白酶-3(Caspase-3)、Cleaved-Caspase-3以及磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/AKT)信号通路相关蛋白的表达情况。结果与PD模型组相比,艾地苯醌低、高剂量组小鼠爬杆完成时间明显缩短(P<0.05),脑内Cleaved-Caspase-3/Caspase-3比值明显降低,黑质区TH阳性细胞数、脑内Bcl2/Bax比值、PI3K磷酸化水平明显增加(均P<0.05),艾地苯醌高剂量组小鼠倒挂实验评分以及脑内AKT磷酸化水平明显增加(均P<0.05)。结论艾地苯醌可能通过激活PI3K/AKT通路抑制多巴胺能神经元线粒体凋亡,进而发挥神经保护作用。Objective The aim of the study was to detect the protective effect of idebenone against Parkinson's disease(PD)in the model mice induced by 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)and its potential mechanism.Methods Forty-eight male C57/BL6 mice were randomly divided into a control group,a PD model group,a low dose and a high dose of idebenone group.Each group had 12 mice.The mice were given intraperitoneal injection of 30 mg/kg MPTP for 5 days consecutively to establish PD model.Starting from 5 days before modeling,the mice in the low dose and high dose of idebenone groups were treated with once daily oral gavage of 100 and 200 mg/kg idebenone per day for 11 consecutive days,respectively.The locomotion ability of mice was detected by the pole climbing test and the hanging test.The number of TH-positive cells in the substantia nigra of mice in each group was detected by immunohistochemistry.Western blot was used to detect the expression level of B-cell lymphoma-2(Bcl-2),Bcl2 associated X,apoptosis regulator(Bax),Caspase-3,Cleaved-Caspase-3 and the protein related to phosphatidylinositol 3-kinase/protein kinase B(PI3K/AKT)signaling pathway in the whole brain of mice in each group.Results Compared with the PD model group,the descent time of pole test in the low-dose and high-dose idebenone group was significantly decreased(P<0.05),the ratio of Cleaved-Caspase-3/Caspase-3 in the brain was significantly down-regulated(P<0.05),and the number of TH-positive cells in substantia nigra,the ratio of Bcl2/Bax in the brain as well as the phosphorylation level of PI3K were all significantly increased(all P<0.05)in the idebenone groups.Compared with the PD model group,the traction test score of the high-dose group of idebenone was significantly increased(P<0.05),so was the phosphorylation level of AKT in the brain(P<0.05).Conclusions Idebenone may suppress mitochondrial apoptosis through activating PI3K/ATK signaling pathway,which in turn exert neuroprotective effect.

关 键 词：艾地苯醌 帕金森病 神经保护药 细胞凋亡 磷脂酰肌醇3-激酶 蛋白激酶B 信号通路 

分 类 号：R742.5[医药卫生—神经病学与精神病学]