线粒体分裂抑制剂1对多发性硬化小鼠神经营养因子、再生抑制信号通路分子的影响  

Effects of mitochondrial fission inhibitor-1 on neurotrophic factor and neural inhibitory signaling pathway in a mouse model of multiple sclerosis

作　　者：张伟[1,2] 刘子铭[2] 张年萍 田思勰[2] 张思羽 李艳花 马存根[3] Zhang Wei;Liu Ziming;Zhang Nianping;Tian Sixie;Zhang Siyu;Li Yanhua;Ma Cungen(Department of Neurology,the Fifth People’s Hospital of Datong,the First Clinical College of Shanxi Datong University,Datong 037009,Shanxi Province,China;Institute of Brain Science,Shanxi Datong University,Datong 037009,Shanxi Province,China;Research Center of Neurobiology,Shanxi University of Chinese Medicine,Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of National Administration of Traditional Chinese Medicine,Jinzhong 030619,Shanxi Province,China)

机构地区：[1]山西省大同市第五人民医院,大同大学第一临床学院,神经内科,山西省大同市037009 [2]山西大同大学,脑科学研究所,山西省大同市037009 [3]山西中医药大学神经生物学研究中心,国家中医药管理局多发性硬化益气活血重点研究室,山西省晋中市030619

出　　处：《中国组织工程研究》2023年第17期2651-2657,共7页Chinese Journal of Tissue Engineering Research

基　　金：山西省回国留学人员项目(HGKY2019089),项目负责人:李艳花;山西省基础研究面上项目(20210302123475),项目负责人:李艳花。

摘　　要：背景:神经营养因子表达减少和再生抑制因子表达增多是神经损伤的主要机制,前期研究显示线粒体分裂抑制剂1(Mdivi-1)能明显降低多发性硬化模型小鼠的临床症状评分和病理学损伤,然而其对神经保护的作用仍需进一步研究。目的:观察实验性自身免疫性脑脊髓炎小鼠模型神经元和轴突的状态,评估线粒体分裂抑制剂1的神经保护作用。方法:C57BL/6小鼠经髓鞘少突胶质细胞糖蛋白第35-55位肽片段(MOG35-55)免疫制备实验性自身免疫性脑脊髓炎小鼠模型,随机分为模型对照组和线粒体分裂抑制剂1干预组。于免疫后第28天麻醉后处死小鼠,免疫荧光染色分析脊髓组织中神经元胞体和突触的状态、动力相关蛋白1磷酸化水平以及神经营养因子、再生抑制因子及其信号通路分子的表达。结果与结论:①与模型对照组相比,线粒体分裂抑制剂1干预组小鼠脊髓组织神经元特异性核蛋白标记的神经元数量较多、胞体形态完整,突触素标记的突触明显更长,中分子质量神经丝蛋白缺失率明显较低,动力相关蛋白1磷酸化水平较低;②线粒体分裂抑制剂1干预可明显促进胶质细胞源性神经营养因子、睫状神经营养因子和脑源性神经营养因子的表达;③线粒体分裂抑制剂1干预可明显降低小鼠髓鞘相关糖蛋白、轴突生长抑制因子A、轴突生长抑制因子蛋白受体、p75神经营养因子蛋白受体、Rho相关蛋白激酶Ⅱ的表达量;④提示线粒体分裂抑制剂1能抑制动力相关蛋白1磷酸化水平,提高神经营养因子蛋白的表达水平,降低再生抑制因子及相关信号通路分子蛋白的表达,进而降低脊髓神经元胞体、轴突和囊胞的损伤。BACKGROUND:Decreased expression of neurotrophic factors and increased expression of regenerating inhibito rs are the main mechanisms of nerve injury.It has been proven that mitochondrial fission inhibitor-1 can decrease clinical score and relieve pathological injury in a mouse model of multiple scle rosis.However,its n euro protective effects still need to be further explored.OBJECTIVE:To observe the state of neurons and axons in a mouse model of experimental autoimmune encephalomyelitis and to evaluate the n euro protective effect of mitochondrial fission inhibitor-1.METHODS:A mouse model of expe rimental autoimmune encephalo myelitis was prepared in C57 BL/6 mice by immunizing with myelin oligodendrocyte glycoprotein peptide fragment 35-55.Animal models were randomly divided into two groups(n=15 per group):model group and mitochondrial fission inhibitor-1 group.Mice were euthanized and lumbar spinal cord consecutive sections were harvested at day 28 post immunization.Immunofluorescence staining was used to analyze the state of neuronal cell body and synapse,the phosphorylation level of dynamin-related protein 1,and the expression of neurotrophic factor,regeneration inhibitor and its signaling pathway molecules in spinal cord tissue.RESULTS AND CONCLUSION:Compared with the model group,treatment with mitochondrial fission inhibitor-1 increased the number of neurons marked by neuron-specific nuclear protein in the spinal cord tissue,improved neuronal body morphology, increased the length of synaptophysin-positive synapse,decreased the loss of Neurofilament M,and inhibited the phosphorylation of dynamin-related protein 1.Mitochondrial fission inhibito r-1 treatment could significantly pro mote the expression of glial cell-de rived neurotrophic facto r,ciliary neurotrophic facto r,and brain-derived neurotrophic factor.Mitochondrial fission inhibitor-1 inte rvention could markedly reduce the expression of myelin-associated glycoprotein,axon growth inhibitory factor A,axon growth inhibitory factor protein recepto r,p7

关 键 词：实验性自身免疫性脑脊髓炎 线粒体分裂抑制剂1 神经保护 神经营养因子 再生抑制因子 

分 类 号：R459.9[医药卫生—治疗学] R318[医药卫生—临床医学] R744.5