补体C3基因敲除对MPTP致小鼠多巴胺能神经元损伤的影响及低剂量γ射线照射对多巴胺能神经元的保护作用

发布时间：2018-03-27 20:20

本文选题：补体C3　切入点：帕金森病　出处：《第三军医大学》2006年硕士论文

【摘要】： 帕金森病(PD)是一种以震颤、肌肉僵直、运动迟缓等一系列症状为临床特征的中枢神经系统退行性疾病[1]。在中枢神经系统(CNS)神经变性疾病(如AD)中,发现脑内炎症反应在其病理发生中的重要性,炎症反应引起的继发损伤及这种损伤在PD病理进展中的作用逐渐引起人们的重视[2]。免疫机制在神经退行性疾病(如PD)中的作用,已经成为一个重要的研究领域[3]。补体系统是天然免疫系统的重要组成部分,在机体抗感染免疫中发挥重要作用。PD发生中存在补体活化:PD发生过程中产生的C反应蛋白[4]以及凋亡或坏死的神经元[4]均可活化脑内补体系统。尸检资料也显示,PD患者脑内的Lewy小体中存在C3d、C4d、C7、C9等补体活化产物的沉积[5]。Defazio[6]曾报道补充兔血清后,灭活了补体活性的PD患者血清可溶破大鼠中脑原代培养细胞,揭示补体系统可能通过这一机制介导DA神经元损伤。但目前仍缺乏PD患者脑内补体溶破多巴胺神经元的直接证据,更缺乏整体动物水平上,补体系统的综合作用结果。已有研究证实,低剂量全身照射在视神经损伤及脊髓撞伤动物模型中均对神经元有保护作用。低剂量γ射线照射预处理动物后,会引起稳态驱动的T细胞增殖(homeostasis-driven proliferation of T cells )[7]。而最近的一则报道发现,自身抗原刺激产生的T细胞在SNpc聚集后,会保护黑质纹状体神经元不受MPTP损伤的影响[8]。然而,目前仍无直接证据提示低剂量全身γ射线照射对MPTP诱发的SNpc变性是否有保护作用。本研究首先利用C3基因敲除小鼠建立MPTP损伤黑质多巴胺神经元的PD模型,运用HPLC和免疫组织化学方法,在生化水平和细胞水平观察C3基因敲除对MPTP诱发的DA神经元损伤的影响,并观察了C3在MPTP损伤后黑质纹状体通路恢复过程中的作用;同时在已经建立的MPTP模型中,观察了低剂量全身γ射线照射对DA神经元的保护作用,并观察了射线对MPTP诱发的胶质细胞反应的影响,旨在揭示其作用机制。
[Abstract]:Parkinson's disease (PD) is a neurodegenerative disease of the central nervous system (CNS) characterized by a series of symptoms such as tremor, muscle stiffness and motor retardation. It was found that the importance of inflammation in the pathogenesis of PD, the secondary injury caused by inflammation and the role of this injury in the pathological progression of PD gradually attracted attention [2]. The role of immune mechanism in neurodegenerative diseases, such as PD2, was found. Has become an important research field [3]. The complement system is an important part of the innate immune system. Play an important role in the body's anti-infective immunity. The presence of complement activation in the pathogenesis of PD, C-reactive protein [4] and apoptosis or necrosis of neurons [4] can activate the complement system in the brain. Autopsy data also show that the complement system in the brain can be activated. In the brain of PD patients, the deposition of complement activation products such as C3dC4dC7C9 in the Lewy bodies of PD patients [5] .Defazio [6] has been reported after supplementation of rabbit serum. In PD patients whose complement activity was inactivated, the serum could dissolve the primary cultured cells in the midbrain of rats, suggesting that the complement system may mediate DA neuron damage through this mechanism. However, there is still no direct evidence of dopamine neurons in PD patients. More lack of the overall animal level, the complement system of the combined effect of the results. It has been proved that low dose whole body irradiation has protective effect on neurons in the animal models of optic nerve injury and spinal cord injury. Homeostasis-driven proliferation of T cells [7] and a recent report found that autoantigen-stimulated T cells protect nigral striatal neurons from MPTP damage after SNpc aggregates [8]. There is no direct evidence to indicate whether low-dose 纬-ray irradiation has protective effect on SNpc denaturation induced by MPTP. In this study, the PD model of nigra dopaminergic neurons damaged by MPTP was established by using C3 knockout mice. HPLC and immunohistochemical methods were used. The effects of C3 knockout on MPTP induced DA neuron damage were observed at the biochemical and cellular levels, and the role of C3 in the recovery of nigra striatum pathway after MPTP injury was also observed, and in the established MPTP model, The protective effect of low dose whole-body 纬 -ray irradiation on DA neurons and the effect of irradiation on glial response induced by MPTP were observed in order to reveal its mechanism.
【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2006
【分类号】：R392

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