Chronic Dichlorvos Exposure: Microglial Activation, Proinflammatory Cytokines and Damage to Nigrostriatal Dopaminergic System
Chronic Dichlorvos Exposure: Microglial Activation, Proinflammatory Cytokines and Damage to Nigrostriatal Dopaminergic System
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DOI：
10.1007/s12017-011-8156-8
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发表时间：
2011-12-01
影响因子：
3.5
通讯作者：
Gill, Kiran Dip
中科院分区：
文献类型：
--
作者：
Binukumar, B. K.;Bal, Amanjit;Gill, Kiran Dip
黑质中的多巴胺能细胞对帕金森病的神经退行性变过程非常脆弱。因此，增强其损伤易感性的机制对疾病的发病机制具有重要的意义。我们之前已经证明，长期接触敌敌畏会导致黑质纹状体多巴胺能变性和显著的行为障碍。在这项研究中，我们分析了小胶质细胞激活与多巴胺能神经变性的关系，以探讨神经炎症可能导致黑质纹状体系统中的多巴胺能神经元丢失的可能性。长期接触敌敌畏可引起大鼠小胶质细胞活化，包括NADPH氧化酶的诱导和多巴胺能神经元的选择性丢失。敌敌畏染毒大鼠黑质(SN)和纹状体(CS)的小胶质细胞标志物表达在转录和翻译水平均升高。敌敌畏处理组的SN和CS内可见活化的小胶质细胞，而对照组的小胶质细胞很少观察到。免疫组织化学染色显示，敌敌畏处理后，黑质和海马区TH阳性神经元数量减少，小胶质细胞数量增加。给予敌敌畏后，NADPH氧化酶主要亚单位gp91(Phox)的mRNA和蛋白水平显著升高。敌敌畏暴露还导致小胶质细胞伤害性介质如IL-1β、TNF-α和IL-6在转录和翻译水平的腹侧中脑和CS中的水平增加。数据表明，小胶质细胞的激活以及NADPH氧化酶和促炎细胞因子如肿瘤坏死因子-α、白介素1-β和白介素6的诱导可能通过增加多巴胺能细胞对敌敌畏毒性损伤的易感性而成为帕金森病的危险因素。
Dopaminergic cells in the substantia nigra are highly vulnerable to the neurodegenerative process of Parkinson's disease. Therefore, mechanisms that enhance their susceptibility to injury bear important implications for disease pathogenesis. We have previously shown that chronic dichlorvos exposure caused nigrostriatal dopaminergic degeneration and significant behavioral impairments. In this study, we analyzed the relationship between microglial activation and dopaminergic neurodegeneration to examine the possibility that neuroinflammation may induce dopaminergic neuronal loss in the nigrostriatal system. Chronic dichlorvos exposure causes microglial activation including induction of NADPH oxidase and a selective loss of dopaminergic neurons in rat. Microglial marker expression was increased at transcription as well as translational levels in the substantia nigra (SN) and corpus striatum (CS) of rats exposed to dichlorvos. Activated microglia were seen in SN and CS of dichlorvos-treated animals but were rarely observed in controls. Immunostaining revealed lesser number of TH-positive neurons and higher number of microglia in SN and CS regions after dichlorvos treatment. The mRNA and protein levels of the NADPH oxidase main subunit gp91(phox) were significantly increased after dichlorvos administration. Dichlorvos exposure also leads to increased level of microglial noxious mediators such as IL-1 beta, TNF-alpha and IL-6 in ventral midbrain and CS at transcription as well as translational levels. Data indicate that microglial activation and consequent induction of NADPH oxidase and proinflammatory cytokines such as TNF-alpha, IL-1 beta and IL-6 may act as risk factors for Parkinson's disease by increasing the vulnerability of dopaminergic cells to dichlorvos toxic injury.