Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons
Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons
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DOI：
10.1523/jneurosci.22-03-00782.2002
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发表时间：
2002-02-01
影响因子：
5.3
通讯作者：
Liu, B
中科院分区：
文献类型：
--
作者：
Gao, HM;Hong, JS;Liu, B
越来越多的证据表明，环境因素如接触农药在帕金森病的发病机制中起着重要作用。在实验动物中，暴露于一种常见的除草剂鱼藤酮，诱导帕金森综合征的特征;从机制上讲，鱼藤酮诱导的多巴胺能神经元的破坏归因于其抑制神经元线粒体复合物I的活性。然而，小胶质细胞，常驻脑免疫细胞在鱼藤酮诱导的神经变性中的作用尚未报道。使用主要的神经元富集和神经元/胶质细胞培养从大鼠中脑，我们发现了一个非凡的功能鱼藤酮诱导的培养多巴胺能神经元的变性。虽然很少的神经毒性检测到在神经元富集培养物治疗后8天，高达20 nM鱼藤酮，显着和选择性多巴胺能神经变性观察到神经元/神经胶质细胞培养后2天，20 nM鱼藤酮治疗或8天后，与1 nM鱼藤酮治疗。鱼藤酮的神经变性能力大大增强归因于神经胶质细胞，特别是小胶质细胞的存在，因为向神经元富集培养物中加入小胶质细胞显著增加了它们对鱼藤酮的易感性。从机制上讲，鱼藤酮刺激小胶质细胞释放超氧化物，而NADPH氧化酶抑制剂则减弱了这种释放。此外，抑制NADPH氧化酶或清除超氧阴离子显着降低鱼藤酮引起的神经毒性。这是第一份证明小胶质细胞在鱼藤酮诱导的多巴胺能神经元变性中起关键作用的报告。这项研究的结果应该推进我们对农药在帕金森病发病机制中的作用机制的理解。
Increasing evidence has suggested an important role for environmental factors such as exposure to pesticides in the pathogenesis of Parkinson's disease. In experimental animals the exposure to a common herbicide, rotenone, induces features of parkinsonism; mechanistically, rotenone-induced destruction of dopaminergic neurons has been attributed to its inhibition of the activity of neuronal mitochondrial complex I. However, the role of microglia, the resident brain immune cells in rotenone-induced neurodegeneration, has not been reported. Using primary neuron-enriched and neuron/glia cultures from the rat mesencephalon, we discovered an extraordinary feature for rotenone-induced degeneration of cultured dopaminergic neurons. Although little neurotoxicity was detected in neuron-enriched cultures after treatment for 8 d with up to 20 nM rotenone, significant and selective dopaminergic neurodegeneration was observed in neuron/glia cultures 2 d after treatment with 20 nM rotenone or 8 d after treatment with 1 nM rotenone. The greatly enhanced neurodegenerative ability of rotenone was attributed to the presence of glia, especially microglia, because the addition of microglia to neuron-enriched cultures markedly increased their susceptibility to rotenone. Mechanistically, rotenone stimulated the release of superoxide from microglia that was attenuated by inhibitors of NADPH oxidase. Furthermore, inhibition of NADPH oxidase or scavenging of superoxide significantly reduced the rotenone-induced neurotoxicity. This is the first report demonstrating that microglia play a pivotal role in rotenone-induced degeneration of dopaminergic neurons. The results of this study should advance our understanding of the mechanism of action for pesticides in the pathogenesis of Parkinson's disease.