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首页> 美国卫生研究院文献>The Journal of Neuroscience >Critical Role for Microglial NADPH Oxidase in Rotenone-Induced Degeneration of Dopaminergic Neurons
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Critical Role for Microglial NADPH Oxidase in Rotenone-Induced Degeneration of Dopaminergic Neurons

机译：小胶质细胞NADPH氧化酶在鱼藤酮诱导的多巴胺能神经元变性中的关键作用。

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Increasing evidence has suggested an important role for environmental toxins such as pesticides in the pathogenesis of Parkinson's disease (PD). Chronic exposure to rotenone, a common herbicide, reproduces features of Parkinsonism in rats. Mechanistically, rotenone-induced dopaminergic neurodegeneration has been associated with both its inhibition of neuronal mitochondrial complex I and the enhancement of activated microglia. Our previous studies with NADPH oxidase inhibitors, diphenylene iodonium and apocynin, suggested that NADPH oxidase-derived superoxide might be a major factor in mediating the microglia-enhanced rotenone neurotoxicity. However, because of the relatively low specificity of these inhibitors, the exact source of superoxide induced by rotenone remains to be further determined. In this study, using primary mesencephalic cultures from NADPH oxidase—null (gp91phox-/-) or wild-type (gp91phox+/+) mice, we demonstrated a critical role for microglial NADPH oxidase in mediating microglia-enhanced rotenone neurotoxicity. In neuron—glia cultures, dopaminergic neurons from gp91phox-/- mice were more resistant to rotenone neurotoxicity than those from gp91phox+/+ mice. However, in neuron-enriched cultures, the neurotoxicity of rotenone was not different between the two types of mice. More importantly, the addition of microglia prepared from gp91phox+/+ mice but not from gp91phox-/- mice to neuron-enriched cultures markedly increased rotenone-induced degeneration of dopaminergic neurons. Furthermore, apocynin attenuated rotenone neurotoxicity only in the presence of microglia from gp91phox+/+ mice. These results indicated that the greatly enhanced neurotoxicity of rotenone was attributed to the release of NADPH oxidase-derived superoxide from activated microglia. This study also suggested that microglial NADPH oxidase may be a promising target for PD treatment.
机译：越来越多的证据表明，环境毒素（例如农药）在帕金森氏病（PD）的发病机理中具有重要作用。长期暴露于鱼藤酮（一种常见的除草剂）可重现大鼠帕金森病的特征。从机制上讲，鱼藤酮诱导的多巴胺能神经退行性变与抑制神经元线粒体复合体I和激活小胶质细胞增强有关。我们以前对NADPH氧化酶抑制剂，二亚苯基碘鎓和Apocynin的研究表明，NADPH氧化酶衍生的超氧化物可能是介导小胶质增强鱼藤酮神经毒性的主要因素。然而，由于这些抑制剂的相对较低的特异性，鱼藤酮诱导的超氧化物的确切来源仍有待进一步确定。在本研究中，使用来自NADPH氧化酶的原发中脑培养物-空（gp91 phox - / -）或野生型（gp91 phox + / + ）小鼠，我们证明了小胶质NADPH氧化酶在介导中起关键作用小胶质细胞增强鱼藤酮的神经毒性。在神经胶质细胞培养物中，来自gp91 phox - / -小鼠的多巴胺能神经元对鱼藤酮神经毒性的抵抗力大于来自gp91 phox + / + 小鼠的那些。但是，在富含神经元的培养物中，鱼藤酮的神经毒性在两种类型的小鼠之间没有差异。更重要的是，添加了从gp91 phox + / + 小鼠制备的小胶质细胞，但不是从gp91 phox - / -小鼠到富含神经元的培养物中，鱼藤酮诱导的多巴胺能神经元变性明显增加。此外，载脂蛋白只有在存在来自gp91 phox + / + 小鼠的小胶质细胞时，才能减弱鱼藤酮的神经毒性。这些结果表明鱼藤酮的神经毒性大大增强归因于活化小胶质细胞释放NADPH氧化酶衍生的超氧化物。这项研究还表明，小胶质细胞NADPH氧化酶可能是PD治疗的有希望的靶标。

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