Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase
Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase
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DOI：
10.1096/fj.04-1945fje
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发表时间：
2004-08-01
期刊：
影响因子：
4.8
通讯作者：
Veronesi, B
中科院分区：
文献类型：
--
作者：
Block, ML;Wu, X;Veronesi, B
环境因素对帕金森病发展的促进作用已变得越来越明显。我们报告，中脑神经元胶质细胞培养物处理柴油机尾气颗粒（DEP; 0.22 μ M）（5 - 50 μ g/ml）导致多巴胺（DA）神经元的剂量依赖性减少，DA-摄取测定和酪氨酸羟化酶免疫细胞化学（ICC）。DEP对DA神经元的选择性毒性表现为对GABA摄取和Neu-N免疫反应阳性细胞数量的缺乏。小胶质细胞的关键作用被证明是失败的神经元富集的文化表现出DEP诱导的DA神经毒性，其中DEP诱导的DA神经元死亡恢复与添加小胶质细胞的神经元富集的文化。DEP处理的神经元培养物的OX-42 ICC染色揭示了指示活化的小胶质细胞形态的变化。富集的小胶质细胞培养物对DEP产生细胞内活性氧和超氧化物。与对照小鼠（PHOX+/+）相比，NADPH氧化酶缺陷（PHOX-/-）小鼠的神经元-胶质细胞培养物对DEP神经毒性不敏感。细胞松弛素D抑制DEP诱导的超氧化物产生富集的小胶质细胞培养物，这意味着DEP必须被吞噬的小胶质细胞产生超氧化物。总之，这些体外数据表明，DEP通过吞噬激活小胶质细胞NADPH氧化酶和随后的氧化损伤选择性损伤DA神经元。
The contributing role of environmental factors to the development of Parkinson's disease has become increasingly evident. We report that mesencephalic neuron-glia cultures treated with diesel exhaust particles (DEP; 0.22 muM) ( 5 - 50 mug/ml) resulted in a dose-dependent decrease in dopaminergic (DA) neurons, as determined by DA-uptake assay and tyrosine-hydroxylase immunocytochemistry (ICC). The selective toxicity of DEP for DA neurons was demonstrated by the lack of DEP effect on both GABA uptake and Neu-N immunoreactive cell number. The critical role of microglia was demonstrated by the failure of neuron-enriched cultures to exhibit DEP-induced DA neurotoxicity, where DEP-induced DA neuron death was reinstated with the addition of microglia to neuron-enriched cultures. OX-42 ICC staining of DEP treated neuronglia cultures revealed changes in microglia morphology indicative of activation. Intracellular reactive oxygen species and superoxide were produced from enriched-microglia cultures in response to DEP. Neuron-glia cultures from NADPH oxidase deficient (PHOX-/-) mice were insensitive to DEP neurotoxicity when compared with control mice (PHOX+/+). Cytochalasin D inhibited DEP-induced superoxide production in enriched-microglia cultures, implying that DEP must be phagocytized by microglia to produce superoxide. Together, these in vitro data indicate that DEP selectively damages DA neurons through the phagocytic activation of microglial NADPH oxidase and consequent oxidative insult.