Gao Hui-Ming, Liu Bin, Zhang Wanqin, Hong Jau-Shyong
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
FASEB J. 2003 Oct;17(13):1957-9. doi: 10.1096/fj.03-0203fje. Epub 2003 Aug 15.
Parkinson's disease (PD) is a profound movement disorder resulting from progressive degeneration of the nigrostriatal dopaminergic pathway. Although its etiology remains unknown, increasing evidence suggests the involvement of multiple factors such as environmental toxins and genetic susceptibilities in the pathogenesis of PD. In this study using mesencephalic neuron-glia cultures as an in vitro PD model, we demonstrated that the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 0.1-0.5 microM) and an inflammogen lipopolysaccharide (LPS, 0.5 ng/ml) synergistically induced a progressive and selective degeneration of dopaminergic neurons. The synergistic neurotoxicity was observed when both agents were applied either simultaneously or in tandem. The synergistic neurotoxicity was more prominent when lower doses of both agents were applied for a longer period of time. Mechanistically, microglial NADPH oxidase-mediated generation of reactive oxygen species played a pivotal role in the synergistic neurotoxicity: MPTP and LPS synergistically stimulated the NADPH oxidase-mediated release of superoxide free radical; pharmacological inhibition and genetic inactivation of NADPH oxidase prevented superoxide production and the synergistic neurotoxicity. Additionally, inhibition of nitric oxide synthase afforded significant neuroprotection, suggesting the involvement of nitric oxide in the synergistic neurotoxicity. This study lends strong support for a multifactorial etiology of PD and provides clues for therapeutic interventions.
帕金森病（PD）是一种严重的运动障碍疾病，由黑质纹状体多巴胺能通路的进行性退化引起。尽管其病因尚不清楚，但越来越多的证据表明，环境毒素和遗传易感性等多种因素参与了PD的发病机制。在本研究中，我们使用中脑神经元-胶质细胞培养物作为体外PD模型，证明神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP，0.1-0.5微摩尔）和炎症原脂多糖（LPS，0.5纳克/毫升）协同诱导多巴胺能神经元进行性和选择性退化。当同时或先后应用这两种药物时，均可观察到协同神经毒性。当两种药物均以较低剂量长时间应用时，协同神经毒性更为明显。从机制上讲，小胶质细胞NADPH氧化酶介导的活性氧生成在协同神经毒性中起关键作用：MPTP和LPS协同刺激NADPH氧化酶介导的超氧自由基释放；NADPH氧化酶的药理抑制和基因失活可防止超氧产生和协同神经毒性。此外，抑制一氧化氮合酶可提供显著的神经保护作用，提示一氧化氮参与了协同神经毒性。本研究为PD的多因素病因提供了有力支持，并为治疗干预提供了线索。
