Tieu Kim, Ischiropoulos Harry, Przedborski Serge
Department of Neurology, Columbia University, New York, NY 10032, USA.
IUBMB Life. 2003 Jun;55(6):329-35. doi: 10.1080/1521654032000114320.
Parkinson's disease is a neurodegenerative disorder of unknown pathogenesis. Oxidative stress has been proposed as one of several pathogenic hypotheses. Evidence for the participation of oxidative processes in the pathogenesis of Parkinson's disease have been obtained in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model by the use of genetically altered mice. MPTP administration has been shown to increase levels of superoxide both intracellularly, via the inhibition of mitochondrial respiration and other mechanisms and extracellularly, via the activation of NADPH-oxidase in microglia. In addition to superoxide, nitric oxide production by nNOS or by microglial iNOS also contributes to the MPTP neurotoxocity. Mice with endowed defences against superoxide or with deficiency in the nNOS and iNOS are protected from MPTP toxicity suggesting that formation of reactive oxygen and nitrogen intermediates both intracellularly and extracellularly contributes to the demise of dopaminergic neurons. Similar contribution of reactive nitrogen and oxygen species may well underlie the neurodegenerative processes in Parkinson's disease.
帕金森病是一种发病机制不明的神经退行性疾病。氧化应激已被提出作为几种致病假说之一。通过使用基因改造小鼠，在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）模型中获得了氧化过程参与帕金森病发病机制的证据。已表明，给予MPTP可通过抑制线粒体呼吸和其他机制在细胞内增加超氧化物水平，并通过激活小胶质细胞中的NADPH氧化酶在细胞外增加超氧化物水平。除超氧化物外，nNOS或小胶质细胞iNOS产生的一氧化氮也导致MPTP的神经毒性。具有抗超氧化物防御能力或nNOS和iNOS缺乏的小鼠对MPTP毒性具有抵抗力，这表明细胞内和细胞外活性氧和氮中间体的形成均导致多巴胺能神经元的死亡。活性氮和氧物种的类似作用很可能是帕金森病神经退行性过程的基础。
