Jenner P, Olanow C W
Neurodegenerative Diseases Research Centre, King's College London, UK.
Neurology. 1996 Dec;47(6 Suppl 3):S161-70. doi: 10.1212/wnl.47.6_suppl_3.161s.
Current concepts of the pathogenesis of Parkinson's disease (PD) center on the formation of reactive oxygen species and the onset of oxidative stress leading to oxidative damage to substantia nigra pars compacta. Extensive postmortem studies have provided evidence to support the involvement of oxidative stress in the pathogenesis of PD; in particular, these include alterations in brain iron content, impaired mitochondrial function, alterations in the antioxidant protective systems (most notably superoxide dismutase [SOD] and reduced glutathione [GSH]), and evidence of oxidative damage to lipids, proteins, and DNA. Iron can induce oxidative stress, and intranigral injections have been shown to induce a model of progressive parkinsonism. A loss of GSH is associated with incidental Lewy body disease and may represent the earliest biochemical marker of nigral cell loss. GSH depletion alone may not result in damage to nigral neurons but may increase susceptibility to subsequent toxic or free radical exposure. The nature of the free radical species responsible for cell death in PD remains unknown, but there is evidence of involvement of hydroxyl radical (OH.), peroxynitrite, and nitric oxide. Indeed, OH. and peroxynitrite formation may be critically dependent on nitric oxide formation. Central to many of the processes involved in oxidative stress and oxidative damage in PD are the actions of monoamine oxidase-B (MAO-B). MAO-B is essential for the activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenylpyridinium ion, for a component of the enzymatic conversion of dopamine to hydrogen peroxide (H2O2), and for the activation of other potential toxins such as isoquinolines and beta-carbolines. Thus, the inhibition of MAO-B by drugs such as selegiline may protect against activation of some toxins and free radicals formed from the MAO-B oxidation of dopamine. In addition, selegiline may act through a mechanism unrelated to MAO-B to increase neurotrophic factor activity and upregulate molecules such as glutathione, SOD, catalase, and BCL-2 protein, which protect against oxidant stress and apoptosis. Consequently, selegiline may be advantageous in the long-term treatment of PD.
帕金森病（PD）发病机制的当前概念集中在活性氧的形成以及氧化应激的发生，氧化应激会导致黑质致密部的氧化损伤。广泛的尸检研究提供了证据支持氧化应激参与PD的发病机制；具体而言，这些证据包括脑铁含量的改变、线粒体功能受损、抗氧化保护系统（最显著的是超氧化物歧化酶[SOD]和还原型谷胱甘肽[GSH]）的改变，以及脂质、蛋白质和DNA氧化损伤的证据。铁可诱导氧化应激，已证明黑质内注射可诱导进行性帕金森病模型。GSH的丧失与偶发性路易体病相关，可能代表黑质细胞丧失的最早生化标志物。单独的GSH耗竭可能不会导致黑质神经元损伤，但可能增加对随后有毒物质或自由基暴露的易感性。PD中导致细胞死亡的自由基种类的性质尚不清楚，但有证据表明羟自由基（OH·）、过氧亚硝酸盐和一氧化氮参与其中。事实上，OH·和过氧亚硝酸盐的形成可能严重依赖于一氧化氮的形成。PD中许多与氧化应激和氧化损伤相关过程的核心是单胺氧化酶-B（MAO-B）的作用。MAO-B对于将1-甲基-4-苯基-1,2,3,6-四氢吡啶激活为1-甲基-4-苯基吡啶离子、多巴胺酶促转化为过氧化氢（H2O2）的一个组分以及激活其他潜在毒素（如异喹啉和β-咔啉）至关重要。因此，像司来吉兰这样的药物对MAO-B的抑制作用可能防止某些毒素的激活以及多巴胺MAO-B氧化形成的自由基。此外，司来吉兰可能通过与MAO-B无关的机制发挥作用，以增加神经营养因子活性并上调诸如谷胱甘肽、SOD、过氧化氢酶和BCL-2蛋白等分子，这些分子可保护免受氧化应激和细胞凋亡。因此，司来吉兰在PD的长期治疗中可能具有优势。
