Zhou Chun, Huang Yong, Przedborski Serge
Department of Neurology, Columbia University, New York, NY 10032, USA.
Ann N Y Acad Sci. 2008 Dec;1147:93-104. doi: 10.1196/annals.1427.023.
Parkinson's disease (PD) is a common adult-onset neurodegenerative disorder. Typically PD is a sporadic neurological disorder, and over time affected patients see their disability growing and their quality of life declining. Oxidative stress has been hypothesized to be linked to both the initiation and the progression of PD. Preclinical findings from both in vitro and in vivo experimental models of PD suggest that the neurodegenerative process starts with otherwise healthy neurons being hit by some etiological factors, which sets into motion a cascade of deleterious events. In these models initial molecular alterations in degenerating dopaminergic neurons include increased formation of reactive oxygen species, presumably originating from both inside and outside the mitochondria. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, time-course experiments suggest that oxidative stress is an early event that may directly kill some of the dopaminergic neurons. In this model it seems that oxidative stress may play a greater role in the demise of dopaminergic neurons indirectly by activating intracellular, cell death-related, molecular pathways. As the neurodegenerative process evolves in the MPTP mouse model, indices of neuroinflammation develop, such as microglial activation. The latter increases the level of oxidative stress to which the neighboring compromised neurons are subjected to, thereby promoting their demise. However, these experimental studies have also shown that oxidative stress is not the sole deleterious factor implicated in the death of dopaminergic neurons. Should a similar multifactorial cascade underlie dopaminergic neuron degeneration in PD, then the optimal therapy for this disease may have to rely on a cocktail of agents, each targeting a different critical component of this hypothesized pathogenic cascade. If correct, this may be a reason why neuroprotective trials using a single agent, such as an antioxidant, have thus far generated disappointing results.
帕金森病（PD）是一种常见的成年起病的神经退行性疾病。典型的帕金森病是一种散发性神经系统疾病，随着时间的推移，受影响的患者会出现残疾加剧、生活质量下降的情况。氧化应激被认为与帕金森病的发病和进展均有关联。帕金森病的体外和体内实验模型的临床前研究结果表明，神经退行性过程始于原本健康的神经元受到某些病因因素的影响，从而引发一系列有害事件。在这些模型中，退化的多巴胺能神经元最初的分子改变包括活性氧的生成增加，推测其来源既有线粒体内也有线粒体外。在帕金森病的1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）小鼠模型中，时间进程实验表明氧化应激是一个早期事件，可能直接杀死一些多巴胺能神经元。在这个模型中，氧化应激似乎可能通过激活细胞内与细胞死亡相关的分子途径，在多巴胺能神经元的死亡中发挥更大的间接作用。随着MPTP小鼠模型中神经退行性过程的发展，神经炎症指标出现，如小胶质细胞活化。后者会增加邻近受损神经元所承受的氧化应激水平，从而促进它们的死亡。然而，这些实验研究也表明，氧化应激并非多巴胺能神经元死亡所涉及的唯一有害因素。如果帕金森病中多巴胺能神经元退化存在类似的多因素级联反应，那么这种疾病的最佳治疗方法可能必须依赖于多种药物的组合，每种药物针对这一假设的致病级联反应的不同关键组成部分。如果这是正确的，那么这可能就是为什么迄今为止使用单一药物（如抗氧化剂）的神经保护试验结果令人失望的原因。
