Marsden C D, Olanow C W
Institute of Neurology, London, United Kingdom.
Ann Neurol. 1998 Sep;44(3 Suppl 1):S189-96. doi: 10.1002/ana.410440727.
There has been significant progress in our knowledge of the cause, the pathogenesis, and the nature of the mechanism of cell death in Parkinson's disease (PD). Mutations in single genes have now been shown to be able to cause PD but likely only account for a small number of cases. Alternatively, there is evidence that environmental factors play a large role in the majority of cases of sporadic PD. Most likely, genetic factors predispose patients to develop PD if combined with other gene mutations or environmental toxins. Interest has thus focused on factors that contribute to the pathogenesis of neurodegeneration and the mechanism of cell death in an attempt to design a neuroprotective therapy. Oxidant stress, mitochondrial dysfunction, excitotoxicity with excess nitric oxide formation, and glia and inflammatory processes are all thought to contribute to the cell death process and agents that interfere with these events may be neuroprotective. It is now generally held that the final culmination of these events is the induction of apoptosis in nigral dopaminergic neurons and this too offers opportunities for providing neuroprotection. A rational argument can be made for investigating a large number of different approaches or combination of approaches in the hope of developing a meaningful neuroprotective therapy, using clinically relevant indices and neuroimaging markers of nigral dopaminergic neurons. It is evident that conventional approaches to trials that utilize large numbers of patients in search of small incremental effects are costly and time consuming. As such, it will be virtually impossible to test all of the potentially valuable neuroprotective agents that are now at hand, let alone those that will likely soon emerge. We suggest that it may be more profitable to test a large number of agents in a small number of selected patients in search of a more robust neuroprotective effect. In this way, we will reduce the risk of missing a powerful neuroprotective treatment with a treatment that might not otherwise have been studied because of a lack of time, money, or patients.
我们对帕金森病（PD）细胞死亡的原因、发病机制及机制本质的认识取得了重大进展。现已表明单基因突变能够导致PD，但可能仅占少数病例。另外，有证据表明环境因素在大多数散发性PD病例中起很大作用。很可能，遗传因素与其他基因突变或环境毒素相结合会使患者易患PD。因此，人们的兴趣集中在导致神经退行性变发病机制和细胞死亡机制的因素上，试图设计一种神经保护疗法。氧化应激、线粒体功能障碍、因过量一氧化氮形成导致的兴奋性毒性以及胶质细胞和炎症过程都被认为与细胞死亡过程有关，干扰这些事件的药物可能具有神经保护作用。现在普遍认为这些事件的最终结果是黑质多巴胺能神经元凋亡的诱导，这也为提供神经保护提供了机会。可以提出一个合理的论点，即研究大量不同的方法或方法组合，以期利用黑质多巴胺能神经元的临床相关指标和神经影像学标志物开发出有意义的神经保护疗法。显然，传统的试验方法是利用大量患者来寻找微小的增量效应，成本高且耗时。因此，几乎不可能测试现有的所有潜在有价值的神经保护药物，更不用说那些可能很快出现的药物了。我们建议，在少数选定的患者中测试大量药物以寻找更强有力的神经保护作用可能更有成效。通过这种方式，我们将降低因缺乏时间、资金或患者而错过一种可能因未被研究而原本无法发现的强大神经保护治疗方法的风险。
