Department of Physiology and Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Rd., Auckland 1142, New Zealand.
Prog Neurobiol. 2011 Sep 1;94(4):389-407. doi: 10.1016/j.pneurobio.2011.06.005. Epub 2011 Jun 24.
There is consensus that amelioration of the motor symptoms of Parkinson's disease is most effective with L-DOPA (levodopa). However, this necessary therapeutic step is biased by an enduring belief that L-DOPA is toxic to the remaining substantia nigra dopaminergic neurons by itself, or by specific metabolites such as dopamine. The concept of L-DOPA toxicity originated from pre-clinical studies conducted mainly in cell culture, demonstrating that L-DOPA or its derivatives damage dopaminergic neurons due to oxidative stress and other mechanisms. However, the in vitro data remain controversial as some studies showed neuroprotective, rather than toxic action of the drug. The relevance of this debate needs to be considered in the context of the studies conducted on animals and in clinical trials that do not provide convincing evidence for L-DOPA toxicity in vivo. This review presents the current views on the pathophysiology of Parkinson's disease, focusing on mitochondrial dysfunction and oxidative/proteolytic stress, the factors that can be affected by L-DOPA or its metabolites. We then critically discuss the evidence supporting the two opposing views on the effects of L-DOPA in vitro, as well as the animal and human data. We also address the problem of inadequate experimental models used in these studies. L-DOPA remains the symptomatic 'hero' of Parkinson's disease. Whether it contributes to degeneration of nigral dopaminergic neurons, or is a 'scapegoat' for explaining undesirable or unexpected effects of the treatment, remains a hotly debated topic.
人们普遍认为，左旋多巴（L-DOPA）最能改善帕金森病的运动症状。然而，这种必要的治疗步骤受到一种持久信念的影响，即 L-DOPA 本身或其特定代谢物如多巴胺对剩余的黑质多巴胺能神经元有毒性。L-DOPA 毒性的概念源于主要在细胞培养中进行的临床前研究，表明 L-DOPA 或其衍生物由于氧化应激和其他机制而损害多巴胺能神经元。然而，体外数据仍然存在争议，因为一些研究表明该药物具有神经保护作用，而不是毒性作用。在动物研究和临床试验中，需要考虑这一争论的相关性，这些研究没有提供体内 L-DOPA 毒性的确凿证据。本文综述了目前对帕金森病病理生理学的看法，重点介绍了线粒体功能障碍和氧化/蛋白水解应激，以及 L-DOPA 或其代谢物可以影响的因素。然后，我们批判性地讨论了支持 L-DOPA 在体外两种相反作用的证据，以及动物和人类数据。我们还解决了这些研究中使用的不充分实验模型的问题。L-DOPA 仍然是帕金森病的症状性“英雄”。它是否导致黑质多巴胺能神经元退化，或者是解释治疗中不良或意外效果的“替罪羊”，仍然是一个争论激烈的话题。
