Faculty of Pharmacy, University of Coimbra and Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Arch Biochem Biophys. 2021 Jun 15;704:108877. doi: 10.1016/j.abb.2021.108877. Epub 2021 Apr 14.
The molecular mechanisms underlying the degeneration and neuronal death associated with Parkinson's disease (PD) are not clearly understood. Several pathways and models have been explored in an overwhelming number of studies. Overall, from these studies, mitochondrial dysfunction and nitroxidative stress have emerged as major contributors to degeneration of dopaminergic neurons in PD. In addition, an excessive or inappropriate production of nitric oxide (NO) and an abnormal metabolism of dopamine have been independently implicated in both processes. However, the participation of NO in reactions with dopamine relevant to neurotoxicity strongly suggests that dopamine or its metabolites may be potential targets for NO, affecting the physiological chemistry of both, NO and dopamine. In this short review, we provide a critical and integrative appraisal of the nitric oxide-dopamine pathway we have previously suggested and that might be operative in PD. This pathway emphasizes a connection between abnormal dopamine and NO metabolism, which may potentially converge in an integrated mechanism with toxic cellular outcomes. In particular, it encompasses the synergistic interaction of NO with 3,4-dihydroxyphenylacetic acid (DOPAC), a major dopamine metabolite, leading to dopaminergic cell death via mechanisms that involve mitochondrial dysfunction, gluthathione depletion and nitroxidative stress.
帕金森病（PD）相关的退行性变和神经元死亡的分子机制尚不清楚。在大量研究中探索了几种途径和模型。总的来说，从这些研究中，线粒体功能障碍和氧化应激已成为 PD 中多巴胺能神经元退行性变的主要原因。此外，一氧化氮（NO）的过度或不适当产生以及多巴胺的异常代谢已被独立牵连到这两个过程中。然而，NO 与与神经毒性相关的多巴胺反应的参与强烈表明，多巴胺或其代谢物可能是 NO 的潜在靶点，影响 NO 和多巴胺的生理化学性质。在这篇简短的综述中，我们对我们之前提出的可能在 PD 中起作用的一氧化氮-多巴胺途径进行了批判性和综合性的评估。该途径强调了异常多巴胺和 NO 代谢之间的联系，这可能通过具有毒性细胞结果的综合机制潜在地汇聚在一起。特别是，它包含了一氧化氮与主要的多巴胺代谢物 3,4-二羟基苯乙酸（DOPAC）的协同相互作用，通过涉及线粒体功能障碍、谷胱甘肽耗竭和氧化应激的机制导致多巴胺能细胞死亡。
