Faculty of Pharmacy, University of Coimbra, Azinhaga Sta. Comba, 3000-548, Coimbra, Portugal.
Center for Neuroscience and Cell Biology, University of Coimbra, Pólo 1, 3000-504, Coimbra, Portugal.
Neurochem Res. 2021 Jan;46(1):64-76. doi: 10.1007/s11064-020-03015-0. Epub 2020 Mar 19.
In this review, we address the regulatory and toxic role of NO along several pathways, from the gut to the brain. Initially, we address the role on NO in the regulation of mitochondrial respiration with emphasis on the possible contribution to Parkinson's disease via mechanisms that involve its interaction with a major dopamine metabolite, DOPAC. In parallel with initial discoveries of the inhibition of mitochondrial respiration by NO, it became clear the potential for toxic NO-mediated mechanisms involving the production of more reactive species and the post-translational modification of mitochondrial proteins. Accordingly, we have proposed a novel mechanism potentially leading to dopaminergic cell death, providing evidence that NO synergistically interact with DOPAC in promoting cell death via mechanisms that involve GSH depletion. The modulatory role of NO will be then briefly discussed as a master regulator on brain energy metabolism. The energy metabolism in the brain is central to the understanding of brain function and disease. The core role of NO in the regulation of brain metabolism and vascular responses is further substantiated by discussing its role as a mediator of neurovascular coupling, the increase in local microvessels blood flow in response to spatially restricted increase of neuronal activity. The many facets of NO as intracellular and intercellular messenger, conveying information associated with its spatial and temporal concentration dynamics, involve not only the discussion of its reactions and potential targets on a defined biological environment but also the regulation of its synthesis by the family of nitric oxide synthases. More recently, a novel pathway, out of control of NOS, has been the subject of a great deal of controversy, the nitrate:nitrite:NO pathway, adding new perspectives to NO biology. Thus, finally, this novel pathway will be addressed in connection with nitrate consumption in the diet and the beneficial effects of protein nitration by reactive nitrogen species.
在这篇综述中，我们将探讨 NO 在从肠道到大脑的几种途径中的调节和毒性作用。首先，我们将重点讨论 NO 在调节线粒体呼吸中的作用，特别是其通过与主要多巴胺代谢物 DOPAC 相互作用的机制，对帕金森病的可能贡献。随着最初发现 NO 抑制线粒体呼吸的发现，人们清楚地认识到潜在的有毒 NO 介导机制涉及产生更具反应性的物质和线粒体蛋白的翻译后修饰。因此，我们提出了一种潜在的导致多巴胺能细胞死亡的新机制，提供了证据表明，NO 与 DOPAC 协同作用通过涉及 GSH 耗竭的机制促进细胞死亡。随后将简要讨论 NO 的调节作用，作为大脑能量代谢的主要调节剂。大脑的能量代谢是理解大脑功能和疾病的核心。NO 在调节大脑代谢和血管反应中的核心作用进一步得到证实，因为它作为神经血管偶联的介质，局部微血管血流增加是对神经元活动的空间限制增加的反应。NO 作为细胞内和细胞间信使的多方面作用，传递与其时空浓度动态相关的信息，不仅涉及其在特定生物环境中的反应和潜在靶标，还涉及一氧化氮合酶家族对其合成的调节。最近，一种新的途径，即不受 NOS 控制的途径，已经成为大量争议的主题，硝酸盐：亚硝酸盐：NO 途径，为 NO 生物学增添了新的视角。因此，最后，将讨论与饮食中硝酸盐消耗以及活性氮物种引起的蛋白质硝化的有益作用有关的这种新途径。
