Blanco Santos, Muñoz-Gallardo María Del Mar, Hernández Raquel, Peinado María Ángeles
Department of Experimental Biology, University of Jaén, 23007 Jaén, Spain.
Antioxidants (Basel). 2025 Jun 13;14(6):724. doi: 10.3390/antiox14060724.
This work reviews the complex interplay between melatonin and nitric oxide (NO) in the central nervous system (CNS), with a detailed focus on its involvement in stroke pathophysiology. Melatonin, a neurohormone with potent antioxidant, anti-inflammatory, and neuroprotective properties, and NO, a gaseous signaling molecule with diverse roles, interact crucially. In the context of ischemic stroke, NO exhibits a dual role: it can be neuroprotective (primarily via endothelial nitric oxide synthase (eNOS)) or neurotoxic (especially through inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS), contributing to the formation of damaging peroxynitrite (ONOO)). Melatonin has consistently demonstrated neuroprotective effects in animal models of stroke. Its key mechanisms related to NO include (1) differential modulation of nitric oxide synthase isoforms, suppressing detrimental iNOS expression/activity while often preserving or enhancing beneficial eNOS; (2) direct scavenging of NO and, critically, highly reactive peroxynitrite, thereby attenuating nitrosative stress; (3) reduction in neuroinflammation, partly by promoting M2 (anti-inflammatory) microglia polarization; and (4) mitochondrial protection and decreased apoptosis. These multifaceted actions of melatonin contribute to reduced infarct volume and improved functional outcomes, underscoring its considerable therapeutic potential for ischemic stroke through the favorable modulation of the melatonin-NO axis.
这项工作综述了褪黑素与一氧化氮（NO）在中枢神经系统（CNS）中的复杂相互作用，特别详细地关注了其在中风病理生理学中的作用。褪黑素是一种具有强大抗氧化、抗炎和神经保护特性的神经激素，而NO是一种具有多种作用的气体信号分子，二者相互作用至关重要。在缺血性中风的背景下，NO具有双重作用：它可以具有神经保护作用（主要通过内皮型一氧化氮合酶（eNOS）），也可以具有神经毒性（特别是通过诱导型一氧化氮合酶（iNOS）和神经元型一氧化氮合酶（nNOS），导致损伤性过氧亚硝酸盐（ONOO）的形成）。褪黑素在中风动物模型中一直显示出神经保护作用。其与NO相关的关键机制包括：（1）对一氧化氮合酶同工型的差异调节，抑制有害的iNOS表达/活性，同时通常保留或增强有益的eNOS；（2）直接清除NO，至关重要的是清除高反应性的过氧亚硝酸盐，从而减轻亚硝化应激；（3）减轻神经炎症，部分是通过促进M2（抗炎）小胶质细胞极化；（4）线粒体保护和减少细胞凋亡。褪黑素的这些多方面作用有助于减少梗死体积并改善功能结局，突出了其通过有利调节褪黑素-NO轴对缺血性中风具有的巨大治疗潜力。
