Neuronal Nitric Oxide Synthase (nNOS) uncoupling in ischemic stroke: Mechanisms of oxidative/nitrosative stress and opportunities for neuroprotection: A review.

The increasing prevalence of ischemic stroke, a subtype caused by restricted cerebral blood flow due to embolism or thrombosis, is exacerbated by aging, lifestyle changes, and limited physical activity. Ischemic stroke triggers hypoxia, oxidative stress, and neuronal damage, with neuronal nitric oxide synthase (nNOS) playing a pivotal role. Nitric oxide (NO), produced by nNOS in the brain, regulates blood flow and neuronal signaling. During ischemic stroke, nNOS uncouples, producing ROS and peroxynitrite, causing oxidative stress, mitochondrial dysfunction, excitotoxicity, and energy loss. Excess NO exacerbates inflammation and apoptosis, worsening neuronal damage during ischemia. Conversely, the therapeutic modulation of nNOS, including its inhibition, has shown promise in reducing neuronal damage in preclinical models. Furthermore, the interplay between nNOS and other NOS isoforms, such as endothelial NOS (eNOS) and inducible NOS (iNOS), influences the overall outcome in ischemic conditions. The interaction between nNOS and N-methyl-d-aspartate (NMDA) receptors emphasizes its critical role in synaptic plasticity, memory formation, and neuronal signaling. This dual role positions nNOS as both a protector and a contributor to neurodegeneration. This review delves into the molecular mechanisms through which nNOS drives oxidative stress and neuronal damage during ischemic stroke. Additionally, it explores the antioxidant capabilities of nNOS and its broader functional roles within the central nervous system, offering insights into innovative therapeutic approaches aimed at modulating nNOS to reduce ischemic brain injury and enhance clinical outcomes.