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

Oct 30, 2025International journal of biological macromolecules

Neuronal Nitric Oxide Synthase Malfunction in Stroke: How Oxidative Stress Happens and Possible Brain Protection Strategies

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Abstract

Ischemic stroke triggers neuronal damage through the dual action of neuronal nitric oxide synthase (nNOS), producing reactive oxygen species and peroxynitrite.

Ischemic stroke, caused by restricted blood flow, leads to hypoxia and oxidative stress in neurons.
nNOS produces nitric oxide, which regulates blood flow but can also result in neuronal damage during ischemia.
During ischemic conditions, nNOS uncouples and generates harmful reactive oxygen species (ROS) and peroxynitrite.
Excess nitric oxide contributes to inflammation and cell death, exacerbating neuronal injury.
Therapeutic modulation of nNOS, including inhibition, has shown potential in reducing neuronal damage in preclinical studies.
The interaction of nNOS with other nitric oxide synthase isoforms affects outcomes in ischemic conditions.

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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.

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