Therapeutic potential of nitric oxide and its donors in hemorrhagic and ischemic stroke: a systematic review.

FactsNitric oxide (NO) exhibits dual roles in stroke pathophysiology, serving as both a neuroprotective agent through vasodilation and anti-thrombotic effects, and a neurotoxic mediator via oxidative stress and glutamate excitotoxicity, depending on its concentration, timing, and source.NO has been shown to play a critical role in improving outcomes after stroke in experimental studies.The efficacy of NO-based interventions varies depending on stroke type and timing. The administration of NO and its donors in stroke therapy should be flexibly integrated based on the temporal dynamics of endogenous NO following stroke onset. Inappropriate timing of medication may exacerbate the patient's condition post-stroke.Open questionsWhat are the precise molecular mechanisms underlying the concentration-dependent dual effects of NO in different stroke subtypes, and how can we selectively enhance its beneficial while suppressing its detrimental actions?How can we optimize the timing and dosing of NO donors across heterogeneous stroke populations, especially in intracerebral hemorrhage where clinical evidence is notably scarce?Can NO-based interventions be safely translated from animal models to human patients? The limited number of clinical studies necessitates larger-scale trials to confirm efficacy and safety in diverse patient populations.What are the long-term neurological consequences of NO administration? While short-term benefits have been observed, the potential for delayed adverse effects or unintended impacts on brain function remains underexplored. Nitric oxide is a gas molecule that serves as a signaling molecule in mammals, regulating the relaxation and contraction of vascular, thereby modulating local blood flow. Stroke encompasses both hemorrhagic and ischemic subtypes, with hemorrhagic strokes further classified into subarachnoid and intracerebral hemorrhages. The vasodilatory effects of nitric oxide and its derivatives have been confirmed in both peripheral and central vascular diseases. Additionally, animal studies have demonstrated that exogenous supplementation of nitric oxide or its donors has beneficial effects on stroke. We systematically reviewed the existing research on the relationship between nitric oxide donors and stroke, and elaborated on the pathophysiological processes in which nitric oxide is involved in different types of strokes. Given the significant differences in the concentration and temporal effects of nitric oxide in various types of strokes and their pathophysiological processes, the optimal timing for exogenous nitric oxide intervention under different conditions was analyzed to enhance clinical awareness regarding the treatment with nitric oxide and its donors. Future research can place greater emphasis on the development of novel nitric oxide donors and their diverse administration routes to further optimize treatment outcomes for stroke. This review underscores the limited progress in the clinical translation of nitric oxide-based therapeutics and aims to offer novel insights for the further optimization of their development, delivery strategies, and administration timing.