The nitrate–nitrite–nitric oxide pathway of neuroinflammation and cognitive impairment in ischemic stroke

Ischemic stroke is the most prevalent type of stroke worldwide and poses a serious threat to human health. Neuroinflammation following an ischemic stroke is a key factor in cognitive impairment and disease progression, yet effective interventions are lacking. The classical L-arginine-nitric oxide synthase (L-arginine-NO) pathway for nitric oxide (NO) synthesis becomes impaired under ischemic and hypoxic conditions. This review focuses on an essential alternative pathway: the nitrate-nitrite-NO pathway, which is preferentially activated under hypoxic conditions and serves as a ‘backup system’ for maintaining NO bioavailability. This review outlines the epidemiology and pathomechanisms of ischemic stroke and introduces the biochemical basis of the NO pathway. It emphasizes the pathway’s dual role in ischemic stroke, exerting anti-inflammatory and neuroprotective effects by mediating vasodilation, improving cerebral perfusion, regulating microglial polarization, preserving blood–brain barrier integrity, and promoting synaptic plasticity. This mitigates cognitive impairment. Conversely, the review also explores the potential neurotoxic effects of excessive NO during the late reperfusion phase. Furthermore, this review discusses novel therapeutic strategies based on this pathway, including exogenous NO supplementation (e.g., dietary nitrates or NO donor drugs), gene therapy, targeted delivery systems incorporating nanotechnology, and combination therapies with other medications. These strategies are all designed to enhance treatment precision and bioavailability. Finally, we summarize current research limitations and highlight potential directions for future investigations. We conclude that an in-depth exploration of the nitrate-nitrite-NO pathway provides strong theoretical foundations and novel perspectives for developing innovative treatments targeting neuroinflammation and cognitive impairment after ischemic stroke.