Anticonvulsant role of nitric oxide synthase inhibitors in epilepsy (Review)

Epilepsy is a pathophysiological process triggered by an imbalance between excitatory and inhibitory mechanisms in the brain, resulting in the sudden and synchronized excessive electrical discharges of neurons. Nitric oxide (NO) is a cellular signaling molecule that functions as both a neurotransmitter and neuromodulator in the central nervous system. Despite its critical role in neuronal function, the impact of the NO pathway on the pathophysiology of epilepsy remains complex. NO, produced by different isoforms of the NO synthase (NOS) enzyme, exerts a bidirectional effect on epileptogenesis. In the present review, the effects of non-selective NOS inhibitors (L-NAME) and isoform-specific selective neuronal NOS (nNOS; 7-nitroindazole) and inducible NOS (iNOS; aminoguanidine) inhibitors on seizure threshold, seizure duration and neuroinflammation are comparatively discussed. Evidence indicates that the selective inhibition of nNOS and iNOS activity significantly suppresses glutamatergic hyperexcitability and nitrosative stress associated with N-methyl-D-aspartate receptor activation. nNOS inhibition increases neuronal survival and reduces seizure severity by decreasing intracellular Ca²⁺ influx. Conversely, endothelial NOS inhibition has been shown to produce proconvulsant effects by reducing cerebral perfusion. This situation highlights the critical importance of isoform specificity in anticonvulsant efficacy. Unlike classical antiepileptic drugs, NOS inhibitors stand out as potent anticonvulsant agents by targeting cellular signaling and inflammation pathways, rather than directly targeting ion channels. Current findings suggest that nNOS- and iNOS-targeted strategies may be strong therapeutic candidates for next-generation combination therapies, particularly in cases of refractory epilepsy. The present review summarizes the roles of the NO signaling pathway in seizure mechanisms and discusses the anticonvulsant potential of NOS inhibitors in the treatment of epilepsy.