Nitric Oxide Pathway in Epileptic Seizures

Nitric oxide (NO) has emerged as a pivotal neuromodulator in the pathophysiology of epileptic seizures. Synthesised from l-arginine by nitric oxide synthase (NOS) isoforms, NO influences neuronal excitability through the activation of soluble guanylate cyclase (sGC) and consequent elevation of cyclic guanosine monophosphate (cGMP). This pathway modulates synaptic transmission, particularly via interactions with N-methyl-D-aspartate (NMDA) receptors, and can exert both pro-convulsant and anticonvulsant effects depending on concentration, cellular context and temporal dynamics. In acute seizures, rapid NO release may facilitate hyperexcitability and oxidative damage through peroxynitrite formation, whereas in chronic settings it can trigger adaptive neuroprotective signalling. The dichotomous role of NO is further compounded by the distinct regulation of neuronal (nNOS) and inducible (iNOS) forms during inflammatory responses. Understanding this balance has become increasingly important for identifying novel therapeutic targets that modulate NO signalling without instigating detrimental side effects. The global burden of epilepsy, together with the limited efficacy of current antiepileptic drugs in drug-resistant cases, underscores the potential of NO-based strategies to refine seizure control and neuroprotection.

Research from Nature Portfolio

Recent studies have illuminated the spatiotemporal dynamics of NO during seizure initiation and propagation. In one investigation, advanced fluorescent NO probes enabled real-time imaging of NO flux in hippocampal circuits of rodent models, revealing transient NO surges that precede synchronized discharges. A parallel study employed conditional nNOS knockout mice to demonstrate that selective ablation of neuronal NO production attenuates seizure severity and limits hippocampal cell loss, while sparing vascular functions. Furthermore, modulation of the NO–sGC–cGMP axis with novel sGC stimulators has been shown to reinforce inhibitory GABAergic transmission and reduce seizure frequency in chronic temporal lobe epilepsy models, offering promising avenues for pharmacological intervention.

Nitric Oxide Pathway in Epileptic Seizures publication trend

The graph below shows the total number of articles in nitric oxide pathway in epileptic seizures across all publications each year (not limited to Nature Index journals).

Technical terms

Nitric oxide synthase (NOS): Enzymes that catalyse the production of NO from l-arginine, with multiple isoforms regulating neuronal and immune responses.

Neuronal NOS (nNOS): The isoform predominantly expressed in neurons, responsible for rapid NO signalling at synapses and modulating excitability.

Inducible NOS (iNOS): The isoform upregulated in glia and immune cells during inflammation, producing sustained NO levels that can be neurotoxic.

cGMP: A second messenger generated by soluble guanylate cyclase activation, mediating many downstream effects of NO, including ion channel modulation.

Peroxynitrite: A highly reactive nitrogen species formed by the reaction of NO with superoxide, implicated in oxidative damage during seizures.

References

1. Anticonvulsant and proconvulsant roles of nitric oxide in experimental epilepsy models. Brazilian Journal of Medical and Biological Research (1997).
2. Unmasking hidden risks: The surprising link between PDE5 inhibitors and seizure susceptibility. PLOS ONE (2023).