Increased neuronal nitric oxide synthase (nNOS) activity triggers picrotoxin-induced seizures in rats and evidence for participation of nNOS mechanism in the action of antiepileptic drugs

Increased neuronal nitric oxide synthase (nNOS) activity was observed during the prodromal period of seizures in various rat brain regions following administration of GABA(A) receptor antagonist, picrotoxin (PCT). Pretreatment with the selective nNOS inhibitor 7-nitroindazole (7-NI), dose- and time-dependently delayed the onset of clonus with a corresponding decrease in nNOS activity. The threshold dose of antiepileptic drugs (AEDs; diazepam, phenobarbitone and gabapentin) have potentiated the anticonvulsant action by pretreatment with graded doses of 7-NI. The increase in efficacy of anticonvulsant action correlated with a corresponding decrease of PCT-evoked increase in nNOS activity. The present data support a role for abnormal nNOS activity in mechanisms that trigger seizures and suggest a possible NO-mediated interplay between GABA(A) and glutamate receptors. The results of the present study provide evidence for a trigger role of neuronally produced NO in epileptogenesis induced by PCT and the participation of nNOS inhibitory mechanisms in the action of AEDs.