Dose-dependent anticonvulsant and proconvulsant effects of nitric oxide synthase inhibitors on seizure threshold in a cortical stimulation model in rats

Abstract

In the central nervous system, nitric oxide (NO) is increasingly being considered as a trans-synaptic retrograde messenger, being involved for instance in cellular responses to stimulation of glutamate receptors of the NMDA subtype. Thus, compounds that modify NO production, such as NO synthase inhibitors, may provide a means of altering NMDA receptor function. The functional consequences of NO synthase inhibition are, however, complicated by the fact that NO not only serves as a messenger to activate guanylyl cyclase and so to raise cGMP in target cells in response to NMDA receptor stimulation but also to induce feedback inhibition of the NMDA receptor via a redox modulatory site on the receptor complex. This may explain the contrasting results obtained previously with NO synthase inhibitors in animal models of ischaemia and seizures. In the present study, we tried to resolve the reported discrepancies about the effects of NO synthase inhibitors in seizure models by studying such drugs at various doses in a novel model of cortical seizure threshold. In this model, the threshold for seizures in rats is determined at short time intervals by applying ramp-shaped electrical pulse-trains directly to the cerebral cortex, allowing one to determine the time course of anti- or proconvulsant drug effects in individual rats. Two NO synthase inhibitors, N G-nitro- l-arginine and N G-nitro- l-arginine methyl ester, were compared with a clinically effective antiepileptic drug, i.e. valproate. Whereas N G-nitro- l-arginine methyl ester, 1–40 mg/kg i.p., did not exert any marked effects on seizure threshold, N G-nitro- l-arginine, 1–10 mg/kg, induced significant threshold increases, which reached about 50% of the increases seen with valproate, 200 mg/kg. At 40 mg/kg N G-nitro- l-arginine, however, a significant and long-lasting decrease in seizure threshold was observed, presumably induced by blockade of the negative feedback exerted by NO on the NMDA receptor. The data demonstrate that a NO synthase inhibitor can produce both anti- and proconvulsant effects in the same model, depending on the dose administered. Similar observations have previously been reported for NMDA receptor antagonists and clinically established antiepileptic drugs, so that the biphasic effects of NO synthase inhibitors are not unusual for drugs with anticonvulsant activity.