DOSE-DEPENDENT ANTICONVULSANT AND PROCONVULSANT EFFECTS OF NITRIC-OXIDE SYNTHASE INHIBITORS ON SEIZURE THRESHOLD IN A CORTICAL STIMULATION MODEL IN RATS

In the central nervous system, nitric oxide (NO) is increasingly being considered as a trans-synaptic retrograde messenger, being involved f or instance in cellular responses to stimulation of glutamate receptor s of the NMDA subtype. Thus, compounds that modify NO production, such as NO synthase inhibitors, may provide a means of altering NMDA recep tor function. The functional consequences of NO synthase inhibition ar e, however, complicated by the fact that NO not only serves as a messe nger 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 rec eptor complex. This may explain the contrasting results obtained previ ously with NO synthase inhibitors in animal models of ischaemia and se izures. In the present study, we tried to resolve the reported discrep ancies about the effects of NO synthase inhibitors in seizure models b y studying such drugs at various doses in a novel model of cortical se izure 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 determin e the time course of anti- or proconvulsant drug effects in individual rats. Two NO synthase inhibitors, N-G-nitro-Larginine and N-G-nitro-L -arginine methyl ester, were compared with a clinically effective anti epileptic drug, i.e. valproate. Whereas N-G-nitro-L-arginine methyl es ter, 1-40 mg/kg i.p., did not exert any marked effects on seizure thre shold, N-G-nitro-Larginine, 1-10 mg/kg, induced significant threshold increases, which reached about 50% of the increases seen with valproat e, 200 mg/kg. At 40 mg/kg N-G-nitro-L-arginine, however, a significant and long-lasting decrease in seizure threshold was observed, presumab ly induced by blockade of the negative feedback exerted by NO on the N MDA receptor. The data demonstrate that a NO synthase inhibitor can pr oduce both anti- and proconvulsant effects in the same model, dependin g on the dose administered. Similar observations have previously been reported for NMDA receptor antagonists and clinically established anti epileptic drugs, so that the biphasic effects of NO synthase inhibitor s are not unusual for drugs with anticonvulsant activity.