Acute and chronic effects of agomelatine on intravenous penthylenetetrazol-induced seizure in mice and the probable role of nitric oxide

Agomelatine is a potent MT1 and MT2 melatonin receptor agonist as well as a 5-HT2C serotonin receptor antagonist. It was approved by the European Medicines Agency as an antidepressant drug in year 2009. On the other hand, the involvement of melatonin and serotonin receptors in the modulation of seizure threshold has been demonstrated previously. The purpose of this study was to investigate the effect of agomelatine on penthylenetetrazol-induced seizure threshold in male mice. Therefore, we evaluated the effect of acute (12.5, 25, 50, 75 and 100 mg/kg, p.o. and chronic (25, 50 and 75 mg/kg, p.o., once a day, for 7 days) agomelatine administration on mouse model of intravenous penthylenetetrazol-induced seizure. For evaluation of nitrergic system involvement in the anticonvulsant effect of agomelatine, co-administration of multiple nitric oxide synthase (NOS) inhibitors [L-NAME, a non-selective NOS inhibitor, (5 mg/kg, p.o.), aminoguanidine, a selective iNOS inhibitor, (100 mg/kg, p.o.) or 7-nitroindazol, a selective nNOS inhibitor, (60 mg/kg, p.o.)] and agomelatine (50 and 75 mg/kg) were examined. In acute study, agomelatine (50 and 75 mg/kg) increased clonic seizure threshold compared to control group < 0.05 and 0.01, respectively). In chronic study, agomelatine had no effect on clonic seizure threshold compared with control mice. Co-administration of L-NAME, aminoguanidine or 7-nitroindazol with agomelatine (50 and 75 mg/kg) prevented a agomelatine-induced anti-convulsant effect. Our results suggest that agomelatine has anticonvulsant activity in intravenous penthylenetetrazol-induced seizure in acute therapy and this effect can be at least in part due to iNOS or nNOS induction. (C) 2014 Elsevier B.V. All rights reserved.