Research reportSub-chronic treatment with pioglitazone exerts anti-convulsant effects in pentylenetetrazole-induced seizures of mice: The role of nitric oxide

ObjectivesPioglitazone delayed the development of seizure responses and shortened the duration of convulsion of genetically epileptic EL mice. The anti-epileptic effect of pioglitazone was attributed partly through the reduction of inflammatory responses and preventing apoptosis. There are also some reports showing that some pioglitazone effects mediate through nitric oxide. In this study we evaluated sub-chronic pioglitazone effects in two models of intravenous and intraperitoneal pentylenetetrazole-induced clonic seizures in mice.Materials and methodsDifferent doses of pioglitazone were administered orally for 10 days in different groups of male mice. l-NAME, a non selective inhibitor of nitric oxide synthase, aminoguanidine, a selective inhibitor of inducible nitric oxide synthase, or l-arginine, a nitric oxide donor, was administered acutely or sub-chronically to evaluate the role of nitric oxide in pioglitazone anti-seizure effects.ResultsWe demonstrated that sub-chronic administration of pioglitazone exerted anti-convulsant effects in both models of intravenous and intraperitoneal pentylenetetrazole. Acute and sub-chronic pre-administration of l-NAME prevented the anti-convulsant effect of pioglitazone in both models of intravenous and intraperitoneal pentylenetetrazole. Aminoguanidine did not alter the anti-convulsant effect of pioglitazone in two models of intravenous and intraperitoneal pentylenetetrazole. Both acute and sub-chronic pre-treatment of mice with l-arginine exerted anti-convulsant effect when administered with a non effective dose of pioglitazone in intraperitoneal method. In intravenous method, acute administration of l-arginine with a non-effective dose of pioglitazone enhanced the seizure clonic latency.ConclusionTaken together, sub-chronic pioglitazone treatment exerts anti-convulsant effects in intravenous and intraperitoneal pentylenetetrazole-induced seizures of mice probably through induction of constitutive nitric oxide synthase.

► Pioglitazone acts as an anticonvulsant in both intravenous and intraperitoneal PTZ models. ► Acute and subchronic l-NAME prevented pioglitazone anticonvulsant effect in iv and ip seizure models. ► Aminoguanidine did not alter the anti-convulsant effect of pioglitazone in iv and ip seizure models. ► l-Arginine enhanced seizure latency of non-effective dose of pioglitazone in both seizure models. ► Nitric oxide signaling probably through cNOS might involve in pioglitazone anti-seizure effects.