Different 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.
We 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.
Taken 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.