Besides the receptor-mediated effects of pioglitazone, the involvement of nitric oxide (NO) has been previously demonstrated in some pioglitazone-induced central and peripheral effects. In the present study, the effects of acutely administered pioglitazone on pentylenetetrazole (PTZ)-induced seizures and involvement of NO were evaluated in mice. To determine the threshold for clonic seizures, PTZ was administered intravenously. A single dose of pioglitazone (10, 20, 40 and 80 mg/kg, p.o.) was administered either 2 or 4h prior to induction of seizures. For determination of possible role of peroxisome proliferator activated receptor gamma (PPAR-γ) and nitric oxide pathway in this effect, the effects of a PPAR-γ antagonist, GW9662 (2 mg/kg); a non-specific nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 0.3, 1, 3, and 10 mg/kg); a specific iNOS inhibitor, aminoguanidine (100mg/kg, i.p.) or a nitric oxide precursor, L-arginine (30, 60, 100 and 200mg/kg, i.p.); each administered 15 min prior to pioglitazone, were investigated on the anticonvulsant effect of this drug. Administration of pioglitazone (40 and 80 mg/kg) increased the threshold of PTZ-induced seizure in a dose-dependent, and time-dependent manner. GW9662 reversed the anticonvulsant effect of pioglitazone (40 mg/kg). Acute administration of L-NAME (1, 3 and 10mg/kg) inhibited the anticonvulsant effect of pioglitazone (40 mg/kg), the same result was detected with aminoguanidine (100mg/kg); whereas L-arginine, in the noneffective dose (100mg/kg), potentiated the seizure threshold when co-administered with a subeffective dose of pioglitazone (20mg/kg).

Conclusion: The present study demonstrates the anticonvulsant effect of acute pioglitazone on PTZ-induced seizures in mice. This effect was reversed by PPAR-γ antagonist, and both a specific- and a non-specific nitric oxide synthase inhibitors, and augmented by nitric oxide precursor, L-arginine. These results support that the anticonvulsant effect of pioglitazone is mediated through PPAR-γ receptor-mediated pathway and also, at least partly, through the nitric oxide pathway.