Anticonvulsant potential of the peroxisome proliferator-activated receptor γ agonist pioglitazone in pentylenetetrazole-induced acute seizures and kindling in mice

Abstract

Pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, is used in inflammatory brain diseases, and it was shown to protect against seizures in genetically epileptic mice. The present study, therefore, verified its potential antiepileptic effect in pentylenetetrazole (PTZ)-induced acute seizures and kindling in mice. Kindling was induced in male Swiss albino mice using a subconvulsive dose of PTZ (40 mg/kg, i.p., on alternate days) for 17 days, while acute epileptic animals received a single dose of PTZ (60 mg/kg, i.p.). Animals were pretreated with either pioglitazone (10 mg/kg, p.o.) or the standard antiepileptic drug valproate (50 mg/kg, p.o.). Kindled mice showed elevated cortical levels of TNF-alpha, IL-10, PGE(2), and caspase-3, while acute PTZ increased only the cytokines. However, inducible nitric oxide synthase (iNOS) was not expressed in the hippocampi of both acutely convulsed and kindled animals. In acute PTZ convulsion, as well as kindled mice, pioglitazone and valproate protected against PTZ-induced seizures and delayed seizure latency onset. Pioglitazone normalized all altered parameters except for PGE(2) in PTZ-kindled animals and, unpredictably, further elevated TNF-alpha in the acute model. Valproate showed also the same pattern but reinstated IL-10 partially in kindled mice. The present results revealed that both models increase pro- and anti-inflammatory cytokines, while only kindling elevates PGE(2) and caspase-3; nonetheless, neither model affects the expression of iNOS. The anticonvulsive effect of either pioglitazone or valproate is presumably associated with attenuating inflammation and preventing apoptosis.