Effects of pioglitazone in the lithium-pilocarpine model of status epilepticus in rats

Introduction. A role of inflammation in the brain, both in human epilepsy and in animal epilepsy models, has been recently recognized. Agonists of the peroxisome proliferator-activated receptors gamma (PPAR-γ ) have been shown to be neuroprotective in models of various neurological diseases such as Parkinson’ s disease, Alzheimer’ s disease, multiple sclerosis, focal cerebral ischemia, mostly through their anti-inflammatory actions. The aim of our study was to investigate the effects of a synthetic PPAR-γ agonist pioglitazone on the 24 hrs-survival rate, as well as on the COX-2 and HSP70 protein expressions in brains of rats with lithium plus pilocarpine-induced status epilepticus (SE). Materials and Methods. SE was induced by administration of pilocarpine hydrochloride (30 mg/kg, i.p.) 20-24 hrs after LiCl (127 mg/kg, i.p) and 30 min after methylscopolamine nitrate (1 mg/kg, s.c.) in 80 to 90 days old male Wistar rats. The onset of SE was defined as uninterrupted generalized motor seizures lasting over 5 min or occurring with intervals lesser than 2 min. Rats were administered i.p. either pioglitazone (1 ; 3 mg/kg) or equivalent volume of the vehicle (DMSO), 10 min after the SE onset. SE was interrupted 2 hrs after its onset by an injection of diazepam (10 mg/kg, i.p.). Control animals received LiCl, saline instead of pilocarpine hydrochloride and methylscopolamine nitrate, DMSO and diazepam. Rats were sacrificed 24 hrs after the SE onset and Western blotting analyses were performed in different rat brain regions. Results. Pioglitazone treatment increased the rate of 24 hrs-survival in rats with lithium-pilocarpine induced SE, in a dose-dependent manner from 27% (vehicle treated rats) to 45.8% (pioglitazone 1 mg/kg) and 55% (pioglitazone 3 mg/kg). Western blotting analyses showed a strong induction of the COX-2 expression in animals with SE, as well as its attenuation in pioglitazone treated rats. Additionally, pioglitazone treatment led to an overexpression of the HSP70. Conclusion. The results of our study suggest a protective role of a single dose of pioglitazone in the lithium-pilocarpine model of SE in the rat. Namely, these data indicate that the inhibition of the post-SE COX-2 overexpression and an enhancement in the HSP70 expression may be involved in the protection mechanisms underlying the prominent increase of the 24 hrs-survival rate of rats in this epilepsy model.