The convulsive effect of PPARα antagonist, GW6471, in kindling model of temporal lobe epilepsy in rats and on DHA anticonvulsant effect in pentylenetetrazole model of mice

Peroxisomal proliferator-activated receptors (PPARs) are nuclear receptor which show well-established interactions in a set of physiological effects. The neuroprotective effects of PPARs agonists in CNS diseases like seizure are shown. Moreover, PPARs antagonist can prevent the anticonvulsive effect of PPARs agonists. However, there is no report on the convulsive effect of PPARs antagonist. So in this study, we evaluated the effect of PPARα antagonist, GW6471, in kindling model of temporal lobe epilepsy and pentylentetrazole model of mice as human abscence seizure.Wistar rats were sterotaxically implanted with electrodes in basolateral amygdala and an injection guide cannula in the lateral ventricle. After recovery period, rats were subjected to rapid amygdala kindling. After Afterdischarge (AD) threshold determination, each animal was stimulated once daily at AD threshold. Rats were stimulated until they exhibited 3 consecutive generalized seizures. The study was conducted in two groups. Full-kindled rats received vehicle (DMSO, 2µl) on the first day, and on the second day animals in Group1 and 2received 2µg/2µl and 1µg/2µl of GW6471, respectively. All injections were performed via i.c.v. (intracerebroventricular) 30 min before electrical stimulation. Mice recieved PTZ(60mg/kg i.p.) and GW6471 (1mg/kg i.c.v. 4hours).Then, seizure parameters including the occurrence of stage 5 seizure behavior, duration of stage 5 (S5D), duration of AD (ADD), and Seizure Behavior Duration (SD) were recorded. i.c.v. injection of GW6471 at the lower dose, 1µg/2µl, could not significantly change the seizure parameters. But GW6471 at the higher dose, 2µg/2µl, could reduce the seizure threshold and significantly increased ADD vs. vehicle injection. Morever, Compared with DHA group, GW6471 could completely reverse DHA anticonvulsant effect GW6471 as PPARα antagonist has dose-dependent convulsive effects. These results could offer the insights into finding the temporal lobe epiepsy and abscence seizure mechanism. Furthermore, PPARα could be suggested as a novel seizure target for the treatment of temporal lobe epilepsy and abscence seizure.

کلیدواژه ها:

seizure ، kindling ، PTZ ، PPARα ، GW6471