Abstracts

Rationale: Mesiotemporal lobe epilepsy (MTLE) is one of the most difficult form of epilepsy to treat as patients are often resistant to antiepileptic drugs (AEDs) and, when possible, surgical resection appears as the only effective therapy. This resistance is far from being understood and identification of new active compounds requires the development of new animal models. Methods: Recently, both morphological and electroclinical features of MTLE were shown to be mimicked following a unilateral injection of kainic acid (KA) in the dorsal hippocampus of adult mice. Here epileptogenesis and appearance of spontaneous focal hippocampal paroxysmal discharges (HPD) were explored by EEG with telemetry. Our initial data suggested that established HPD were not suppressed by classical AEDs. Here we examine the effects of new AEDs, at several doses, on the spontaneous occurrence of HPD by EEG.Results: EEG telemetric recording showed a progressive appearance of HPD with stabilization 3 weeks post-status and expression of 40 HPD/h. Injection of classic AEDs (valproate, carbamazepine and lamotrigine) fails to suppress HPD in a dose-dependent way. Indeed only high doses are effective (400, 100 and 90mg/kg respectively) and are associated with modifications of the general behavior and/or EEG basal activity. A dose-dependent suppression of HPD was however observed with new AEDs: levetiracetam (100, 400, 800, 1000 mg/kg), vigabatrin (10, 50, 100, 200mg/kg), pregabalin (10, 50, 100 mg/kg) and also with diazepam (0,5, 1, 2, 3 mg/kg) without obvious behavioural or EEG side-effects. When diazepam or levetiracetam were administered daily (4 and 1600 mg/kg/day, respectively), their suppressive effects on HPD progressively vanished within 5 days. A significant aggravation of HPD was observed on the first day of a wash-out period.Conclusions: Together these data suggest this mouse model of MTLE provides a new valuable tool to study the potential effects of new AEDs and development of tolerance directly by assessing their effect on the expression of focal hippocampal discharges.