Abstracts

Rationale: Mesiotemporal lobe epilepsy (MTLE) is the most common and difficult form of epilepsy to treat as patients are often resistant to antiepileptic drugs (AEDs). This resistance is far from being understood and identification of new active compounds requires the development of new MTLE animal models. 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. In addition we suggested that spontaneous hippocampal paroxysmal discharges (HPD) were not suppressed by AEDs classically used in clinical practice.Methods: Here we further explored this hypothesis by testing the effects of seven AEDs with different mechanisms of action, at several doses, with acute or chronic administration protocols on the spontaneous occurrence of HPD by deep EEG recordings in this MTLE mouse model.Results: Injection of conventional 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 4 days.Conclusions: Together these data show that this chronic mouse model of MTLE displays immediate or acquired resistance to several AEDs and provides a critical tool to find new treatments with persistent effects.