Abstracts

The syndrome of mesial temporal lobe epilepsy (MTLE) represents a major challenge in the clinical management of focal seizures mainly due to drug refractoriness. Both morphological and electroclinical features of MTLE can be mimicked in the adult mice by a unilateral injection of kainic acid (KA) in the dorsal hippocampus. Neuronal loss in CA1, CA3 and hilus as well as gliosis and mossy fiber sprouting are observed in the injected side, as well as dispersion of the dentate gyrus, as observed in MTLE patients. In addition, recurrent focal hippocampal discharges occur two weeks after KA which share many similarities with human focal discharges. Whether these discharges are suppressed by antiepileptic drugs (AEDs) was addressed in this study where the effects of different classical AEDS were compared to a new AED: pregabalin., C57BL/6 adult mice were stereotaxically injected with KA (1 nmol in 50 nl) in the dorsal hippocampus and equipped with cortical and hippocampal electrodes. After 3 weeks, mice were injected with different doses of AEDs or vehicle in a random order and EEG recordings were performed for 20 min pre-injection and up to 120 min post-injection. Diazepam (0.5, 1, 2, 3 mg/kg) (n=6), valproate (100, 200, 400 mg/kg) (n=6), lamotrigine (30, 60, 90 mg/kg) (n=7), carbamazepine (25, 50 mg/kg) (n=12) and pregabalin (n=8) (10, 50, 100 mg/kg) were injected i.p. Only animals with cell loss and dentate gyrus dispersion were used in the analysis. Cumulated durations of hippocampal discharges during 20 min periods were compared between the different drug conditions and versus vehicle using ANOVA for repeated measures., Hippocampal discharges were suppressed in a dose-dependent way following diazepam (1, 2 and 3 mg/kg). Suppression of seizures was also observed with high doses of valproate (400 mg/kg) and lamotrigine (90 mg/kg) without dose-dependency and with occasional behavioral side-effects. No suppression was obtained following carbamazepine (25 and 50 mg/kg) and aggravation was observed after a low dose of lamotrigine (30 mg/kg). Pregabalin significantly suppressed hippocampal discharges in a dose-dependent way (50 and 100 mg/kg)., Our study shows that besides benzodiazepines, only pregabalin suppresses focal discharges in a dose-dependent way in the kainate-mouse model of MTLE. On the contrary, classical AEDs were effective only at high doses (valproate, lamotrigine) or were without effects (carbamazepine). In addition to the histological, electrophysiological and behavioral features of this model, the resistance to classical AEDs suggest a form of drug-refractoriness often observed in human MTLE. Therefore this model fulfils most criteria for an efficient preclinical development of antiepileptic therapeutical strategies for MTLE. The suppressive effects of pregabalin suggest that this compound could be effective on human MTLE., (Supported by Pfizer France, Inserm and Ligue Fran[ccedil]aise Contre l[apos]Epilepsie.)