Abstracts

RATIONALE: Levetiracetam (LEV) is a new antiepileptic drug (AED) with a unique preclinical profile. (Klitgaard et al., Eur. J. Pharmacol. 353:191-206, 1998). However, its precise mechanism(s) of action still remains to be established. This study combined in vitro and in vivo approaches in order to investigate if the antiepileptic mechanism(s) of action of LEV involve modulation of inhibitory neurotransmission. METHODS: GABA- and glycine-gated currents were studied in vitro using whole-cell patch-clamp techniques applied on cultured hippocampal/cerebellar granule and spinal neurons, respectively. Protection against clonic convulsions was assessed in vivo in sound susceptible mice (18-25 g; n=10). The effect of LEV was compared with the AEDs carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), clonazepam (CZP), phenobarbital (PB) and ethosuximide (ESM). RESULTS:_LEV was devoid (up to 300 M) of any direct effect on glycine-gated currents but induced minor and contrasting effects on GABA-gated currents. These consisted in a small reduction in the peak amplitude and a prolongation of the decay phase. None of the GABAergic drugs showed any of these effects but a similar action was observed with the Na+ blockers CBZ (10 M) and PHT (50 M). These minor effects contrasted a potent ability of LEV (EC50 = 1-10 M) to reverse the inhibitory effects of several negative allosteric modulators of GABA- and glycine-gated currents including beta-carbolines, zinc and Ro 5-4864. Only VPA (1 mM) and CZP (1 M) showed a similar antagonism towards beta-carbolines and zinc, respectively. Likewise, co-administration of beta-carbolines, Ro 5-4864, but not flumazenil, abolished the seizure protection afforded by LEV (17 mg/kg, i.p.). CONCLUSIONS: The results of the present study suggest that a novel ability to oppose the action of negative modulators on the two main inhibitory ionotropic receptors may be of relevance for the antiepileptic mechanism(s) of action of LEV.