Abstracts

RATIONALE: Levetiracetam (LEV) is a new antiepileptic drug with a unique pharmacological profile. LEV is devoid of anticonvulsant activity in the two classical screening tests, the maximal electroshock and the pentylenetetrazol test. This is in contrast to potent seizure suppression, a wide safety margin and antiepileptogenic properties in kindling models of epilepsy (Klitgaard et al., Eur. J. Pharmacol. 353:191-206, 1998). A specific binding site in rat brain has been described for LEV (Noyer et al., Eur. J. Pharmacol. 286:137-146, 1995) but 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 mechanisms of action of LEV involve modulation of glutamatergic excitatory neurotransmission. METHODS: NMDA-, kainic acid- and AMPA-gated currents were studied in vitro using whole-cell patch-clamp techniques applied on cultured hippocampal neurons. Protection against clonic convulsions induced by microinfusion into the lateral ventricle of either NMDA (1 nmol/min), kainic acid (3 nmol/min) or AMPA (3 nmol/min) was assessed in NMRI mice (22-28 g, n=10-20). RESULTS:_LEV (up to 1 mM) was devoid of any effect on the amplitude and the decay time constant of NMDA-gated currents. Likewise, LEV (up to 1 mM) did not modify the peak and plateau phases of kainate induced currents. However, concentrations beyond therapeutic relevance (IC50 = 268 M) did inhibit the peak amplitude of AMPA-gated currents. Seizure testing showed that LEV (up to 540 mg/kg, i.p.) did not suppress clonic convulsions induced by either NMDA, kainic acid or AMPA sufficiently to generate a protective ED50 value. CONCLUSIONS: The results of the present study demonstrate that the mechanisms of the antiepileptic action of LEV are unlikely to derive from a modulation of ionotropic excitatory glutamate receptors.