NMDA- But Not Kainate-Mediated Events Reduce Efficacy of Some Antiepileptic Drugs Against Generalized Tonic-Clonic Seizures in Mice

Summary: Purpose: The aim of this study was to evaluate the efficacy of conventional antiepileptic drugs (AEDs) against the generalized tonic-clonic seizures in mice subjected to the subconvulsive doses of N-methyl-D-aspartate (NMDA) or kainate.

Methods: Mice were given NMDA and kainate in the doses of 50.0 and 9.0 mg/kg i.p., respectively [i.e., equal to 75% of their CD₁₆ values (convulsive dose in 16% of the animals studied)]. Subsequently the anticonvulsive potential of conventional AEDs against the maximal electroshock-induced seizures was estimated. Where necessary, the plasma levels of AEDs were assessed.

Results: NMDA or kainate application did not affect the electroconvulsive threshold. NMDA, but not kainate, diminished the antiepileptic activity of diazepam (DZP) and carbamazepine (CBZ), increasing their 50% effective doses (ED₅₀S) from 14.1 and 8.6 to 19.0 and 12.1 mg/kg i.p., respectively. Neither NMDA nor kainate affected the ED₅₀ for valproate (VPA), phenobarbital (PB), or diphenylhydantoin (DPH) against electroconvulsions. NMDA-evoked effects were reversed with the use of the NMDA antagonist, D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116) and were not accompanied by the alterations in the free plasma levels of AEDs.

Conclusions: The NMDA-mediated events, but not kainate-related ones, seem to be involved in the protective action of DZP and CBZ against maximal electroshock-induced seizures. Moreover, it might be concluded that when subthreshold activation of NMDA receptors adds to other epileptogenic factors, DZP and CBZ are less efficacious. Presented data indicate that in such situations, adding the NMDA receptor antagonist (at very low doses) to the AED may yield beneficial therapeutic effects.