NMDA- but not kainate-mediated events reduce efficacy of some antiepileptic drugs against generalized tonic-clonic seizures mice

Purpose: The aim of this study was to evaluate the efficacy of conventional antiepileptic drugs (AEDs) against the generalized tonic-clonic seizures i n mice subjected to the sub-convulsive 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/k g i.p., respectively [i.e., equal to 75% of their CD,, values (convulsive d ose in 16% of the animals studied)]. Subsequently the anticonvulsive potent ial 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 t hreshold. NMDA, but not kainate, diminished the antiepileptic activity of d iazepam (DZP) and carbamazepine (CBZ), increasing their 50% effective doses (ED(50)s) from 14.1 and 8.6 to 19.0 and 12.1 mg/kg i.p., respectively. Nei ther NMDA nor kainate affected the ED50 for valproate (VPA), phenobarbital (PB), or diphenylhydantoin (DPH) against electroconvulsions. NMDA-evoked ef fects were reversed with the use of the NMDA antagonist, D-(E)-2-amino-4-me thyl-5-phosphono-3-pentenoic acid (CGP 40116) and were not accompanied by t he alterations in the free plasma levels of AEDs. Conclusions: The NMDA-mediated events, but not kainate-related ones, seem t o be involved in the protective action of DZP and CBZ against maximal elect roshock-induced seizures. Moreover, it might be concluded that when subthre shold activation of NMDA receptors adds to other epileptogenic factors, DZP and CBZ are less efficacious. Presented data indicate that in such situati ons, adding the NMDA receptor antagonist (at very low doses) to the AED may yield beneficial therapeutic effects.