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

Abstract

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 mgkg i.p., respectively [i.e., equal to 75% of their CD,, 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 (ED,,s) from 14.1 and 8.6 to 19.0 and 12.1 mg/kg i.p., respectively. Neither NMDA nor kainate affected the ED,, for valproate (VPA), phenobarbital (PB), or diphenylhydantoin (DPH) against electroconvulsions. NMDA-evoked effects were reversed with the use of the NMDA antagonist, o-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 401 16) and were not accompanied by the alterations in the free plasma levels of AEDs.Conclusions: The NMDA-mediated events, but not kainaterelated 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 . Key Words : NMD A-Kain a te-S ei z u re sAnticonvulsant-Mice.The activation of excitatory amino acid (EAA) receptors constitutes the principal route for the fast synaptic transmission in the brain; however, under pathologic conditions, it also may lead to the initiation and propagation of seizures and seizure-related neuronal loss (see for review 1,2). In animals, the agonists of ionotropic receptors of N-methyl-D-aspartate (NMDA) or kainate type applied either systemically or intracerebrally may precipitate the seizure activity (3-5). The NMDA and non-NMDA antagonists were demonstrated to display potent anticonvulsant properties in varying seizure mod-

Intravenous levetiracetam in the rat pilocarpine-induced status epilepticus model: Behavioral, physiological and histological studies

“…Because no new intravenous treatments have been developed and licensed for the treatment of SE, in spite of the fact that existing treatments frequently fail, it is important to discover new drugs with utility in the initial (pre-anesthetic) treatment of status epilepticus. Whereas traditional AEDs target Na + channels, T-type Ca ++ channels, GABA receptors or glutamate receptors [5–7], it is likely that efficacious alternative agents will aim at new molecular targets to achieve specific therapeutic effects.…”