NMDA receptor antagonists and limbic status epilepticus: a comparison with standard anticonvulsants

Abstract

Status epilepticus (SE) evolves through several stages when untreated. The later stages of SE are less responsive to standard anticonvulsants and may require general anesthesia to suppress seizures. Antagonists acting at the N-methyl-D-aspartate (NMDA) subclass of glutamate (excitatory) receptors have been demonstrated to exert antiepileptic activity in some seizure models. We report experiments performed to determine if NMDA receptor antagonists are effective in stopping seizures in the late stages of SE. A model of limbic SE induced by 90 min of 'continuous' electrical stimulation of the hippocampus in rats was employed. Three NMDA receptor antagonists, one 'competitive' (CPP) and two 'non-competitive' (ketamine and MK-801), were compared to 3 standard antiepileptic drugs (diazepam, phenobarbital, and phenytoin) for their ability to suppress seizures at a physiologically defined stage of SE. All NMDA receptor antagonists, diazepam and phenobarbital were effective in suppressing behavioral and electrographic seizures for varying periods of time. Phenytoin had no effect on SE. Ketamine and MK-801 induced a paradoxical enhancement of electrographic seizures that preceded SE suppression. We believe that NMDA-receptor antagonists offer a novel approach for treating the late stages of SE.