The effect of MK-801 on kindled seizures: implications for use and limitations as an antiepileptic drug.

MK-801 is a new drug that produces a noncompetitive blockade at the subclass of glutamate receptors activated by N-methyl-D-asparate (NMDA). The antiepileptic properties of MK-801 were studied using kindled seizures as a model of complex partial seizures with secondary generalization. A test protocol was employed that allowed: (1) examination of the efficacy of MK-801 against several parameters that gauge different aspects of epileptogenesis; (2) determination of the time-action profile of these effects; and (3) examination of the toxicity of MK-801 in animals experiencing seizures. The drug was found to be potent against the spread of seizures but less effective against parameters linked to partial seizures. At the higher doses of the drug required to truncate hippocampal afterdischarges, considerable neurotoxicity was encountered. In addition, the antiepileptic effects of MK-801 showed a use dependence so that, at a given time after the drug was administered, a greater suppression of seizures was noted if there had been preceding seizures in the presence of the drug than if there had not been. These findings indicate that there may be limitations to the clinical utility of MK-801 as an antiepileptic agent and that the drug may provide greatest benefit when used for the suppression of seizure generalization and when seizures are closely spaced.