NMDA RECEPTOR ACTIVATION DURING STATUS EPILEPTICUS IS REQUIRED FOR THE DEVELOPMENT OF EPILEPSY

NMDA receptor activation has been implicated in modulating seizure act ivity; however, its complete role in the development of epilepsy is un known. The pilocarpine model of limbic epilepsy involves inducing stat us epilepticus (SE) with the subsequent development of spontaneous rec urrent seizures (SRSs) and is widely accepted as a model of limbic epi lepsy in humans. The pilocarpine model of epilepsy provides a tool for looking at the molecular signals triggered by SE that are responsible for the development of epilepsy, In this study, we wanted to examine the role of NMDA receptor activation on the development of epilepsy us ing the pilocarpine model, Pretreatment with the NMDA receptor antagon ist MK-801 does not block the onset of SE in the pilocarpine model. Th us, we could compare animals that experience similar lengths of SE in the presence or absence of NMDA receptor activation. Animals treated w ith MK-801 (4 mg/kg) 20 min prior to pilocarpine (350 mg/kg) (MK-Pilo) were compared to the pilocarpine treated epileptic animals 3-8 weeks after the initial episode of SE. The pilocarpine-treated animals displ ayed both ictal activity and interictal spikes on EEG analysis, wherea s MK-801-pilocarpine and control animals only exhibited normal backgro und EEG patterns. In addition, MK-801-pilocarpine animals did not exhi bit any SRSs, while pilocarpine-treated animals exhibited 4.8 +/- 1 se izures per 40 h. MK-801-pilocarpine animals did not demonstrate any de crease in pyramidal cell number in the CA1 subfield of the hippocampus , while pilocarpine animals averaged 15% decrease in cell number. In s ummary, the MK-801-pilocarpine animals exhibited a number of character istics similar to control animals and were statistically significantly different from pilocarpine-treated animals. Thus, NMDA receptor inhib ition by MK-801 prevented the development of epilepsy and interictal a ctivity following SE. These results indicate that NMDA receptor activa tion is required for epileptogenesis following SE in this model of Lim bic epilepsy. (C) 1998 Elsevier Science B.V.