Abstracts

RATIONALE: Clinical manifestations, EEG findings, brain damage and mortality associated with convulsive status epilepticus (SE) suggest that it can be divided into two distinct phases, an early (initiation) phase and a late (self- sustaining) phase. Treatment studies indicate that current therapy is more effective in early phase but ineffective in the late phase. Experimental studies demonstrate that NMDA antagonists are effective during the late stages of status epilepticus, when GABA agonists begin to fail. However, these studies did not compare different classes of NMDA receptor antagonists. It is also not known whether NMDA receptor antagonists administered late during SE can offer neuroprotection.
METHODS: SE was induced in adult male rats by the continuous hippocampal stimulation for 90 minutes as described by Lothman. Animals in behavioral and electrographic SE were treated 60 min post-stimulation (150 minutes of SE) by intraperitoneal administration of increasing doses of NMDA receptor antagonists. Control group was saline treated. EEG recordings of all animals were monitored continuously for 5 hr post-injection. Data for the logarithm of drug doses and the percentage of animals seizure-free were fit to an equation for a sigmoidal curve with a variable slope; and the maximum and minimum responses were fixed to 100% and 0%, respectively. All animals were evaluated for the development of chronic epilepsy by video [ndash]EEG monitoring.
RESULTS: Control animals had continuous seizures during 300 minutes of observation and 80% developed epilepsy. MK-801 acts by a use dependent open channel block mechanism. MK-801 (2mg/kg) controlled SE in 75% animals, shortening mean post treatment seizure duration to 81 min. Smaller doses of MK -801were less effective and the ED50 was 1.5 mg/kg. Epilepsy developed in 10 of 19 (52%) MK-801-treated rats. Ifenprodil is a selective NR2B-containing NMDA receptor antagonist, which increases the sensitivity of NMDA receptors to inhibition by protons. The highest dose of Ifenprodil (30 mg/Kg) controlled SE in only 50% of the rats, reduced post treatment seizure duration to 180 min and lower doses were less effective. Epilepsy developed in 8 of 13 (63%) ifenprodil treated animals. CPP binds to the agonist-binding site on the NMDA receptor and competes with the neurotransmitter glutamate. CPP (15 mg/Kg) controlled SE in all animals tested, shortened SE duration to 109 min and its ED50 was 6.4 mg/Kg. Development of epilepsy in these animals is being studied.
CONCLUSIONS: The rank order of efficacy in controlling prolonged SE was CPP, MK 801 followed by Ifenprodil; that for shortening SE it was MK 801, CPP followed by Ifenprodil; and for preventing development of epilepsy it was MK 801 followed by ifenprodil. Both competitive and non-competitive NMDA antagonists can control prolonged self-sustaining SE. Ifenprodil was less effective.
[Supported by: NINDS grants NS 02081 and NS 40337]