THE COMPETITIVE NMDA RECEPTOR ANTAGONIST CGP-40116 PROTECTS AGAINST STATUS EPILEPTICUS-INDUCED NEURONAL DAMAGE

We studied the efficacy of the competitive NMDA receptor antagonist CG P 40116 in protecting against seizure-induced neuronal necrosis from l ithium-pilocarpine-induced status epilepticus (SE). Rats were given CG P 40116 either before SE (12 mg/kg i.p.) or 15 min after the onset of SE (4, 12 and 24 mg/kg); controls received normal saline 15 min after SE began. Diazepam and phenobarbital were given i.p. after 3 h of SE t o stop the seizures. Rats were killed 24 h later, and their brains wer e processed for light microscopic examination. Neuronal damage occurre d in 24 of 25 brain regions examined in saline-injected animals. Prote ction was maximal in rats given 12 and 24 mg/kg CGP 40116 after SE ons et: 19 and 21 of the 24 damaged regions were protected respectively, b ut the 24 mg/kg group had a mortality rate comparable to saline-inject ed controls. No necrotic neurons were found in posterior cingulate and retrosplenial neurons at the two highest CGP 40116 doses, suggesting that the transient cytoplasmic vacuolization induced by NMDA receptor antagonists does not progress to frank necrosis. In rats given CGP 401 16 seizure discharges were not eliminated, but their amplitudes were s ignificantly reduced 2 h after SE began. The periodic epileptiform dis charge (PED) EEG pattern, probably a sign of widespread neuronal damag e, developed in saline-injected controls after 2-2.5 h of SE but not i n rats given 12 and 24 mg/kg of CGP 40116. CGP 40116 provided widespre ad protection against seizure-induced neuronal necrosis, suggesting th at an esssential step in its production is NMDA receptor activation by endogenous glutamate. The neuroprotection provided was not simply an antiepileptic effect, since electrographic seizures persisted despite NMDA receptor blockade. CGP 40116 and NMDA receptor antagonists in gen eral could be useful as adjunctive neuroprotectants in patients with r efractory SE.