The competitive NMDA receptor antagonist CGP 40116 protects against status epilepticus-induced neuronal damage.
We studied the efficacy of the competitive NMDA receptor antagonist CGP 40116 in protecting against seizure-induced neuronal necrosis from lithium-pilocarpine-induced status epilepticus (SE). Rats were given CGP 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 to stop the seizures. Rats were killed 24 h later, and their brains were processed for light microscopic examination. Neuronal damage occurred in 24 of 25 brain regions examined in saline-injected animals. Protection was maximal in rats given 12 and 24 mg/kg CGP 40116 after SE onset: 19 and 21 of the 24 damaged regions were protected respectively, but the 24 mg/kg group had a mortality rate comparable to saline-injected 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 40116 seizure discharges were not eliminated, but their amplitudes were significantly reduced 2 h after SE began. The periodic epileptiform discharge (PED) EEG pattern, probably a sign of widespread neuronal damage, developed in saline-injected controls after 2-2.5 h of SE but not in rats given 12 and 24 mg/kg of CGP 40116. CGP 40116 provided widespread protection against seizure-induced neuronal necrosis, suggesting that an essential 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 general could be useful as adjunctive neuroprotectants in patients with refractory SE.
Fujikawa
D G
DG
Experimental Neurology Laboratory, Sepulveda VA Medical Center, CA 91343.
Daniels
A H
AH
Kim
J S
JS
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000473:pathology; D003975:Diazepam / Q000627:therapeutic use; D004569:Electroencephalography / Q000187:drug effects; D008094:Lithium; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D010634:Phenobarbital / Q000627:therapeutic use; D010862:Pilocarpine; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology*
D000927:Anticonvulsants; D016194:Receptors, N-Methyl-D-Aspartate; D010862:Pilocarpine; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D015763:2-Amino-5-phosphonovalerate; D008094:Lithium; D003975:Diazepam; D010634:Phenobarbital