Neuroprotective effect of ketamine administered after status epilepticus onset.
We investigated the neuroprotective effect of the noncompetitive N-methyl-D-asparatate (NMDA) antagonist ketamine when administered after onset of lithium-pilocarpine-induced status epilepticus (SE). Seizures were induced in Wistar rats with lithium chloride (3 mEq/kg) and pilocarpine (PC) (30-60 mg/kg intraperitoneally, i.p.). Fifteen minutes after SE onset, either ketamine 100 mg/kg or normal saline was injected i.p., and 3 h after SE onset atropine, diazepam (DZP), and phenobarbital (PB) were administered i.p. to terminate the seizures. Twenty-four hours later, rats underwent brain perfusion-fixation, with subsequent brain processing for light-microscopic examination. Rats adminstered saline (n = 5) had neuronal damage in 24 of 25 brain regions examined. Rats administered ketamine (n = 7) had significant neuroprotection in 22 of 24 damaged regions. Ketamine reduced the amplitude of seizure discharges, and in 3 rats EEG seizure activity ceased in 30 min; none of these rats had neuronal damage. In the other 4 rats, EEG seizure discharges persisted > 90 min; in these animals, 21 of 24 damaged regions were protected. In contrast, rats with 1-h high-dose PC-induced SE (400 mg/kg i.p. without lithium chloride preadministration) had 14 damaged regions, of which 7 were significantly different from the undamaged regions of the ketamine subgroup with persistent electrographic seizures. Thus, ketamine is remarkably neuroprotective when administered after onset of SE, whether or not seizure discharges are eliminated.
Fujikawa
D G
DG
Experimental Neurology Laboratory, Sepulveda VA Medical Center, CA 91343.
D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects; D004569:Electroencephalography / Q000187:drug effects; D005625:Frontal Lobe / Q000187:drug effects / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D018021:Lithium Chloride / Q000008:administration & dosage; D008297:Male; D010862:Pilocarpine / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology*
D016194:Receptors, N-Methyl-D-Aspartate; D010862:Pilocarpine; D007649:Ketamine; D018021:Lithium Chloride