Pre- and post-ischemic administration of dizocilpine (MK-801) reduces cerebral necrosis in the rat.
The purpose of this study was to determine the effectiveness of the non-competitive N-methyl-D-aspartate receptor antagonist dizocilpine, or (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801) in mitigating ischemic neuronal necrosis in the rat. Ten minutes of transient forebrain ischemia was induced by a combination of bilateral carotid clamping and hypotension to 50 mm Hg. Control animals received intravenous saline, whereas treated animals received dizocilpine, either 1 mg/kg iv 20 min. pre ischemia, 1 mg/kg iv 20 min. post ischemia, 10 mg/kg iv 20 min. post ischemia, 10 mg/kg ip 2 hrs. post ischemia, 10 mg/kg ip 24 hrs. post ischemia. The groups receiving dizocilpine before or up to 20 min. after ischemia all showed a significant reduction in the number of dead neurons as assessed by quantitative histopathology in hippocampus, caudate nucleus and cerebral cortex after one week of recovery. However, dizocilpine administered either 2 or 24 hrs. after ischemia afforded no protection. These results suggest that the potent non-competitive NMDA antagonist dizocilpine may have some value in protecting the brain from hippocampal and cortical neuronal necrosis after a short insult consisting of dense transient cerebral ischemia. Noteworthy is the fact that pharmacologic intervention in the post-ischemic period was successful in preventing neuronal death, provided that drug administration occurred within dizocilpine's "therapeutic window".
Rod
M R
MR
Department of Pathology, University of Calgary, Alberta, Canada.
Auer
R N
RN
D000818:Animals; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000150:complications* / Q000473:pathology; D003986:Dibenzocycloheptenes / Q000627:therapeutic use*; D016291:Dizocilpine Maleate; D004341:Drug Evaluation; D008297:Male; D009336:Necrosis / Q000517:prevention & control*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D003986:Dibenzocycloheptenes; D016291:Dizocilpine Maleate