Pre- and post-ischemic administration of dizocilpine (MK-801) reduces cerebral necrosis in the rat.

Abstract

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".

• Authors: M R Rod, R N Auer
• Journal: The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques (Can J Neurol Sci) Vol. 16 Issue 3 Pg. 340-4 (Aug 1989) ISSN: 0317-1671 [Print] England
• PMID: 2670155 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dibenzocycloheptenes
• Dizocilpine Maleate

Topics

• Animals
• Brain (pathology)
• Brain Ischemia (complications, pathology)
• Dibenzocycloheptenes (therapeutic use)
• Dizocilpine Maleate
• Drug Evaluation
• Male
• Necrosis (prevention & control)
• Rats
• Rats, Inbred Strains
• Time Factors