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Pre- and Post-Ischemic Administration of Dizocilpine (MK-801) Reduces Cerebral Necrosis in the Rat

Published online by Cambridge University Press:  18 September 2015

M.R. Rod
Affiliation:
Departments of Pathology and Clinical Neurosciences, Neuroscience Research Group, Health Sciences Centre, University of Calgary, Calgary, Alberta, Canada T2N 4N1
R.N. Auer*
Affiliation:
Departments of Pathology and Clinical Neurosciences, Neuroscience Research Group, Health Sciences Centre, University of Calgary, Calgary, Alberta, Canada T2N 4N1
*
Neuropathology, Health Sciences Centre, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1
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Abstract:

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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,l l-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”.

Type
Original Articles
Copyright
Copyright © Canadian Neurological Sciences Federation 1989

References

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