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Stroke, Vol 23, 82-86, Copyright © 1992 by American Heart Association

ARTICLES

Combined treatment with MK-801 and nicardipine reduces global ischemic damage in the gerbil

K Hewitt and D Corbett
Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.

BACKGROUND AND PURPOSE: Excessive activation of the N-methyl-D- aspartate receptor by glutamate produces an influx of Ca2+, which in turn is thought to lead to ischemic cell death. In this study we evaluated the combined treatment of the N-methyl-D-aspartate antagonist dizocilpine (MK-801) and the dihydropyridine Ca2+ channel blocker nicardipine for the reduction of hippocampal CA1 neuronal loss. METHODS: Global ischemia was induced by bilateral carotid artery occlusion in the gerbil. Body temperature was maintained between 36.5 degrees C and 37.5 degrees C during surgery. MK-801 (5.0 mg/kg) was injected 15 minutes after occlusion whereas nicardipine was given by injection and via a micro-osmotic pump (1.0 mg/kg/day) for 3 days. RESULTS: Postischemic treatment with MK-801 reduced CA1 cell loss by 27.0%, whereas nicardipine reduced CA1 cell loss by 13.3%. Combined postischemic treatment with these drugs yielded an additive, protective effect (44.5% reduction of CA1 loss) that did not appear to result from postischemic hypothermia as assessed by skull and rectal temperature recordings. CONCLUSIONS: Our results demonstrate that MK-801 plus nicardipine significantly attenuates CA1 cell death after forebrain ischemia in the gerbil. Excitatory amino acid antagonists in combination with Ca2+ channel antagonists may be an effective therapy in patients exposed to global ischemic insult.

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