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Combined therapy with MK-801 and nimodipine for protection of ischemic brain damage

Cerebrovascular Research Center (Drs. Uematsu, Araki, Greenberg, and Reivich), Department of Neurology (Dr. Sladky), University of Pennsylvania, Philadelphia, PA.

Calcium ion can enter ischemic neurons through both receptor-operated and voltage-sensitive Ca²⁺channels. To attenuate this Ca²⁺ entry and Ca²⁺-induced neuronal injury, we tried a combined treatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, MK-801, and the dihydropyridine calcium antagonist, nimodipine, in a cat middle cerebral artery occlusion (1 hour) and reperfusion (3 hours) model. We measured changes in cytosolic free calcium, nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide redox state, and blood flow in the cat cortex using a newly developed fluorometric technique with indo-1, a fluorescent intracellular Ca²⁺ indicator. The combined treatment, starting 5 minutes into ischemia, was effective in reducing both Ca²⁺ entry and histologic damage and in enhancing recovery of the electroencephalogram following reperfusion. MK-801 alone was also effective, but to a lesser extent. These data suggest that the dual blockade of Ca²⁺ entry using MK-801 and nimodipine may be a useful tool for protection against ischemic brain damage.

Address correspondence and reprint requests to Dr. Joel H. Greenberg, Cerebrovascular Research Center, Room 429, Johnson Pavilion, 36th & Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104.

Supported by a grant from the National Institutes of Health, NS 10939-17 and a grant from the Pew Memorial Trust.

Received March 7,1990. Accepted for publication in final form June 1,1990.

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