Combined therapy with MK-801 and nimodipine for protection of ischemic brain damage.
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.
Uematsu
D
D
Cerebrovascular Research Center, University of Pennsylvania, Philadelphia 19104.
Araki
N
N
Greenberg
J H
JH
Sladky
J
J
Reivich
M
M
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002415:Cats; D002560:Cerebrovascular Circulation; D003600:Cytosol / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004569:Electroencephalography; D008297:Male; D009243:NAD / Q000378:metabolism; D009553:Nimodipine / Q000627:therapeutic use*; D010084:Oxidation-Reduction; D015424:Reperfusion
D009243:NAD; D009553:Nimodipine; D016291:Dizocilpine Maleate; D002118:Calcium