Combined treatment with MK-801 and nicardipine reduces global ischemic damage in the gerbil.
OBJECTIVE
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.
Hewitt
K
K
Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
Corbett
D
D
D000818:Animals; D001831:Body Temperature; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000008:administration & dosage*; D004338:Drug Combinations; D005260:Female; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects; D009529:Nicardipine / Q000008:administration & dosage*; D012007:Rectum / Q000503:physiopathology; D012886:Skull / Q000503:physiopathology
D004338:Drug Combinations; D016291:Dizocilpine Maleate; D009529:Nicardipine