TY - JOUR
T1 - MK-801 (dizocilpine) protects the brain from repeated normothermic global ischemic insults in the rat
AU - Lin, B.
AU - Dietrich, W. D.
AU - Ginsberg, M. D.
AU - Globus, M. Y.T.
AU - Busto, R.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 1993
Y1 - 1993
N2 - We investigated the neuroprotective potential of MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, in the setting of three 5-min periods of global cerebral ischemia separated by 1-h intervals in halothane-anesthetized rats. Each ischemic insult was produced by bilateral carotid artery occlusions plus hypotension (50 mm Hg). Brain temperature was maintained at normothermic levels (36.5-37.0°C) throughout the experiment. MK-801 (3 mg/kg) (n = 6) or saline (n = 6) was injected intraperitoneally 45 min following the end of the first ischemic insult. Following 7-day survival, quantitative neuronal counts of perfusion-fixed brains revealed severe ischemic damage in hippocampal CA1 area, neocortex, ventrolateral thalamus, and striatum of untreated rats. By contrast, significant protection was observed in MK-801-treated rats. In area CA1 of the hippocampus, numbers of normal neurons were increased 11- to 14-fold by MK-801 treatment (p < 0.01). The ventrolateral thalamus of MK-801-treated rats showed almost complete histologic protection, and neocortical damage was reduced by 71% (p < 0.01). The degree of MK-801 protection of striatal neurons was less complete than that seen in other vulnerable structures, amounting to 63% for central striatum (p = 0.02, Mann-Whitney U test) and 48% in the dorsolateral striatum (NS). A repeated-measures analysis of variance demonstrated a highly significant overall protective effect of MK-801 treatment (F1.10 = 37.2, p = 0.0001). These findings indicate that excitotoxic mechanisms play a major role in neuronal damage produced by repeated ischemic insults and that striking cerebroprotection is conferred by MK-801 administered following the first insult in animals with cerebral normothermia. NMDA antagonists may prove useful in patients at risk of repeated episodes of cerebral ischemia.
AB - We investigated the neuroprotective potential of MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, in the setting of three 5-min periods of global cerebral ischemia separated by 1-h intervals in halothane-anesthetized rats. Each ischemic insult was produced by bilateral carotid artery occlusions plus hypotension (50 mm Hg). Brain temperature was maintained at normothermic levels (36.5-37.0°C) throughout the experiment. MK-801 (3 mg/kg) (n = 6) or saline (n = 6) was injected intraperitoneally 45 min following the end of the first ischemic insult. Following 7-day survival, quantitative neuronal counts of perfusion-fixed brains revealed severe ischemic damage in hippocampal CA1 area, neocortex, ventrolateral thalamus, and striatum of untreated rats. By contrast, significant protection was observed in MK-801-treated rats. In area CA1 of the hippocampus, numbers of normal neurons were increased 11- to 14-fold by MK-801 treatment (p < 0.01). The ventrolateral thalamus of MK-801-treated rats showed almost complete histologic protection, and neocortical damage was reduced by 71% (p < 0.01). The degree of MK-801 protection of striatal neurons was less complete than that seen in other vulnerable structures, amounting to 63% for central striatum (p = 0.02, Mann-Whitney U test) and 48% in the dorsolateral striatum (NS). A repeated-measures analysis of variance demonstrated a highly significant overall protective effect of MK-801 treatment (F1.10 = 37.2, p = 0.0001). These findings indicate that excitotoxic mechanisms play a major role in neuronal damage produced by repeated ischemic insults and that striking cerebroprotection is conferred by MK-801 administered following the first insult in animals with cerebral normothermia. NMDA antagonists may prove useful in patients at risk of repeated episodes of cerebral ischemia.
KW - Excitotoxicity
KW - Multiple insults
KW - N-methyl-D-aspartate antagonist
KW - Selective vulnerability
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U2 - 10.1038/jcbfm.1993.115
DO - 10.1038/jcbfm.1993.115
M3 - Article
C2 - 8408318
AN - SCOPUS:0027383441
VL - 13
SP - 925
EP - 932
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
SN - 0271-678X
IS - 6
ER -