MK-801 (dizocilpine) protects the brain from repeated normothermic global ischemic insults in the rat.
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 degrees 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).(ABSTRACT TRUNCATED AT 250 WORDS)
Lin
B
B
Department of Neurology, University of Miami School of Medicine, FL 33101.
Dietrich
W D
WD
Ginsberg
M D
MD
Globus
M Y
MY
Busto
R
R
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001927:Brain Diseases / Q000209:etiology / Q000517:prevention & control*; D002339:Carotid Arteries; D002540:Cerebral Cortex / Q000473:pathology; D003250:Constriction; D003342:Corpus Striatum / Q000473:pathology; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D006624:Hippocampus / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013788:Thalamus / Q000473:pathology; D013997:Time Factors
D001786:Blood Glucose; D016291:Dizocilpine Maleate