MK-801 (dizocilpine) protects the brain from repeated normothermic global ischemic insults in the rat

B. Lin, W. D. Dietrich, M. D. Ginsberg, M. Y.T. Globus, R. Busto

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)925-932
Number of pages8
JournalJournal of Cerebral Blood Flow and Metabolism
Volume13
Issue number6
DOIs
StatePublished - Jan 1 1993

Keywords

  • Excitotoxicity
  • Multiple insults
  • N-methyl-D-aspartate antagonist
  • Selective vulnerability

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Neuroscience(all)

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