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 setti ng of three 5-min periods of global cerebral ischemia separated by 1-h intervals in halothane-anesthetized rats. Each ischemic insult was pr oduced 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 sa line (n = 6) was injected intraperitoneally 45 min following the end o f the first ischemic insult. Following 7-day survival, quantitative ne uronal counts of perfusion-fixed brains revealed severe ischemic damag e in hippocampal CA1 area, neocortex, ventrolateral thalamus, and stri atum of untreated rats. By contrast, significant protection was observ ed 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 w as less complete than that seen in other vulnerable structures, amount ing to 63% for central striatum (p = 0.02, Mann-Whitney U test) and 48 % in the dorsolateral striatum (NS). A repeated-measures analysis of v ariance 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 produ ced by repeated ischemic insults and that striking cerebroprotection i s conferred by MK-801 administered following the first insult in anima ls with cerebral normothermia. NMDA antagonists may prove useful in pa tients at risk of repeated episodes of cerebral ischemia.