REGIONAL NEUROPROTECTIVE EFFECTS OF THE NMDA RECEPTOR ANTAGONIST MK-801 (DIZOCILPINE) IN HYPOGLYCEMIC BRAIN-DAMAGE

Current evidence points to an important role of N-methyl-D-aspartate (NMDA) receptor activation in the pathogenesis of hypoglycemic neuronal death. MK-801 {dizocilpine maleate, (+)-5-methyl-10,11-dihydro-5H-di[a,d]cyclohepten-5, 10-imine} is an anticonvulsant compound also known to be a potent noncompetitive antagonist at NMDA receptors, readily crossing the bloodbrain barrier after parental administration. Treatment of rats with dizocilpine (1.5-5.0 mg/kg) injected intravenously during profound hypoglycemia (blood glucose levels 1.5-2.0 mM) at the stage of δ-wave (1-4 Hz) slowing of the EEG mitigated selective neuronal necrosis in the hippocampus and striatum, assessed histologically after 1-week survival. The degree of neuroprotection in the striatum and in the CA1 pyramidal cells of the hippocampus was dose dependent. Because of concern for a possible hypothermic mechanism of brain protection by MK-801, core temperature was closely monitores and was found not to decrease significantly. Since CBF is normal or increased in hypoglycemia, a fall in brain temperature during hypoglycemia is unlikely to play a role in the mechanism of the neuroprotection seen with the drug. The findings indicate that in profound hypoglycemia, intravenous administration of the NMDA antagonist dizocilpine, even after the appearance of δ-wave EEG slowing, can reduce the number of necrotic neurons in several brain regions and suggest that the neuroprotective effect of MK-801 is not related to hypothermia.