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 blood-brain barrier after parenteral 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 delta-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 monitored 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 delta-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.