Regional Neuroprotective Effects of the NMDA Receptor Antagonist MK-801 (Dizocilpine) in Hypoglycemic Brain Damage

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Abstract
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-5 H-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 m M) 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 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 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.