MK801 decreases glutamate release and oxidative metabolism during hypoglycemic coma in piglets

Hypoglycemic coma increases extracellular excitatory amino acids, which med iate hypoglycemic neuronal degeneration. Cerebral oxygen consumption increa ses during hypoglycemic coma in piglets, We tested the hypothesis that the NMDA-receptor antagonist dizocilpine (MK801) attenuates the increase in cer ebral oxygen consumption during hypoglycemia. We measured EEG, cerebral blo od flow (CBF), cerebral oxygen consumption (CMRO2) and cortical microdialys ate levels of glutamate, aspartate and glycine in pentobarbital-anesthetize d piglets during 60 min of insulin-induced hypoglycemic coma. NMDA-receptor distribution was measured by autoradiography. MK801 (0.75 mg/kg i.v.) was given within 5 min after onset of isoelectric EEG. Saline- and MK801-treate d normoglycemic control animals were also studied. Brain temperature was ma intained at 38.5 +/- 0.5 degreesC. MK801 prevented the 5-10-fold increase i n glutamate and aspartate occurring in saline-treated hypoglycemic animals, and attenuated the increase in CMRO2. Increases in CBF of 200-400% during hypoglycemic coma were not affected by MK801. MK801 did not alter CBF, CMRO 2 or microdialysate amino acid levels in normoglycemic control animals. Par ietal cortex corresponding to microdialysis sites was highly enriched in NM DA receptors, and the density and distribution overall of NMDA receptor bin ding sites were comparable to that reported in other species. We conclude t hat NMDA receptor activation plays a central role in hypoglycemia-induced g lutamate release, and contributes to increased cerebral oxygen consumption. Neuroprotective effects of MK801 during hypoglycemia in piglets may involv e inhibitory effects on glutamate release and oxidative metabolism. (C) 200 1 Elsevier Science BY All rights reserved.