Protective effect of MgSO 4 infusion on NMDA receptor binding characteristics during cerebral cortical hypoxia in the newborn piglet

Abstract

This study tests the hypothesis that magnesium, a selective non-competitive antagonist of the NMDA receptor, will attenuate hypoxia-induced alteration in NMDA receptors and preserve MK-801 binding characteristics during cerebral hypoxia in vivo. Anesthetized, ventilated and instrumented newborn piglets were divided into three groups: normoxic controls were compared to untreated hypoxic and Mg 2+-treated hypoxic piglets. Cerebral hypoxia was induced by lowering the FiO 2 to 5–7% and confirmed biochemically by a decrease in the levels of phosphocreatine (82% lower than control). The Mg 2+-treated group received MgSO 4 600 mg/kg over 30 min followed by 300 mg/kg administered during 60 min of hypoxia. Plasma Mg 2+ concentrations increased from1.6 ± 0.1mg/dl to17.7 ± 3.3mg/dl. 3H-MK-801 binding was used as an index of NMDA receptor modification. The B max in control, hypoxic and Mg 2+-treated hypoxic piglets was1.09 ± 0.17, 0.70 ± 0.25and0.96 ± 0.14pmoles/mg protein, respectively. The K d for the same groups were10.02 ± 2.04, 4.88 ± 1.43and8.71 ± 2.23nM, respectively. The B max and K d in the hypoxic group were significantly lower compared to the control and Mg 2+-treated hypoxic groups, indicating a preservation of NMDA receptor number and affinity for MK-801 during hypoxia with Mg 2+. The activity of Na +, K + ATPase, a marker of neuronal membrane function, was lower in the hypoxic group compared to the control and Mg 2+-treated hypoxic groups. These findings show that MgSO 4 prevents the hypoxia-induced modification of the NMDA receptor and attenuates neuronal membrane dysfunction. We suggest that the administration of Mg 2+ prior to and during hypoxia may be neuroprotective in vivo, possibly by reducing the NMDA receptor-mediated influx of calcium.