Mg super(2+)-dependent modification of the N-methyl-D-aspartate receptor following graded hypoxia in the cerebral cortex of newborn piglets

The present study tests the hypothesis that Mg super(2+) modification of N-methyl-D-aspartate receptor ion channel opening is altered during hypoxia and correlates with the progressive decrease in cerebral energy metabolism induced by hypoxia. Studies were performed in five normoxic and nine hypoxic ventilated piglets. In the hypoxic group, varying degrees of cerebral energy metabolism were achieved by administration of different fractions of inspired oxygen (FiO sub(2)) (5-9%) for varying durations of time and were documented by cortical tissue phosphocreatine levels. [ super(3)H]Dizocilpine maleate binding was performed with increasing concentrations of MgSO sub(4) from 0.01 to 15 mM in cortical P sub(2) membrane fractions. Mg super(2+) percentage activation and Mg super(2+) 50% inhibitory concentrations (IC sub(50)) were determined. The mean plus or minus S.D. phosphocreatine value was 3.0 plus or minus 1.3 mu mol/g brain in the normoxic group and 1.4 plus or minus 1.0 mu mol/g brain in the hypoxic group (P < 0.01). Low concentrations of Mg super(2+) (0.01-1 mM) increased [ super(3)H]dizocilpine maleate binding in the normoxic group (to 137 plus or minus 26% of baseline), significantly greater than in the hypoxic group (109 plus or minus 13%, P < 0.05). Receptor activation correlated with brain tissue levels of phosphocreatine, with percentage maximal activation decreasing linearly as phosphocreatine levels decreased (r = 0.7). Higher levels of Mg super(2+) (1.5-15 mM) caused inhibition of [ super(3)H]dizocilpine maleate binding, with IC sub(50) levels significantly higher in the normoxic group (3.2 plus or minus 1.1 mM) than in the hypoxic group (1.9 plus or minus 0.4 mM). Mg super(2+) IC sub(50) values decreased in a linear fashion as phosphocreatine values decreased (r = 0.9). The data demonstrate that, as brain cell energy metabolism decreases during hypoxia, maximal receptor activation by low levels of Mg super(2+) decreases and receptor inhibition by high levels of Mg super(2+) increases in a linear fashion. We speculate that, during hypoxia, dephosphorylation of the ion channel of the N-methyl-D-aspartate receptor increases Mg super(2+) blockade of the receptor by increasing Mg super(2+) accessibility to its binding site and that receptor modification may be initiated by subtle decreases in cortical oxygenation in the newborn brain.