Mg2+-dependent modification of the N-methyl-D-aspartate receptor followinggraded hypoxia in the cerebral cortex of newborn piglets

The present study tests the hypothesis that Mg2+ modification of N-methyl-D -aspartate receptor ion channel opening is altered during hypoxia and corre lates with the progressive decrease in cerebral energy metabolism induced b y hypoxia. Studies were performed in Five normoxic and nine hypoxic ventila ted piglets. In the hypoxic group, varying degrees of cerebral energy metab olism were achieved by administration of different fractions of inspired ox ygen (FiO(2)) (5-9%) for varying durations of time and were documented by c ortical tissue phosphocreatine levels. [H-3]Dizocilpine maleate binding was performed with increasing concentrations of MgSO4 from 0.01 to 15 mM in co rtical P-2 membrane fractions. Mg2+ percentage activation and Mg2+ 50% inhi bitory concentrations (IC50) were determined. The mean +/- S.D. phosphocrea tine value was 3.0 +/- 1.3 mu mol/g brain in the normoxic group and 1.4 +/- 1.0 mu mol/g brain in the hypoxic group (P < 0.01). Low concentrations of Mg2+ (0.01-1 mM) increased [H-3]dizocilpine maleate binding in the normoxic group (to 137 +/- 26% of baseline), significantly greater than in the hypo xic group (109 +/- 13%, P < 0.05). Receptor activation correlated with brai n tissue levels of phusphocreatine, with percentage maximal activation decr easing linearly as phosphocreatine levels decreased (r = 0.7). Higher level s of Mg2+ (1.5-15 mM) caused inhibition of [H-3]dizocilpine maleate binding , with IC50 levels significantly higher in the normoxic group (3.2 +/- 1.1 mM) than in the hypoxic group (1.9 +/- 0.4 mM). Mg2+ IC50 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 Mg2+ decreases and r eceptor inhibition by high levels of Mg2+ increases in a linear fashion. We speculate that, during hypoxia, dephosphorylation of the ion channel of th e N-methyl-D-aspartate receptor increases Mg2+ blockade of the receptor by increasing Mg2+ accessibility to its binding site and that receptor modific ation may be initiated by subtle decreases in cortical oxygenation in the n ewborn brain. (C) 1999 IBRO. Published by Elsevier Science Ltd.