Mg2+-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 Mg2+ 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 (FiO2) (5-9%) for varying durations of time and were documented by cortical tissue phosphocreatine levels. [3H]Dizocilpine maleate binding was performed with increasing concentrations of MgSO4 from 0.01 to 15 mM in cortical P2 membrane fractions. Mg2+ percentage activation and Mg2+ 50% inhibitory concentrations (IC50) were determined. The mean +/- S.D. phosphocreatine value was 3.0 +/- 1.3 micromol/g brain in the normoxic group and 1.4 +/- 1.0 micromol/g brain in the hypoxic group (P < 0.01). Low concentrations of Mg2+ (0.01-1 mM) increased [3H]dizocilpine maleate binding in the normoxic group (to 137 +/- 26% of baseline), significantly greater than in the hypoxic group (109 +/- 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 Mg2+ (1.5-15 mM) caused inhibition of [3H]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 receptor inhibition by high levels of Mg2+ increases in a linear fashion. We speculate that, during hypoxia, dephosphorylation of the ion channel of the N-methyl-D-aspartate receptor increases Mg2+ blockade of the receptor by increasing Mg2+ accessibility to its binding site and that receptor modification may be initiated by subtle decreases in cortical oxygenation in the newborn brain.
Allegheny University of the Health Sciences, Department of Pediatrics, Medical College of Pennsylvania, and St Christopher's Hospital for Children, Philadelphia 19129, USA.
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Fritz
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Mishra
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Delivoria-Papadopoulos
D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D008274:Magnesium / Q000008:administration & dosage*; D010725:Phosphocreatine / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D013552:Swine
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D010725:Phosphocreatine; D016291:Dizocilpine Maleate; D008274:Magnesium