NMDA receptor and neonatal hypoxic brain injury.
The NMDA-type glutamate receptor is a predominant mediator of excitotoxicity in the immature brain due to overexpression of the receptor in the developing brain. Within the development period however, the extent of NMDA receptor mediated processes including hypoxia-induced excitotoxicity may depend on the ontogeny of the NMDA receptor recognition and modulation sites, and subunits leading to altered function of the ion-channel comples. The function of the receptor may be modified by intracellular mechanisms such as phosphorylation/dephosphorylation, nitration, and generation of free radicals including nitric oxide. The susceptibility of the developing brain to hypoxia depends on several factors: the lipid composition of the brain cell membrane; the rate of membrane lipid peroxidation and the status of anti-oxidant defenses; the development and modulation of the NMDA receptor sites; the intracellular Ca(2+) influx mechanisms; expression of apoptotic and antiapoptotic genes such as Bax and Bcl-2; and the activation of initiator caspases and caspase-3, the "executioner" of cell death. The developmental status of these cellular mechanisms and their response to hypoxia determine the fate of the hypoxic cell in the developing brain in the fetus and the newborn.
Mishra
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Department of Pediatrics, MCP Hahnemann University and St. Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA. mishra@drexel.edu
Fritz
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Delivoria-Papadopoulos
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D017209:Apoptosis / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D019254:Genes, bcl-2 / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D002534:Hypoxia, Brain / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D007231:Infant, Newborn; D015227:Lipid Peroxidation / Q000502:physiology; D008274:Magnesium / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology*
D005609:Free Radicals; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D018698:Glutamic Acid; D020169:Caspases; D008274:Magnesium; D002118:Calcium