Mechanisms of cerebral injury in perinatal asphyxia and strategies for prevention.
We have investigated the mechanisms of hypoxic brain cell injury in the immature animal by examining (1) the role of excitatory amino acid neurotransmitter receptors, (2) the receptor-mediated increase in intracellular Ca2+, and (3) the generation of oxygen free radicals. We examined the effect of brain tissue hypoxia on the NMDA receptor-ion channel complex including the glutamate, Mg2+, spermine, CPP, and the non-NMDA receptor kainate sites. Brain tissue hypoxia resulted in modification of the NMDA receptor ion channel and its modulatory sites. Hypoxia increased the affinity of both the ion channel and the glutamate recognition site. Pretreatment of animals with the glutamate antagonist CPP prevented hypoxia-induced modification of the channel. Similarly, pretreatment of animals with Mg2+, a blocker of the NMDA receptor ion channel, prevented the hypoxia-induced modification of the receptor. In addition, an increased agonist-dependent entry of Ca2+ into synaptosomes was observed in hypoxic animals compared with normoxic animals. Increased free radical generation in the cerebral cortex during hypoxia was demonstrated using spin labeling technique and electron spin resonance spectroscopy. We conclude that hypoxia-induced modification of the NMDA receptor-ion channel complex leads to increased intracellular Ca2+ potentiating free radical generation and resulting in hypoxic cell injury.
Delivoria-Papadopoulos
M
M
Department of Pediatrics, Allegheny University School of Medicine, Philadelphia, Pennsylvania, USA.
Mishra
O P
OP
D000818:Animals; D001238:Asphyxia Neonatorum / Q000503:physiopathology* / Q000517:prevention & control; D001921:Brain / Q000503:physiopathology; D001925:Brain Damage, Chronic / Q000503:physiopathology* / Q000517:prevention & control; D015687:Cell Hypoxia / Q000502:physiology; D005260:Female; D005609:Free Radicals; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology
D005609:Free Radicals; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate