MECHANISMS OF CEREBRAL INJURY IN PERINATAL ASPHYXIA AND STRATEGIES FOR PREVENTION

We have investigated the mechanisms of hypoxic brain cell injury in th e immature animal by examining (1) the role of excitatory amino acid n eurotransmitter receptors, (2) the receptor-mediated increase in intra cellular Ca2+, and (3) the generation of oxygen free radicals. We exam ined the effect of brain tissue hypoxia on the NMDA receptor-ion chann el complex including the glutamate, Mg2+, spermine, CPP, and the non-N MDA receptor kainate sites. Brain tissue hypoxia resulted in modificat ion of the NMDA receptor ion channel and its modulatory sites. Hypoxia increased the affinity of both the ion channel and the glutamate reco gnition site. Pretreatment of animals with the glutamate antagonist CP P prevented hypoxia-induced modification of the channel. Similarly, pr etreatment of animals with Mg2+, a blocker of the NMDA receptor ion ch annel, prevented the hypoxia-induced modification of the receptor. In addition, an increased agonist-dependent of Ca2+ into synaptosomes was observed in hypoxic animals compared with normoxic animals. Increased free radical generation in the cerebral cortex during hypoxia was dem onstrated using spin labeling technique and electron spin resonance sp ectroscopy. We conclude that hypoxia-induced modification of the NMDA receptor-ion channel complex leads to increased intracellular Ca2+ pot entiating free radical generation and resulting in hypoxic cell injury .