title: Nuclear mechanisms of hypoxic cerebral injury in the newborn.
abstract: In early studies, we demonstrated that cerebral tissue hypoxia leads to N-methyl-D-aspartate receptor modification and results in increased intracellular Ca2+. Our subsequent studies have demonstrated an alteration in nuclear Ca2+ influx mechanisms and an increase in the nuclear Ca2+ influx after hypoxia. The hypoxia induced nuclear Ca2+ influx increase correlated in a curvilinear function with the increase in the degree of cerebral tissue hypoxia. The activity of nuclear membrane high-affinity Ca2+-ATPase also increased with the increase in cerebral hypoxia. The expression of the proapototic protein Bax increased as an inverse function with cerebral tissue ATP and phosphocreatine concentrations. However,the expression of the antiapoptotic protein Bcl-2 did not increase after hypoxia. Cerebral tissue hypoxia also led to the activation of caspases 3, 8, and 9. Furthermore, our studies demonstrated that the fragmentation of neuronal genomic DNA increased with increase in degree of cerebral tissue hypoxia. Studies presented in this article elucidate nuclear Ca2+ influx and nuclear Ca2+-mediated mechanisms, including signal transduction, apoptotic gene transcription,caspase activation, and nuclear DNA fragmentation, that result in hypoxic neuronal injury in the newborn brain.
authors.affiliation: Drexel University College of Medicine, Philadelphia, PA 19102, USA. delivoria@drexel.edu
authors.forename: Maria
authors.initials: M
authors.lastname: Delivoria-Papadopoulos
authors.forename: Om Prakash
authors.initials: OP
authors.lastname: Mishra
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D053938:DNA Fragmentation; D004789:Enzyme Activation; D002534:Hypoxia, Brain / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D020169:Caspases; D002118:Calcium