The overall objective of the present research is to elucidate biochemical and physiologic mechanisms responsible for perinatal hypoxic-ischemic brain damage and to develop methods which will arrest or retard these processes.
Specific aims i nclude: 1) to characterize the evolution of the threshold lesions which arise from cerebral hypoxia-ischemia in the immature rat and to determine whether or not a delayed neuronal necrosis occurs, especially of the hippocampus; 2) to characterize those critical cellular metabolic events which either precede or parallel the evolution of identifiable lesions resulting from cerebral hypoxia-ischemia in the immature rat: 3) to determine the influence of alterations in glucose and lactate homeostasis on hypoxic-ischemic brain damage in the immature rat and to identify those mechanisms whereby glucose exerts either a beneficial or harmful effect on neuropathologic outcome; 4) to determine the extent to which mild hypothermia ameliorates hypoxic-ischemic brain damage in the immune rat; 5) to investigate the potential beneficial effect of carbon dioxide on hypoxic-ischemic brain damage in the immature rat and to determine the mechanism(s) whereby carbon dioxide is protective; and 6) to investigate the presumed beneficial effects of specific pharmacologic interventions on hypoxic ischemic brain damage, such interventions to include specific calcium blockers, excitatory amino acid receptor antagonists, pyruvate dehydrogenase activators, and nitric oxide synthase inhibitors. To accomplish these goals, we plan to use the following analytical techniques: 1) the iodo-[14C]-amphetamine technique to measure regional cerebral blood flow; 2) modification of the 2- deoxy[14C]-glucose technique to measure regional cerebral glucose utilization; 3) in vivo analysis of glycolytic and Krebs cycle intermediates and high-energy phosphate reserves in brain tissue; 4) determination of cerebral energy utilization, intracellular pH and the redox state of brain tissue on a global, regional and micro-regional basis; 5) regional analysis of calcium and sodium uptake and turnover by brain using autoradiography; 6) light and electron microscopic analysis of brain specimens; 7) MR spectroscopy. Seven-day postnatal rats will be subjected to unilateral common carotid artery occlusion combined with exposure to 8% oxygen for varying intervals. During the course of and following hypoxia-ischemia, the animals will be subjected to those procedures necessary to measure regional cerebral blood flow and metabolism as well as the evolution of the neuropathologic alterations. Additional studies will investigate the regional cerebrovascular and metabolic responses of hypoxic-ischemic immature rats subjects to 1) hyperglycemia; 2) hypothermia, 3) carbon dioxide; and 4) therapeutic interventions, including calcium channel blockers, pyruvate dehydrogenase activators, excitatory amino acid receptor antagonists and nitric oxide synthase inhibitors.
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