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 identify and examine the evolution of the threshold lesion which arises from cerebral hypoxia-ischemia in the immature rat; 2) to characterize the early cerebrovascular and metabolic events which 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 4) to investigate biochemical mechanisms by which specific pharmacologic interventions (calcium channel blockers, xanthine oxidase inhibitors, excitatory neurotransmitter receptor inhibitors) protect the perinatal brain from hypoxic-ischemic brain damage. To accomplish these goals, we plan to use the following analytical techniques: 1) modification of the iodo-[14C]- antipyrine 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 uptake and turnover by brain using [45Ca]- autoradiography; and 6) light and electron microscopic analysis of pathologic brain specimens. 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 subjected to: 1) hypoglycemia; 2) hyperglycemia in the recovery period and 3) therapeutic interventions, including calcium channel blockers, xanthine oxidase inhibitors, and excitatory amino acid receptor antagonists. It is anticipated that the results of the proposed research will provide a more rational basis for the management of human infants who sustain cerebral hypoxia-ischemia (asphyxia) during the perinatal period.
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