REGIONAL CEREBRAL BLOOD FLOW AND OXIDATIVE METABOLISM

本研究的总体目标是阐明生化 围产期缺氧缺血的生理机制 大脑损伤，并开发方法来阻止或延缓这些 流程。具体目标包括：1)描述 大鼠脑缺氧缺血所致的阈值损害 并确定是否存在迟发性神经元坏死。 发生，特别是在海马体；2)描述那些关键的 先于或平行于进化的细胞代谢事件 由脑缺氧缺血引起的可识别损伤 未成熟大鼠：3)确定血糖和血糖变化的影响 乳酸稳态对幼年大鼠缺氧缺血性脑损伤的影响 并确定这些机制，使葡萄糖发挥一个 对神经病理结果有利或有害的影响；4)确定 亚低温改善缺氧缺血性脑损伤的程度 对免疫大鼠的损害；5)调查潜在的益处 二氧化碳对幼年缺氧缺血性脑损伤的影响 并确定二氧化碳的作用机制(S) 保护性；以及6)调查推定的有益影响 对缺氧缺血性脑损伤的特殊药物干预， 这种干预措施包括特定的钙阻滞剂、兴奋性氨基 酸受体拮抗剂、丙酮酸脱氢酶激活剂和硝酸 氧化物合成酶抑制剂。为了实现这些目标，我们计划使用 以下分析技术：1)碘-[14C]-苯丙胺技术 测量局部脑血流量；2)改良2- 脱氧[~(14)C]-葡萄糖技术测定局部脑葡萄糖 3)糖酵解循环和Krebs循环的体内分析 脑组织中的中间体和高能磷酸盐储备；4) 测定脑能量利用率、细胞内pH和 全球、区域和微区域脑组织的氧化还原状态 基础；5)钙和钠吸收和周转的区域分析 脑放射自显影；6)光镜和电子显微镜分析 7)磁共振波谱。出生后7天的大鼠将 单侧颈总动脉闭塞合并 暴露在8%的氧气中不同的时间间隔。在和的过程中 在缺氧缺血后，动物将受到 测量局部脑血流量和 代谢以及神经病理改变的演变。 其他研究将调查区域脑血管和 1)缺氧缺血幼鼠的代谢反应 高血糖；2)体温过低；3)二氧化碳；4)治疗 干预措施，包括钙通道阻滞剂、丙酮酸脱氢酶 激活剂、兴奋性氨基酸受体拮抗剂和一氧化氮 合成酶抑制剂。

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 include: 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.