REGIONAL CEREBRAL BLOOD FLOW AND OXIDATIVE METABOLISM

区域脑血流和氧化代谢

• 批准号: 6272279
• 负责人: ROBERT C. VANNUCCI
• 金额: $ 12.04万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6272279
• 关键词: Krebs' cycle; aerobiosis; autoradiography; bioenergetics; brain injury; brain metabolism; calcium channel blockers; cerebral ischemia /hypoxia; dizocilpine; glucose metabolism; glycolysis; histopathology; hypercapnia; hyperglycemia; hypothermia; immature animal; laboratory rat; lactates; neuroprotectants; nitric oxide synthase; nuclear magnetic resonance spectroscopy; oxidoreductase inhibitor; perinatal

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.

本研究的总体目标是阐明生物化学 和生理机制负责围产期缺氧缺血性 并开发出能够阻止或延缓这些脑损伤的方法 流程. 具体目标包括：1）描述 脑缺血缺氧引起的阈值损害， 未成熟大鼠并确定是否出现迟发性神经元坏死 发生，特别是海马体; 2）描述那些关键的 在进化之前或同时发生的细胞代谢事件 脑缺氧缺血引起的可识别的病变， 未成熟大鼠：3）确定葡萄糖和葡萄糖代谢的改变的影响， 乳鼠缺氧缺血性脑损伤时乳酸稳态的变化 并确定这些机制，使葡萄糖发挥， 对神经病理结果的有益或有害影响; 4）确定 亚低温改善缺氧缺血性脑损伤的程度 5）研究免疫大鼠的潜在益处 二氧化碳对未成熟大鼠缺氧缺血性脑损伤的影响 大鼠和确定机制（S），其中二氧化碳是 保护;和6）调查推定的有益效果 对缺氧缺血性脑损伤的特定药理学干预， 这些干预包括特异性钙阻滞剂、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-[14 C]-安非他明技术 测量局部脑血流量; 2）修改2- 脱氧[14 C]-葡萄糖技术测量局部脑葡萄糖 糖酵解和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值和 对脑组织的氧化还原状态进行了全局、局部和微局部的研究 5）钙和钠的吸收和周转的区域分析， 脑放射自显影; 6）光镜和电镜分析 7）磁共振波谱。 出生后7天的大鼠将 单侧颈总动脉闭塞， 暴露在8%的氧气中不同的时间间隔。 在此期间， 在缺氧-缺血后，动物将经受那些 测量局部脑血流量所需的程序， 代谢以及神经病理学改变的演变。 其他研究将调查局部脑血管和 缺氧缺血性未成熟大鼠受试者对1） 高血糖症; 2）体温过低; 3）二氧化碳;和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