BIOCHEMISTRY OF DELAYED NEURONAL DEATH AFTER ISCHEMIA

这项研究的长期目标是确定 导致细胞损伤的生化损伤， 缺血发作 致病事件是什么，以及 当它发生时，一直是一些争议的主题。 的 组织的命运可以在局部缺血期间确定，但是 也证明了氧气和葡萄糖的重新引入 独特的代谢反应，表明恢复过程是 而不仅仅是缺血诱发事件的逆转。 观察 大脑前叶的整个CA 1神经元 海马在再循环5分钟后4天时死亡， 沙鼠的双侧缺血提供了可重复的反应， 研究细胞死亡前的生化事件。 所提出的实验旨在：1）检查影响 短暂性脑缺血对长期脑代谢恢复的影响 表现出对局部缺血不同程度敏感性的区域， 2)测试一些目前的假设， 缺血性细胞死亡和迟发性神经元死亡的病理机制 进一步评价GABA能神经保护作用 剂. 在这些体内实验中， 磷酸盐、葡萄糖相关代谢物、环核苷酸和 某些氨基酸神经递质将在染色体中测量。 海马和皮质的CA 1和CA 3区域的层 在5分钟的双侧再循环后的不同时间 缺血 组织样品重约1 μ g， 将需要微量定量组织化学方法来测量 pmole范围内的代谢物。 最后，CA的损失 1个神经元在双侧缺血5分钟后再流4天 极大地增加了该区域神经胶质与神经元的比例。 这 神经元缺失区域将在第二次 缺血和再循环，以确定一个 富含胶质的组织对缺血反应的影响。 大胶质细胞 已经证明了缺血期间的酸化，但是 神经胶质中的代谢相关性尚未被研究。 的 胶质细胞酸碱平衡的重要性可以很好地解释 缺血性细胞损伤的演变。 延迟的自然历史 神经元死亡将更好地描述这些离散的 测量，预计这些信息将有助于 作为测试新型治疗药物的时间和生物化学指南， 中风的治疗方法

The long-term objective of this research is to identify the biochemical lesion(s) responsible for cell damage following an ischemic episode. What the pathogenic event is, as well as where and when it occurs, has been the subject of some controversy. The fate of the tissue may be determined during ischemia, but there is also evidence that reintroduction of oxygen and glucose elicits a unique metabolic response, suggesting that the recovery process is not a mere reversal of ischemia-induced events. The observation that the entire population of CA 1 neurons in the anterior hippocampus die at 4 days of recirculation following 5 min of bilateral ischemia in the gerbil provides a reproducible response for investigating the biochemical events that precede cell death. The proposed experiments are designed to: 1) examine the effects of transient ischemia on long-term metabolic recovery in brain regions exhibiting different levels of susceptibility to ischemia, 2) test a number of current hypotheses concerning the pathomechanisms of ischemic cell death and delayed neuronal death and 3) further evaluate the neuroprotective effects of GABAergic agents. In these experiments in vivo, the levels of high-energy phosphates, glucose-related metabolites, cyclic nucleotides and certain amino acid neurotransmitters will be measured in the somal layer of the CA 1 and CA 3 region of the hippocampus and the cortex at various times of recirculation following 5 min of bilateral ischemia. The tissue samples weigh approximately 1 ug and microquantitative histochemical methods will be required to measure the metabolites in the pmole range. Finally, the loss of the CA 1 neurons at 4 days of reflow following 5 min of bilateral ischemia greatly increases the glia to neuron ratio in this region. This neuron-depleted area will be examined both during a secondary ischemia and recirculation to determine the contribution of a glial-enriched tissue to the ischemic response. A greater glial acidification during ischemia has been demonstrated, but the metabolic correlates in glia have not been examined. The importance of acid-base balance in glia may well explain the evolution of ischemic cell damage. The natural history of delayed neuronal death will be better described by these discrete measurements and it is anticipated that the information will serve as a temporal and biochemical guide for testing novel therapeutic approaches to the treatment of stroke.