BIOCHEMISTRY OF DELAYED NEURONAL DEATH AFTER ISCHEMIA

这项研究的长期目标是确定 导致局部缺血后细胞损伤的病变。 什么 致病事件是，以及何时何地发生，一直是 一些争议的话题。 组织的命运可能取决于 但也有证据表明，重新引入氧气 和葡萄糖在再循环过程中激发了独特的代谢反应 这表明缺血后的恢复过程不仅仅是 逆转缺血诱导的事件。 最近的观察表明， 双侧缺血5分钟，海马CA1区锥体神经元 海马在再循环4天时死亡，为 对细胞死亡前的生化事件的研究。 的 建议的实验设计1）检查的影响， 近完全缺血对离散脑区长期恢复的影响 其表现出不同程度的对缺血的脆弱性，和2）为了测试 关于缺血细胞的根本原因的假设数量 死亡 在这些体内实验中，高能量 磷酸盐，葡萄糖代谢物，某些氨基酸和环状氨基酸 将在CA 1和CA 3区域的体层中测量核苷酸 海马体和大脑皮层的一部分， 不同的时间间隔，最多可循环7天。 组织样本 重量小于1微克，需要使用微量 用于测量代谢物的组织化学方法。 离散 组织取样应能更精确地测定 受影响组织内发生的实际变化。 在此基础上的变化 包括较长时间缺血的选择性脆弱性模型， 还将检查戊巴比妥治疗和高血糖症。 的 研究结果应明确与神经元死亡相关的病理生理学 并提供对长期恢复过程的额外见解。 的 后者应提供时间和生化基础的测试， 在再循环期间的新治疗方法。

The long-term objective of this research is to identify the biochemical lesion(s) responsible for cell damage following ischemia. 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 during recirculation elicits a unique metabolic response suggesting that the recovery process following ischemia is more than a reversal of ischemia-induced events. The recent observation that following 5 minutes of bilateral ischemia the CA 1 pyramidal neurons of the hippocampus die at 4 days of recirculation provides an excellent model for the investigation of the biochemical events that precede cell death. The proposed experiments are designed 1) to examine the effects of near-complete ischemia on long-term recovery in discrete brain regions which exhibit varying degrees of vulnerability to ischemia and 2) to test a number of hypotheses concerning the underlying causes of ischemic cell death. In these in vivo experiments, the concentrations of high-energy phosphates, glucose metabolites, certain amino acids and the cyclic nucleotides will be measured in the somal layer of the CA 1 and CA 3 region of the hippocampus as well as in a portion of the cerebral cortex at various intervals for up to 7 days of recirculation. The tissue samples weigh less than 1 ug and will require the use of microquantitative histochemical methods for the measurement of the metabolites. The discrete sampling of tissue should provide a more precise determination of the actual changes that occur within the affected tissue. Variations on this model of selective vulnerability including longer periods of ischemia, pentobarbital treatment and hyperglycemia will also be examined. The results should define the pathophysiology associated with neuronal death and provide additional insight into the long-term recovery process. The latter should give a temporal and a biochemical basis for the testing of novel therapeutic approaches during recirculation.