GLUCOCORTICOIDS AND ISCHEMIC CELL DEATH

短暂性前脑缺血发生时，血液流向大脑停止 一段时间，然后重新开始。 在患者中，一过性 前脑缺血发生于心脏骤停、溺水或麻醉剂 事故发生后，成功复苏。 短暂性前脑 缺血与脑内迟发性和选择性神经元死亡有关， 海马CA/1区。 虽然大脑的其他区域也可能显示 损害的证据，CA/1地区似乎特别容易受到 短暂性缺血 我们研究了CA/1锥体细胞的调节 死于糖皮质激素 我们发现即使在24岁时做肾上腺切除术 在短暂缺血发作后24小时， CA/1神经元 我们的初步数据表明，有一个后- 糖皮质激素的缺血性激增， CA/1锥体细胞死亡量。 这项建议的目的是 这些初步实验的逻辑进程 我们将测试 假设糖皮质激素影响CA/1死亡率，而不是 通过仔细检查时间进程， CA/1损害后，各种干预，这将增加或 降低循环糖皮质激素水平。 然后我们将测试 假设糖皮质激素的作用是独立的变化 大脑温度 最后，我们将检验缺血性心脏病的假设， 细胞死亡代表程序性细胞死亡的一种形式。 我们将寻找 CA/1锥体细胞层DNA片段化并检测时间进程 短暂性脑缺血后糖皮质激素受体易位的研究。 我们将 研究蛋白质合成抑制对CA/1损伤的影响。 在这些 在实验中，我们将特别注意碎片化的时间， 受体转位和蛋白质合成抑制的影响。 我们 将决定脑温和血浆变化的影响 糖皮质激素在这个时间。 这些实验将扩展我们的 观察糖皮质激素在缺血性细胞损伤中的作用， 这将有助于深入了解缺血细胞的分子基础， 死亡 CA/1的缺血性细胞死亡似乎是一个重要的后果， 心脏骤停，并可能证明是一个有用的模型， 局灶性脑梗死周围的半暗带。 因此，提出的实验 这里应该提供药理学干预的基本原理， 可能与其他药物联合使用，以防止脑损伤， 心脏骤停和中风的患者。

Transient forebrain ischemia occurs whenever blood flow to the brain stops for a period of time and then is restarted. In patients, transient forebrain ischemia occurs with cardiac arrest, drowning, or anesthetic accidents followed by successful resuscitation. Transient forebrain ischemia is associated with delayed and selective neuronal death in the CA/1 region of the hippocampus. While other brain regions may also show evidence of damage, the CA/1 regions seems particularly susceptible to transient ischemia. We have studied the regulation of CA/1 pyramidal cell death by glucocorticoids. We found that adrenalectomy even as late as 24 hours after a brief episode of ischemia results in significant protection of CA/1 neurons. Our preliminary data suggests that there is a post- ischemic surge in glucocorticoids which substantially contributes to the amount of CA/1 pyramidal cell death. The objectives of this proposal are the logical progression of these preliminary experiments. We will test the hypothesis that glucocorticoids affect the rate of CA/1 death rather than the absolute amount of damage by carefully examining the time course of CA/1 damage after various interventions which will either increase or decrease circulating glucocorticoid levels. We will then test the hypothesis that the glucocorticoid effects are independent of changes in brain temperature. Finally we will examine the hypothesis that ischemic cell death represents a form of programmed cell death. We will look for DNA fragmentation in the CA/1 pyramidal layer and examine the time course of glucocorticoid receptor translocation after transient ischemia. We will study the effect of protein synthesis inhibition on CA/1 damage. In these experiments, we will pay special attention to the timing of fragmentation, receptor translocation and the effects of protein synthesis inhibition. We will determine the effect of changes in brain temperature and plasma glucocorticoids on this timing. These experiments will extend our observations on the role of glucocorticoids in ischemic cell damage and should provide useful insights into the molecular basis of ischemic cell death. Ischemic cell death in CA/1 appears to be an important consequence of cardiac arrest in humans and may prove a useful model for studying the penumbra around focal cerebral infarction. Thus the experiments proposed here should provide a rationale for pharmacological interventions that might be used in combination with other agents to prevent brain damage in patient with cardiac arrest and stroke.