CALCIUM BLOCKER AND RELATED THERAPY FOR STROKE

这项建议的主要目标是评估疗效和 临床相关神经保护作用机制的研究进展 旨在防止钙激活紊乱的药物疗法 可逆性脑缺血后的酶系统。尽管前景看好 结果在动物中风模型中，仍然没有临床证明 急性中风的有效治疗是#年第三大常见死亡原因 美国的这种困境可能在一定程度上是因为两者之间的相关性很差 临床前和临床疗效研究设计之间的差异。 在这项提案中，我们希望通过努力调和这些分歧中的一些 尽可能多地模拟临床中风的重要组成部分，在 特殊的再灌流，其发生、时机和后果。按顺序 为了开展这项工作，我们制定了一套特别严格和 临床相关的卒中大鼠模型，并测定颞叶 神经保护性治疗必须达到的阈值 有效。我们将通过建立一个 缺血持续时间与损伤严重程度的“剂量-反应”曲线及S的研究 如果它能通过治疗顺利转移的话。组织学和功能性都很强 结果将会被衡量。我们将通过以下方式解决第二个具体目标 在再灌流期间产生严重的和可预测的水肿量 看看是否可以通过治疗来限制它。我们将评估的治疗方法有 根据初步数据显示在人体耐受剂量下的有效性， 以及一种改善钙紊乱的作用机制 通过影响缺血后级联反应中的特定步骤来代谢 谷氨酸兴奋性毒性。拟议的工作应有助于确定 最有可能取得成功的药物疗法和治疗策略 在超急性中风的临床试验中。 这项工作的第二个主要目标是探索 CaM-K-II与缺血性损伤的关系CaM-K-II是含量最丰富的蛋白激酶 在大脑中，并被激活后细胞内钙的增加 缺血的部分原因是细胞外谷氨酸和 激活NMDA受体。我们已经证明了坚持不懈 酶易位导致CaM-K-II活性下调 与不可逆转的神经元损伤有关。我们将研究大自然和 这种易位的可逆性可能导致新的治疗策略 神经保护性干预。

The primary objective of this proposal is to assess the efficacy and mechanism of action of clinically relevant neuronal protective pharmacotherapies aimed at preventing disturbances in calcium activated enzyme systems after reversible cerebral ischemia. Despite promising results in animal stroke models there is still no clinically proven effective therapy for acute stroke, the third most common cause of death in the U.S. This dilemma may be explained in part by a poor correlation between the design of preclinical and clinical efficacy studies. In this proposal, we hope to reconcile some of these differences by trying as much as possible to model important components of clinical stroke, in particular reperfusion, its occurrence, timing, and consequences. In order to carry out this work, we have developed a particularly rigorous and clinically relevant model of stroke in rats, and determined the temporal thresholds before which neuronal protective therapies must be started to be effective. We will address the first specific aim by establishing a duration of ischemia vs severity of damage "dose-response" curve and s ee if it can be shifted favorably by therapy. Both histologic and functional outcome will be measured. We will address the second specific aim by producing a severe and predictable amount of edema during reperfusion and see if it can be limited by therapy. The therapies we will evaluate are based on preliminary data indicating efficacy at doses tolerated in man, and a mechanism of action thought to ameliorate disturbances in calcium metabolism by impacting specific steps in the cascade of post-ischemic glutamate excitotoxicity. The proposed work should help identify pharmacotherapies and therapeutic strategies most likely to lead to success in clinical trials for hyperacute stroke. The second major objective of this work is to explore the relationship of Cam-K-II to ischemic injury. Cam-K-II is the most abundant protein kinase in the brain, and is activated by increases in intracellular calcium after ischemia caused, in part, by increased extracellular glutamate and activation of the NMDA receptor. We have shown that persistent downregulation of Cam-K-II activity due to enzyme translocation is associated with irreversible neuronal damage. We will study the nature and reversibility of this translocation which may lead to new strategies for neuronal protective intervention.