CALCIUM BLOCKER AND RELATED THERAPY FOR STROKE

本提案的主要目的是评估有效性， 临床相关神经元保护的作用机制 目的在于预防钙激活紊乱的药物疗法 可逆性脑缺血后的酶系统。 尽管有希望 结果在动物中风模型中，仍然没有临床证明 有效治疗急性中风，第三个最常见的死亡原因， 这种困境的部分原因可能是相关性差 临床前和临床有效性研究的设计之间的差异。 在这一建议中，我们希望通过尝试 尽可能多地模拟临床卒中的重要组成部分， 特别是再灌注，其发生，时机和后果。 为了 为了开展这项工作，我们制定了一个特别严格的， 临床相关的中风模型，并确定了时间 阈值之前，神经元保护治疗必须开始， 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”曲线和see 如果它能通过治疗得到改善的话 组织学和功能学 结果将被衡量。 我们将针对第二个具体目标， 在再灌注期间产生严重的和可预测量的水肿， 看看是否能通过治疗来控制 我们将评估的疗法是 基于表明在人类耐受剂量下的功效的初步数据， 和一种被认为可以改善钙离子紊乱的作用机制 通过影响缺血后代谢级联中的特定步骤， 谷氨酸兴奋毒性 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讨 Cam-K-II对缺血性损伤的影响。 Cam-K-II是最丰富的蛋白激酶 在大脑中，并通过细胞内钙的增加激活后， 部分由细胞外谷氨酸盐增加引起的缺血， 激活NMDA受体。 我们已经证明， 由于酶易位导致的Cam-K-II活性下调是 与不可逆的神经元损伤有关。 我们将研究自然， 这种易位的可逆性，这可能导致新的战略， 神经元保护性干预

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.