CALCIUM BLOCKER AND RELATED THERAPY FOR STROKE

钙阻滞剂及相关中风治疗

• 批准号: 2265036
• 负责人: JAMES C GROTTA
• 金额: $ 26.18万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2265036
• 关键词: NMDA receptors; brain disorder chemotherapy; calcium channel blockers; calcium flux; calmodulin dependent protein kinase; cerebral ischemia /hypoxia; disease /disorder model; drug screening /evaluation; enzyme activity; enzyme mechanism; glutamates; neuroprotectants; nonhuman therapy evaluation; protein kinase; protein transport; reperfusion; spontaneous hypertensive rat; stroke

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.

该提案的主要目的是评估有效性和 临床相关神经元保护作用机制 旨在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 动物中风模型的结果目前尚无临床证明 急性中风的有效治疗方法，急性中风是第三大常见死因 美国这种困境的部分原因可能是相关性较差 临床前和临床疗效研究的设计之间。 在本提案中，我们希望通过尝试来调和其中一些差异 尽可能多地模拟临床卒中的重要组成部分 特定的再灌注、其发生、时间和后果。 为了 为了开展这项工作，我们制定了特别严格和 大鼠中风的临床相关模型，并确定了时间 必须开始神经元保护治疗的阈值 有效的。 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 EE 如果可以通过治疗有利地改变它。 组织学和功能 将衡量结果。 我们将通过以下方式解决第二个具体目标： 再灌注期间产生严重且可预测的水肿量 看看是否可以通过治疗来限制。 我们将评估的疗法是 基于表明人类耐受剂量的功效的初步数据， 以及一种被认为可以改善钙紊乱的作用机制 通过影响缺血后级联中的特定步骤来促进新陈代谢 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 超急性中风的临床试验。 这项工作的第二个主要目标是探索 Cam-K-II 对缺血性损伤。 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而被激活 局部缺血部分是由细胞外谷氨酸增加引起的 NMDA 受体的激活。 我们已经证明，坚持不懈 由于酶易位导致 Cam-K-II 活性下调 与不可逆的神经元损伤有关。 我们将研究自然并 这种易位的可逆性可能会导致新的策略 神经元保护性干预。