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Treatment of Acute Embolic Stroke with Statins and rt-PA

他汀类药物和 rt-PA 治疗急性栓塞性中风

基本信息

批准号：
7600439
负责人：
ZHENG GANG ZHANG
金额：
$ 35.2万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-03-02 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7600439
关键词：
1-Phosphatidylinositol 3-Kinase Acute Adjuvant Adverse effects Aftercare Alteplase Attenuated Blood - brain barrier anatomy Cardiovascular Diseases Cell Survival Cerebrovascular Circulation Cerebrum Cholesterol Data Dose Endothelial Cells Event Extravasation Fibrinolysis Gene Expression Genes Goals Human Hydroxymethylglutaryl coenzyme A reductase Incidence Infarction Inflammation Ischemic Stroke LDL Cholesterol Lipoproteins Laser Scanning Confocal Microscopy Lead Lipids Magnetic Resonance Imaging Mediating Middle Cerebral Artery Occlusion Modeling Neurons Pathway interactions Pharmaceutical Preparations Rattus Recombinants Serum Signal Pathway Signal Transduction Pathway Stroke Techniques Testing Therapeutic Therapeutic Effect Therapeutic Intervention Thromboembolism Thrombosis Time Vascular Patency Vascular Permeabilities Western Blotting acute stroke atorvastatin cerebrovascular design human NOS3 protein human tissue inhibitor/antagonist laser capture microdissection neurotoxic neurotoxicity novel prophylactic research study thrombolysis treatment strategy wortmannin

项目摘要

DESCRIPTION (provided by applicant): Approximately 80-90% of human cerebral ischemic events are caused by thromboembolism. There is a compelling need to develop acute therapeutic interventions for the treatment of stroke. We present preliminary data indicating that atorvastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, extends the therapeutic window of thrombolysis in a rat model of embolic stroke by activation of the PI3- K/Akt signaling pathway. However, the atorvastatin mediated therapeutic effect is independent of eNOS and lipid levels. The goals of this application are to determine the efficacy of statins in combination with thrombolysis for treatment of acute ischemic stroke and to investigate mechanisms underlying the therapeutic effects of atorvastatin as an adjuvant agent to recombinant human tissue plasminogen activator (rht-PA). Our hypotheses are: 1) Treatment of stroke with atorvastatin in combination with rht-PA extends the therapeutic window for acute stroke; 2) Atorvastatin activates the PI3-K/Akt signaling transduction pathway in cerebral endothelial cells, which decreases cerebral microvascular thrombosis and blood brain barrier (BBB) leakage by negatively regulating endothelial cell genes that promote thrombogenicity, vascular permeability, and inflammation; 3) Activation of the PI3-K/Akt cell survival pathway in neurons by atorvastatin attenuates ischemic neuronal damage exacerbated by delayed treatment of rht-PA. The proposed experiments have been designed to test these hypotheses. Using Magnetic Resonance Imaging (MRI) and 3D laser scanning confocal microscopy (LSCM) techniques, we will first investigate the effects of short-term, high-dose atorvastatin on cerebral vascular patency and integrity including cerebral blood flow (CBF) and BBB leakage, and the neurotoxic effects of tPA. Using laser capture microdissection in combination with real time PCR, Western blot analysis and specific inhibitors which block PI3-K/Akt activation, we will then delve into the mechanisms by which the PI3K/Akt signaling pathway mediates expression of endothelial cell genes involved in thrombosis and BBB leakage, and expression of neuronal genes engaged in the neurotoxic effects of tPA. These studies will lead to a comprehensive understanding of mechanisms underlying the therapeutic effects of statins on extending the window of thrombolysis for acute ischemic stroke and may provide a novel and useful treatment strategy for human ischemic stroke.

描述（由申请方提供）：约80-90%的人类脑缺血事件由血栓栓塞引起。迫切需要开发用于治疗中风的急性治疗干预措施。我们目前的初步数据表明，阿托伐他汀，羟甲基戊二酰辅酶A还原酶抑制剂，延长血栓溶解的治疗窗口，在大鼠模型的栓塞性中风的激活PI 3- K/Akt信号通路。然而，阿托伐他汀介导的治疗作用不依赖于eNOS和脂质水平。本申请的目的是确定他汀类药物联合溶栓治疗急性缺血性卒中的疗效，并研究阿托伐他汀作为重组人组织型纤溶酶原激活剂（rht-PA）辅助剂的治疗作用机制。我们的假设是：2）阿托伐他汀激活脑内皮细胞中的PI 3-K/Akt信号转导通路，这通过负调节促进血栓形成、血管通透性和炎症的内皮细胞基因来减少脑微血管血栓形成和血脑屏障（BBB）渗漏; 3）通过阿托伐他汀激活神经元中的PI 3-K/Akt细胞存活途径减轻了由rht-PA延迟治疗加重的缺血性神经元损伤。所提出的实验旨在验证这些假设。使用磁共振成像（MRI）和三维激光扫描共聚焦显微镜（LSCM）技术，我们将首先研究短期，大剂量阿托伐他汀对脑血管通畅性和完整性的影响，包括脑血流量（CBF）和BBB泄漏，以及tPA的神经毒性作用。利用激光捕获显微切割结合真实的时间PCR、Western blot分析和阻断PI 3-K/Akt活化的特异性抑制剂，我们将深入研究PI 3-K/Akt信号通路介导参与血栓形成和BBB渗漏的内皮细胞基因表达以及参与tPA神经毒性作用的神经元基因表达的机制。这些研究将有助于全面了解他汀类药物延长急性缺血性卒中溶栓窗口的治疗作用机制，并可能为人类缺血性卒中提供一种新的有用的治疗策略。