Mechanisms of Vascular Protection after Acute Stroke

急性中风后的血管保护机制

• 批准号: 7727066
• 负责人: SUSAN C FAGAN
• 金额: $ 28.56万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727066
• 关键词: Acute; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensins; Blood Pressure; Blood Pressure Monitors; Blood Vessels; Brain; Cell Culture Techniques; Cerebral Ischemia; Cerebrum; Clinical; Clinical Trials; Commit; Data; Development; Diabetes Mellitus; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Goals; Health; Hour; Human; Hydralazine; Hyperglycemia; Hypertension; Hypotension; Immunoblotting; Injury; Intervention; Investigation; Ischemic Stroke; Knowledge; Laboratories; Laser-Doppler Flowmetry; Matrix Metalloproteinases; Measures; Methods; Modeling; Neurological outcome; Nitric Oxide; Outcome; Oxidative Stress; Pathway interactions; Patients; Performance; Perfusion; Pharmaceutical Preparations; Pharmacologic Substance; Rattus; Recovery; Recovery of Function; Reperfusion Therapy; Research; Scientist; Stroke; Superoxide Dismutase; Talents; Telemetry; Testing; Therapeutic; Therapeutic Human Experimentation; Time; United States; Vascular Diseases; Vascular Endothelial Growth Factors; Work; acute stroke; cerebrovascular biology; design; functional outcomes; improved; interest; neurobehavioral test; new therapeutic target; normotensive; novel therapeutics; oxidative damage; preclinical study; protective effect; public health relevance; research study; response; therapy development

DESCRIPTION (provided by applicant): Of the more than 600,000 acute ischemic strokes treated annually in the United States, 98% of patients receive no acute therapy. Patients with co-morbid vascular diseases, like diabetes and uncontrolled hypertension, have worse outcomes and have historically been underrepresented in preclinical studies. Long-term recovery is limited by the brain's inherent plasticity and ability to actively remodel after injury. The brain vasculature is undoubtedly a key component of recovery and therapeutic strategies that are vascular protective are likely to promote better function. The facilitation of natural recovery mechanisms, especially when cerebral ischemia is layered on preexisting vascular compromise, has great promise as a therapeutic strategy. The objective of this application is to further elucidate the mechanisms involved in vascular protection after cerebral ischemia. The central hypothesis for the proposed research is that neurovascular protection after cerebral ischemia and reperfusion can be achieved by optimization of oxidative stress and activation of remodeling. We plan to achieve this objective through the following three specific aims: Aim #1: Determine the contribution of oxidative stress and MMP modulation to the beneficial effects of angiotensin antagonism on experimental ischemic stroke outcome. Aim #2: Determine the extent to which premorbid vascular damage impacts the neurovascular protective effects of angiotensin antagonism after acute ischemic stroke. Aim #3: Determine whether reperfusion is essential for optimal vascular protection with candesartan after cerebral ischemia We will achieve these aims using normotensive, hypertensive and hyperglycemic rat models of temporary cerebral ischemia, continuous BP monitoring via telemetry, laser Doppler flowmetry, BP lowering and pharmacologic MMP and oxidative stress modulation. In addition, we will employ MMP zymography, and quantitative measures of microvascular integrity and oxidative damage using ELISA and immunoblotting and a sensitive battery of neurobehavioral tests at 3, 7 and 30 days. Lastly, we will use brain microvascular endothelial cell culture studies. At the completion of 12 experiments over 5 years, we expect that changes in oxidative stress and MMP activity will contribute to the vascular protection afforded by angiotensin blockade in the acute stroke period. We expect that the presence of prior hypertension, hyperglycemia, endogenous vascular protectors and the method and timing of treatment in relation to reperfusion status will be important in the ultimate degree of neurovascular damage. This is important because it will provide impetus and guidance for a clinical trial to improve outcome of human stroke patients. PUBLIC HEALTH RELEVANCE: Most stroke patients recover some brain function in the long-term but not enough to return to normal. Development of treatments that protect the blood vessels during a stroke may promote functional recovery. This project will determine the mechanisms of vascular protection after stroke and develop a medication treatment likely to work in stroke patients.

描述（由申请人提供）：在美国每年治疗的60多万例急性缺血性卒中中，98%的患者未接受急性治疗。患有共病血管疾病的患者，如糖尿病和不受控制的高血压，结局更差，并且在临床前研究中历来代表性不足。长期恢复受到大脑固有的可塑性和损伤后主动重塑能力的限制。脑血管系统无疑是恢复的关键组成部分，血管保护性治疗策略可能会促进更好的功能。促进自然恢复机制，特别是当脑缺血是分层的预先存在的血管妥协，有很大的希望作为一种治疗策略。本申请的目的是进一步阐明脑缺血后血管保护的机制。这项研究的中心假设是，脑缺血和再灌注后的神经血管保护可以通过优化氧化应激和激活重塑来实现。我们计划通过以下三个具体目标来实现这一目标：目标#1：确定氧化应激和MMP调节对血管紧张素拮抗剂对实验性缺血性卒中结局的有益作用的贡献。目标二：确定发病前血管损伤对急性缺血性卒中后血管紧张素拮抗剂的神经血管保护作用的影响程度。目标3：确定再灌注是否是脑缺血后坎地沙坦最佳血管保护所必需的。我们将使用血压正常、高血压和高血糖大鼠暂时性脑缺血模型、通过遥测的连续BP监测、激光多普勒血流仪、BP降低和药理学MMP和氧化应激调节来实现这些目标。此外，我们将采用MMP酶谱，并定量测量微血管的完整性和氧化损伤，使用ELISA和免疫印迹和一个敏感的电池的神经行为测试在3，7和30天。最后，我们将利用脑微血管内皮细胞培养进行研究。在5年内完成12项实验后，我们预计氧化应激和MMP活性的变化将有助于在急性卒中期间通过血管紧张素阻断提供的血管保护。我们预期，既往高血压、高血糖、内源性血管保护剂的存在以及与再灌注状态相关的治疗方法和时机对于神经血管损伤的最终程度将是重要的。这一点很重要，因为它将为临床试验提供动力和指导，以改善人类中风患者的预后。公共卫生相关性：大多数中风患者在长期内恢复了一些脑功能，但不足以恢复正常。在中风期间保护血管的治疗方法的发展可能会促进功能恢复。该项目将确定中风后血管保护的机制，并开发可能对中风患者有效的药物治疗。