Utility of a Novel Carotenoid for Treating Stroke

新型类胡萝卜素治疗中风的效用

• 批准号: 7795733
• 负责人: KEVIN Scott LEE
• 金额: $ 30万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795733
• 关键词: Acute; Address; Affect; Alteplase; Animal Model; Attenuated; Behavioral; Blood Vessels; Blood flow; Brain; Brain Injuries; Brain hemorrhage; Caring; Carotenoids; Cause of Death; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Cerebrovascular Circulation; Cerebrovascular Spasm; Cerebrum; Cessation of life; Clinical; Clinical Treatment; Coagulation Process; Cytolysis; Data; Diagnosis; Differential Diagnosis; Dose; Early treatment; Experimental Models; FDA approved; Failure; Glucose; Goals; Hemorrhage; Hemorrhagic Shock; Incidence; Individual; Injury; Intervention; Ischemia; Ischemic Stroke; Metabolic; Modeling; Morbidity - disease rate; Neurological outcome; Neurons; Obstruction; Outcome; Oxidative Stress; Oxygen; Patients; Pharmaceutical Preparations; Physiological; Plasma; Probability; Process; Recovery of Function; Reperfusion Therapy; Research Project Grants; Risk; Role; Speed; Stroke; Subarachnoid Hemorrhage; Testing; Therapeutic; Time; Tissues; Treatment Step; United States; base; brain tissue; disability; dosage; effective therapy; improved; insight; mortality; novel; novel therapeutic intervention; novel therapeutics; protective effect; public health relevance; relating to nervous system; research study; response; small molecule; stroke therapy; trans-sodium crocetinate

DESCRIPTION (provided by applicant): Ischemic stroke is a highly heterogeneous clinical condition resulting from an obstruction in cerebral blood flow due to thrombotic and/or embolic vascular occlusion. A key priority in the treatment of any such disturbance is to rapidly re-establish the supply of essential metabolic substrates to the affected neural tissue. This is the rationale behind fibrinolytic (clot-lysis) therapy, which facilitates the recanalization of occluded vessels, thus improving neurological outcome. It is currently the only FDA-approved drug-based therapy for the treatment of acute ischemic stroke; however, its utility is dramatically constrained by a relatively brief window of therapeutic opportunity, partial or incomplete recanalization of occluded vessels, slow recanalization of vessels, and the potential to exacerbate injury in hemorrhagic strokes. An alternative, yet complementary, approach to reestablishing metabolic competency is to facilitate the delivery of essential metabolites to the ischemic tissue. This proposal will define and characterize the utility of a therapeutic approach, termed "metabolic reflow", in which the delivery of metabolic substrates is enhanced to protect ischemic tissue. Trans-sodium crocetinate (TSC) is a novel carotenoid compound that increases the diffusivity in plasma of small molecules, including oxygen and glucose. This compound has been shown to improve oxygen delivery to a variety of tissues, including the brain parenchyma. Our preliminary studies provide the first evidence that TSC enhances oxygenation of ischemic brain tissue, exerts a potent and highly significant protective effect against cerebral injury in experimental models of both temporary and permanent ischemia, and is protective even when administered on a delayed basis. The central goal of this application is to define the protective effects of TSC in the context of ischemic stroke. The studies will examine the hypothesis that metabolic reflow is the mechanism underlying cerebral protection by TSC. The studies will identify the therapeutic window for TSC treatment, determine its optimal therapeutic dosage range, establish whether TSC is capable of extending the therapeutic window for reperfusion (clot-lysis) therapy, and define the influence of TSC on hemorrhagic stroke. Together these studies will provide key evidence for defining the mechanism(s) and utility of TSC- induced cerebral protection as a novel therapeutic candidate for early intervention in stroke. PUBLIC HEALTH RELEVANCE: This research project will study the efficacy of a new candidate therapy for treating stroke. Stroke is the third most common cause of death and the number one cause of disability in the United States. A primary cause of injury in stroke is a reduction in blood flow to the brain. This results in a loss of metabolic supply (i.e. loss of oxygen and glucose supply) to the nerve cells and ultimately leads to their death. The new candidate therapy, termed metabolic reflow will use a drug called trans-sodium crocetinate to reinstate the metabolic supply to the brain and protect against the loss of nerve cells. The overall goal of the studies is to test whether this novel therapeutic approach is effective in protecting the brain during stroke.

描述（由申请人提供）：缺血性中风是由于血栓形成和/或栓塞血管闭塞引起的脑血流阻塞而导致的高度异质临床状况。治疗任何此类障碍的关键优先级是快速重新建立对受影响神经组织的必需代谢底物的供应。这是纤维蛋白水解（凝块赖以溶解）疗法的基本原理，促进了闭塞血管的再通行，从而改善了神经系统结果。目前，它是唯一的基于FDA的药物治疗，用于治疗急性缺血性中风。然而，它的效用受到相对短暂的治疗机会，闭塞血管的部分或不完全重新定性的窗口的巨大限制，缓慢的血管重新加固以及在出血性中风中加剧损伤的可能性。重建代谢能力的一种替代但互补的方法是促进必需代谢物向缺血组织的递送。该建议将定义并表征治疗方法的实用性，称为“代谢回流”，其中增强了代谢底物的递送以保护缺血性组织。跨钠永远信（TSC）是一种新型类胡萝卜素化合物，可增加小分子（包括氧和葡萄糖）的血浆中的扩散。该化合物已被证明可以改善对包括脑实质在内的各种组织的氧气递送。我们的初步研究提供了第一个证据，表明TSC可以增强缺血性脑组织的氧合，在临时和永久性缺血的实验模型中对脑损伤产生有效且极为显着的保护作用，即使在延迟的基础上进行给药也是保护性的。该应用的核心目标是在缺血性中风的背景下定义TSC的保护作用。研究将研究以下假设：代谢回流是TSC的大脑保护的基础机制。这些研究将确定用于TSC治疗的治疗窗口，确定其最佳治疗剂量范围，确定TSC是否能够扩展再灌注（CLOT-LYSIS）治疗的治疗窗口，并确定TSC对出血性中风的影响。这些研究将共同​​为定义TSC诱导的大脑保护的机制和实用性提供关键证据，作为新型中风早期干预的新型治疗候选者。公共卫生相关性：该研究项目将研究新候选疗法治疗中风的功效。中风是美国第三大常见的死亡原因，也是美国残疾的第一原因。中风损伤的主要原因是流向大脑的血液流量减少。这会导致代谢供应损失（即氧气和葡萄糖供应量的损失），并最终导致其死亡。新的候选疗法称为代谢回流将使用一种称为跨钠的药物来恢复对大脑的代谢供应并预防神经细胞的丧失。研究的总体目标是测试这种新型治疗方法是否有效地保护了中风期间的大脑。