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: 7872312
• 负责人: KEVIN Scott LEE
• 金额: $ 6.01万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7872312
• 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）：缺血性中风是一种高度异质性的临床病症，是由于血栓和/或栓塞血管闭塞导致脑血流受阻而导致的。治疗任何此类紊乱的首要任务是快速重建受影响神经组织的必需代谢底物的供应。这就是纤溶（溶栓）疗法背后的基本原理，该疗法促进闭塞血管的再通，从而改善神经系统结果。它是目前唯一获得FDA批准的治疗急性缺血性中风的药物疗法；然而，其实用性受到治疗机会相对较短、闭塞血管部分或不完全再通、血管再通缓慢以及可能加剧出血性中风损伤的严重限制。重建代谢能力的另一种补充方法是促进必需代谢物向缺血组织的输送。该提案将定义并描述一种称为“代谢回流”的治疗方法的实用性，其中增强代谢底物的输送以保护缺血组织。反式藏红花酸钠 (TSC) 是一种新型类胡萝卜素化合物，可增加小分子（包括氧气和葡萄糖）在血浆中的扩散率。这种化合物已被证明可以改善多种组织（包括脑实质）的氧气输送。我们的初步研究提供了第一个证据，表明 TSC 可以增强缺血脑组织的氧合，在暂时性和永久性缺血的实验模型中对脑损伤发挥有效且非常显着的保护作用，并且即使延迟给药也具有保护作用。该应用的中心目标是确定 TSC 在缺血性中风背景下的保护作用。这些研究将检验代谢回流是 TSC 脑保护机制的假设。这些研究将确定 TSC 治疗的治疗窗，确定其最佳治疗剂量范围，确定 TSC 是否能够延长再灌注（溶栓）治疗的治疗窗，并确定 TSC 对出血性中风的影响。这些研究将为定义 TSC 诱导的脑保护作为中风早期干预的新型治疗候选者的机制和效用提供关键证据。公共健康相关性：该研究项目将研究治疗中风的新候选疗法的功效。中风是美国第三大常见死因，也是第一大残疾原因。中风损伤的主要原因是流向大脑的血流减少。这会导致神经细胞代谢供应丧失（即氧气和葡萄糖供应丧失），并最终导致神经细胞死亡。新的候选疗法被称为代谢回流，将使用一种名为反式藏红花酸钠的药物来恢复大脑的代谢供应，并防止神经细胞损失。研究的总体目标是测试这种新颖的治疗方法是否能有效保护中风期间的大脑。