Utility of a Novel Carotenoid for Treating 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疾病，由血栓性和/或栓塞性血管闭塞引起的脑血流阻塞引起。治疗任何此类紊乱的关键优先事项是迅速重建受影响神经组织必需代谢底物的供应。这就是纤溶（凝块溶解）治疗的基本原理，它可以促进闭塞血管的再通，从而改善神经系统的预后。它是目前fda批准的唯一一种用于治疗急性缺血性中风的药物疗法；然而，它的应用受到相对较短的治疗机会窗口、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。本提案将定义和描述一种称为“代谢回流”的治疗方法的实用性，其中代谢底物的递送被增强以保护缺血组织。反式藏红花酸钠（TSC）是一种新型类胡萝卜素化合物，可以增加血浆中小分子（包括氧气和葡萄糖）的扩散率。这种化合物已被证明可以改善多种组织的氧气输送，包括脑实质。我们的初步研究提供了第一个证据，证明TSC增强缺血脑组织的氧合，对暂时性和永久性缺血的实验模型的脑损伤具有有效和高度显著的保护作用，并且即使在延迟给药的基础上也具有保护作用。本应用的中心目标是确定TSC在缺血性卒中中的保护作用。本研究将探讨代谢回流是TSC脑保护机制的假说。本研究将确定TSC治疗的治疗窗口期，确定其最佳治疗剂量范围，确定TSC是否能够延长再灌注（凝块溶解）治疗的治疗窗口期，明确TSC对出血性卒中的影响。总之，这些研究将为确定TSC诱导的脑保护作为卒中早期干预的一种新的候选治疗方法的机制和效用提供关键证据。公共卫生相关性：本研究项目将研究一种治疗中风的新候选疗法的疗效。中风是美国第三大最常见的死亡原因，也是导致残疾的第一大原因。中风损伤的一个主要原因是流向大脑的血流量减少。这导致神经细胞代谢供应的丧失（即氧气和葡萄糖供应的丧失），并最终导致其死亡。新的候选疗法被称为代谢回流疗法，它将使用一种名为反式丁酸钠的药物来恢复大脑的代谢供应，防止神经细胞的损失。这些研究的总体目标是测试这种新的治疗方法是否能有效地在中风期间保护大脑。

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.