Treatment of traumatic brain injury with vepoloxamer

维泊洛沙姆治疗颅脑损伤

• 批准号: 10621791
• 负责人: Yanlu Zhang
• 金额: $ 32.92万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621791
• 关键词: Affect; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Injuries; Brain Ischemia; Cause of Death; Cell Death; Cell membrane; Cerebrovascular Circulation; Cerebrum; Clinical; Clinical Trials; Cognitive; Contusions; Development; Disintegrins; Dose; Endothelial Cells; Endothelium; Environment; Event; Experimental Models; Extravasation; Female; Goals; Heart failure; Hour; Human; Injury; Intravenous; Ischemia; Laser Scanning Confocal Microscopy; Lead; Magnetic Resonance Imaging; Measures; Mechanics; Mediating; Membrane; Metalloproteases; Muscular Dystrophies; Neurodegenerative Disorders; Neurological outcome; Outcome; Perfusion; Pharmaceutical Preparations; Plasma; Platelet Activation; Platelet aggregation; Poloxamer 188; Polyethylenes; Polypropylenes; Quality of life; Rattus; Recovery of Function; Reporting; Research; Secondary to; Sensorimotor functions; TBI Patients; TBI treatment; Technology; Testing; Therapeutic; Therapeutic Effect; Thrombosis; Thrombospondins; Thrombus; Tissues; Toxic effect; Traumatic Brain Injury; Traumatic Brain Injury recovery; Treatment Efficacy; Work; amphiphilicity; blood-brain barrier permeabilization; cell injury; controlled cortical impact; copolymer; disability; effective therapy; efficacy evaluation; electrical injury; improved; in vivo; injured; intravenous administration; kidney dysfunction; male; mortality; neuroinflammation; neurological recovery; neuron loss; neuroprotection; neurorestoration; novel strategies; novel therapeutic intervention; novel therapeutics; preclinical trial; preservation; prevent; release factor; seal; therapy design; treatment strategy; von Willebrand Factor

PROJECT SUMMARY/ABSTRACT Traumatic brain injury (TBI) is a major cause of death and disability worldwide. There are no effective therapies available for TBI patients. Thus, there is a compelling need to develop novel therapeutics in order to improve neurological recovery after TBI. Among many secondary injury events that occur after TBI, cerebral microthrombosis is an under-recognized, yet important contributor to the secondary brain ischemia and damage that occurs after TBI, and would therefore seem to be one of the central secondary events after brain trauma to bear in mind when designing treatment strategies. Cerebral microthrombi not only lead to ischemia and cell death but also prevent therapeutic drugs from entering into the affected brain and therefore constrain the efficacy of therapeutic drugs, which may be one of important factors ignored during preclinical and clinical trials. Our recent study indicates that early (2 hours post injury) intravenous administration of Vepoloxamer promotes sensorimotor function and cognitive functional recovery after TBI induced by controlled cortical impact (CCI-TBI), which is associated with its robust effect on reducing cerebral microthrombosis formation and neuroinflammation. Vepoloxamer is a purified form of Poloxamer 188 where impurities associated with renal dysfunction have been removed, which is an amphiphilic polyethylene-polypropylene-polyethylene tri-block copolymer that is reported to seal membranes and restore plasma membrane integrity in damaged cells. However, to date, there is a paucity of information about Vepoloxamer for treatment of TBI and the mechanisms underlying its therapeutic effects. von Willebrand factor (vWF) released into blood from injured endothelial cells inversely correlates with clinical outcome of severe TBI. vWF can induce microthrombosis formation. Our previous study demonstrated that the level of vWF released into plasma increases at 1-4 hours, peaks at 1-3 days, declines at 8 days, and returns to normal at 15 days in rats after CCI-TBI. We hypothesize that TBI induces the blood-brain barrier (BBB) damage and release of endothelial-derived vWF, which leads to platelet aggregate and subsequent cerebral microthrombosis-induced secondary injury. In Aim 1, we will first conduct a dose-finding study to identify Vepoloxamer dose and therapeutic window effect on functional recovery without toxicity in young rats (male and female) with TBI. In Aim 2, we will then investigate the mechanisms by which IV administration of Vepoloxamer enhances cerebral microvascular perfusion and promotes functional recovery after TBI. Microvascular integrity, cerebral blood flow, and BBB leakage will be measured dynamically using either laser scanning confocal microscopy or magnetic resonance imaging (MRI). This work will address a previously understudied important issue and is highly translational. Successful completion of this proposed research will elucidate mechanisms underlying IV Vepoloxamer-mediated promotion of TBI recovery, and facilitate development of Vepoloxamer as a novel therapeutic approach targeting endothelial cells/microthrombi to improve neurological outcome for TBI patients.

项目摘要/摘要 创伤性脑损伤是世界范围内死亡和致残的主要原因。目前还没有有效的治疗方法 适用于脑外伤患者。因此，迫切需要开发新的治疗方法，以改善 颅脑损伤后神经功能恢复情况。在颅脑损伤后发生的许多继发性损伤事件中，脑部 微血栓形成是继发性脑缺血和损伤的重要因素，但尚未得到充分认识。 这发生在脑外伤后，因此似乎是脑创伤后的中心继发性事件之一。 设计治疗策略时要牢记这一点。脑微血栓不仅导致脑缺血和细胞 死亡，但也阻止治疗药物进入受影响的大脑，从而限制 治疗药物的疗效，这可能是临床前和临床试验中被忽视的重要因素之一。 我们最近的研究表明，早期(受伤后2小时)静脉注射维泊洛沙姆可促进 控制性皮质撞击致颅脑损伤后感觉运动功能和认知功能恢复 (CCI-TBI)，这与其在减少脑微血栓形成和 神经炎。维泊洛沙姆是泊洛沙姆188的一种纯化形式，其中与肾脏相关的杂质 功能已被去除，这是一种两亲性的聚乙烯-聚丙烯-聚乙烯三嵌段 据报道，这种共聚物可以密封细胞膜，恢复受损细胞的质膜完整性。 然而，到目前为止，关于维泊洛沙姆治疗颅脑损伤及其机制的信息还很少。 潜在的治疗效果。血管性血友病因子(VWF)从受损内皮细胞释放到血液中 与重型颅脑损伤的临床转归呈负相关。VWF可诱导微血栓形成。我们的 先前的研究表明，vWF释放到血浆中的水平在1-4小时内增加，在1-3小时达到峰值 大鼠CCI-TBI后8天开始下降，15天恢复正常。我们假设TBI 诱导血脑屏障损伤，释放内皮源性vWF，导致血小板 聚集体和随后的脑微血栓形成导致的继发性损伤。在目标1中，我们将首先进行 剂量发现研究确定维泊洛沙姆的剂量和治疗窗对功能恢复的影响 脑外伤幼鼠(雌雄)的毒性。在目标2中，我们将研究IV 维泊洛沙姆增强脑微血管灌注促进功能恢复 在TBI之后。微血管完整性、脑血流量和血脑屏障渗漏将使用 激光扫描共聚焦显微镜或磁共振成像(MRI)。这项工作将解决一个 以前对重要问题的研究不足，具有很高的翻译性。圆满完成这项建议 研究将阐明静脉维泊洛沙姆促进创伤性脑损伤恢复的潜在机制，以及 促进维泊洛沙姆作为靶向内皮细胞/微血栓的新治疗方法的开发 目的：改善脑外伤患者的神经预后。