Treatment of traumatic brain injury with vepoloxamer

维泊洛沙姆治疗颅脑损伤

• 批准号: 9814366
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9814366
• 关键词: Address; Affect; Blood; Blood - brain barrier anatomy; Blood Platelets; Brain; Brain Injuries; Brain Ischemia; Cause of Death; Cell Death; Cell membrane; Cerebrovascular Circulation; Cerebrum; Cleaved cell; Clinical; Clinical Trials; Cognitive; Contusions; Development; Disintegrins; Dose; Endothelial Cells; Endothelium; Environment; Event; Experimental Models; Extravasation; Female; Goals; Heart failure; Hour; Human; Imaging technology; Injury; Intravenous; Ischemia; Laser Scanning Confocal Microscopy; Lead; Magnetic Resonance Imaging; Measures; Mechanics; Mediating; Membrane; Metalloproteases; Mind; Muscular Dystrophies; Nerve Degeneration; Neurological outcome; Outcome; Patients; Perfusion; Permeability; Pharmaceutical Preparations; Plasma; Platelet Activation; Platelet aggregation; Poloxamer 188; Polyethylenes; Polypropylenes; Quality of life; Rattus; Recovery of Function; Reporting; Research; Secondary to; Sensorimotor functions; Testing; Therapeutic; Therapeutic Effect; Thrombosis; Thrombospondins; Tissues; Toxic effect; Traumatic Brain Injury; Traumatic Brain Injury recovery; Treatment Efficacy; Ursidae Family; Work; amphiphilicity; cell injury; controlled cortical impact; copolymer; disability; effective therapy; 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.

项目总结/摘要 创伤性脑损伤（TBI）是世界范围内死亡和残疾的主要原因。没有有效的治疗方法 可用于TBI患者。因此，迫切需要开发新的治疗剂，以改善患者的免疫功能。 TBI后的神经恢复在TBI后发生的许多继发性损伤事件中，脑损伤是最常见的。 微血栓形成是继发性脑缺血和脑损伤的重要因素， 这发生在TBI之后，因此似乎是脑外伤后的中心继发事件之一， 在设计治疗策略时要牢记。脑微血栓不仅导致缺血和细胞凋亡， 死亡，但也阻止治疗药物进入受影响的大脑，因此限制了 治疗药物的有效性，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（损伤后2小时）静脉注射维泊洛沙姆可促进 控制性皮质撞击诱导脑外伤后感觉运动功能和认知功能恢复 （CCI-TBI），这与其减少脑微血栓形成的强大作用有关， 神经炎症维泊洛沙姆是泊洛沙姆188的纯化形式，其中杂质与肾脏相关 功能障碍已被删除，这是一个两亲性聚乙烯-聚丙烯-聚乙烯三嵌段 据报道，该共聚物可密封膜并恢复受损细胞中的质膜完整性。 然而，到目前为止，关于维泊洛沙姆治疗TBI及其机制的信息还很少。 其治疗效果的基础。血管性血友病因子（vWF）从受损的内皮细胞释放到血液中 与严重TBI的临床结果呈负相关。vWF可诱导微血栓形成。我们 先前的研究表明，释放到血浆中的vWF水平在1-4小时增加，在1-3小时达到峰值， 在CCI-TBI大鼠中，在第8天下降，并且在第15天恢复正常。我们假设创伤性脑损伤 诱导血脑屏障（BBB）损伤和内皮源性vWF的释放，这导致血小板聚集。 聚集和随后的脑微血栓形成引起的继发性损伤。在目标1中，我们将首先进行 剂量探索研究，以确定维泊洛沙姆剂量和治疗窗对功能恢复的影响， TBI幼鼠（雄性和雌性）的毒性。在目标2中，我们将研究IV 给予维泊洛沙姆增强脑微血管灌注并促进功能恢复 脑外伤后。微血管完整性、脑血流量和BBB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 以前未充分研究的重要问题，是高度翻译。圆满完成本次拟 研究将阐明IV维泊洛沙姆介导的促进TBI恢复的潜在机制， 促进Vepoloxamer作为靶向内皮细胞/微血栓的新型治疗方法的开发 以改善TBI患者的神经功能结局。