Treatment of traumatic brain injury with vepoloxamer

维泊洛沙姆治疗颅脑损伤

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要创伤性脑损伤（TBI）是全世界死亡和残疾的主要原因。没有有效的治疗方法适用于 TBI 患者。因此，迫切需要开发新的治疗方法以改善 TBI 后的神经功能恢复。 TBI 后发生的众多继发性损伤事件中，脑损伤微血栓形成是继发性脑缺血和损伤的一个未被充分认识的但却重要的因素发生在 TBI 后，因此似乎是脑外伤后的主要继发事件之一设计治疗策略时请记住。脑微血栓不仅会导致脑缺血，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，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受控皮质冲击诱导 TBI 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，其中与肾脏相关的杂质功能障碍已被去除，是两亲性聚乙烯-聚丙烯-聚乙烯三嵌段据报道，这种共聚物可以密封膜并恢复受损细胞质膜的完整性。然而，迄今为止，关于维泊洛沙姆治疗 TBI 及其机制的信息还很少。其治疗作用的基础。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。我们的先前的研究表明，释放到血浆中的 vWF 水平在 1-4 小时内增加，在 1-3 小时达到峰值 CCI-TBI 后的大鼠中，第 8 天下降，第 15 天恢复正常。我们假设 TBI 诱导血脑屏障 (BBB) 损伤并释放内皮源性 vWF，从而导致血小板聚集和随后的脑微血栓引起的继发性损伤。在目标 1 中，我们将首先进行剂量探索研究，旨在确定维泊洛沙姆剂量和治疗窗对功能恢复的影响，而无需患有 TBI 的幼年大鼠（雄性和雌性）的毒性。在目标 2 中，我们将研究 IV 的机制维泊洛沙姆给药增强脑微血管灌注并促进功能恢复 TBI 后。将使用动态测量微血管完整性、脑血流量和 BBB 渗漏激光扫描共焦显微镜或磁共振成像 (MRI)。这项工作将解决一个以前没有研究过重要问题并且具有高度转化性。顺利完成本次提议研究将阐明 IV 维泊洛沙姆介导的 TBI 恢复促进机制促进维泊洛沙姆作为针对内皮细胞/微血栓的新型治疗方法的发展改善 TBI 患者的神经系统结果。