Brain Injury Treatment by Modulation of Hemodynamics with Blood Soluble Drag Reducing Molecules

用血溶性减阻分子调节血流动力学治疗脑损伤

• 批准号: 10470005
• 负责人: Denis E. Bragin
• 金额: $ 29.13万
• 依托单位: LOVELACE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470005
• 关键词: Acute; Address; Anatomy; Antiinflammatory Effect; Area; Arteries; Astrocytes; Autopsy; Blood; Blood Circulation; Blood Flow Velocity; Blood Vessels; Blood Volume; Blood capillaries; Blood flow; Brain; Brain Injuries; Cells; Cerebrovascular Circulation; Cerebrum; Chronic; Clinical; Clinical Treatment; Contusions; Core-Binding Factor; Development; Diffuse; Diffuse Brain Injury; Diffusion; Dose; Edema; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Failure; Female; Gender; Glucose; Goals; Health; Histology; Homeostasis; Hour; Hypoxia; Immune; Immunohistochemistry; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Intracranial Pressure; Intravenous; Knowledge; Laser Microscopy; Laser Scanning Microscopy; Laser Speckle Imaging; Lateral; Liquid substance; Magnetic Resonance Imaging; Metabolic; Metabolism; Microcirculation; Microglia; Mission; Modality; Modeling; NADH; Neurological outcome; Outcome; Oxygen; Pathogenesis; Pathologic; Pathology; Perfusion; Physiological; Polymers; Process; Property; Public Health; Rattus; Recovery; Research; Sampling; Serum; Severities; Shunt Device; Stroke; Survivors; TBI treatment; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Sample; Tissues; Translations; Traumatic Brain Injury; Treatment Efficacy; United States; United States National Institutes of Health; arteriole; base; behavior test; blood pressure reduction; blood-brain barrier permeabilization; brain tissue; cerebrovascular; chemokine; clinically relevant; cytokine; density; disability; effective therapy; fluid percussion injury; hemodynamics; improved; in vivo; injury-related death; macrophage; male; metabolic rate; migration; mortality; nanomolar; neurological recovery; novel; novel therapeutic intervention; nutrient deprivation; pressure; receptor; recruit; sex; stroke patient; tissue oxygenation; two-photon

Abstract Traumatic brain injury (TBI) is a major health problem, representing a third of all injury-related deaths in the United States and 70% of long-term disabilities in survivors. Decades of TBI research focused almost exclusively on neuroprotective strategies, has failed to develop any therapeutics for clinical treatment. One less explored potential target is the cerebral circulation. In TBI, there is increasing recognition that the peri-contusional areas of TBI suffer microvascular failure and diffusional hypoxia and edema. Our studies on microvascular shunts (MVS) with high intracranial pressure (ICP) corroborate microcirculatory failure. We propose here modulation of hemodynamics with blood soluble drag reducing polymers (DRP) as a novel treatment modality for TBI that specifically targets cerebral microcirculation and that based on physical but not pharmacological principles. Nanomolar amounts of intravenous DRP reduce blood pressure loss in arterioles by diminishing flow separations and microvortices at vessel bifurcations, increase precapillary pressure and the density of functioning capillaries. Increased vascular wall shear rate may reduce transcapillary macrophage migration and inflammation. We showed that 140 µg/kg of intravenous DRP (ED70) increased blood flow velocity in cerebral arterioles, reduced MVS, restored perfusion in capillaries and reduced tissue hypoxia in a rat model of TBI when i.v. injected 30 minutes after the insult. The next logical step, our objective, is to perform a comprehensive study of the dose and time-related efficacy of DRP and to examine the therapeutic mechanisms involved. Central hypothesis: DRP, through their general dose-dependent action on cerebrovascular microcirculation, can present a unique and effective therapy for TBI, applicable at both, early and later time. The rationale is that unlike other TBI therapies tested thus far, the hemorheological effects of DRP are independent of tissue status in terms of tissue or vascular receptor reactivity or sensitivity for its mechanism of action. Our long-term goal is to optimize the application of DRP after TBI for maximal efficacy on long-term recovery and provide for the first time, a therapeutic intervention that may be effective even if delayed hours after injury. Using the lateral fluid percussion injury TBI model in rats, we will address two aims: 1) to study the acute dose-dependent effects of DRP on the time course and relative changes in cerebral microvascular flow, i.e. MVS, tissue oxygenation and metabolism using in-vivo 2-photon laser microscopy and laser speckle imaging after moderate and severe TBI; and 2) to define the optimal dose and therapeutic time window of DRP for clinically relevant long-term outcomes and mechanisms involved using magnetic resonance imaging, behavioral testing and histology, possible anti-inflammatory effects of rheological modulation will be evaluated by ELISA and immunohistochemistry. To comply with NIH requirement, studies will be done on both sexes to evaluate possible female/male differences. The proposed research is significant since it will provide the first non-pharmacologic rheological treatment for TBI targeting impaired cerebral microcirculation and will reveal the blood flow-related pathogenesis and recovery mechanisms in TBI.

摘要 创伤性脑损伤（TBI）是一个主要的健康问题，占美国所有与损伤相关的死亡的三分之一。 美国70%的长期残疾幸存者。数十年的TBI研究几乎完全集中在 在神经保护策略方面，未能开发出任何用于临床治疗的治疗方法。少探索一个 潜在的靶点是脑循环。在TBI中，越来越多的人认识到， TBI的患者出现微血管功能衰竭和弥漫性缺氧水肿。微血管分流的研究 (MVS)高颅内压（ICP）证实微循环衰竭。我们在这里建议调制 血液动力学与血溶性减阻聚合物（DRP）作为一种新的治疗模式TBI， 特异性靶向脑微循环和基于物理而非药理学原理的治疗。 纳摩尔量的静脉注射DRP通过减少流动分离来减少小动脉中的血压损失 和微涡旋，增加毛细血管前压力和功能性毛细血管的密度。 增加血管壁剪切率可以减少跨毛细血管巨噬细胞迁移和炎症。我们 结果显示，140 µg/kg静脉注射DRP（ED 70）可增加脑小动脉血流速度， 当静脉注射30 μ l MVS时， 几分钟后，侮辱。下一步，我们的目标，是对剂量进行全面研究。 和时间相关的疗效，并检查所涉及的治疗机制。中心假设：DRP， 通过其对脑血管微循环的一般剂量依赖性作用，可以呈现独特的， 有效治疗TBI，适用于早期和晚期。理由是，与其他TBI疗法不同， 到目前为止，经测试，DRP的血液流变学效应与组织或血管的组织状态无关。 受体反应性或敏感性的作用机制。我们的长期目标是优化 TBI后DRP对长期恢复的最大疗效，并首次提供治疗干预 即使在受伤后延迟数小时也可能有效。采用大鼠侧位液压冲击伤TBI模型， 我们将致力于两个目标：1）研究DRP对时间过程和相对时间的急性剂量依赖性效应。 脑微血管流量的变化，即MVS、组织氧合和使用体内2-光子的代谢 中度和重度TBI后的激光显微镜和激光散斑成像;以及2）确定最佳剂量 DRP的临床相关长期结局和机制的治疗时间窗 磁共振成像，行为测试和组织学，流变学可能的抗炎作用 将通过ELISA和免疫组织化学评价调节。为了符合NIH的要求，研究将 对两性进行测试，以评估可能的女性/男性差异。这项研究意义重大，因为 它将为TBI提供第一个非药物流变学治疗， 微循环，并将揭示TBI中与血流相关的发病机制和恢复机制。