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: 9803305
• 负责人: Denis E. Bragin
• 金额: $ 4.38万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 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 2019-11-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9803305
• 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; Cessation of life; 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; Permeability; Physiological; Polymers; Process; Property; Public Health; Rattus; Recovery; Research; Sampling; Serum; Severities; Shunt Device; Stroke; Survivors; 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; brain tissue; cerebrovascular; chemokine; clinically relevant; cytokine; density; disability; effective therapy; fluid percussion injury; hemodynamics; improved; in vivo; 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.

抽象的 创伤性脑损伤 (TBI) 是一个主要的健康问题，占美国所有伤害相关死亡的三分之一 美国70%的幸存者长期残疾。数十年的 TBI 研究几乎完全集中于 在神经保护策略方面，未能开发出任何用于临床治疗的疗法。少探索一处 潜在目标是脑循环。在 TBI 中，人们越来越认识到挫伤周围区域 TBI 患者遭受微血管衰竭和弥散性缺氧和水肿。我们对微血管分流的研究 (MVS) 与高颅内压 (ICP) 证实微循环衰竭。我们在这里建议调制 血流动力学减阻聚合物（DRP）作为 TBI 的新型治疗方式 专门针对大脑微循环，并且基于物理原理而不是药理学原理。 纳摩尔量的静脉注射 DRP 通过减少血流分离来减少小动脉血压损失 和血管分叉处的微涡流，增加毛细血管前压力和功能毛细血管的密度。 血管壁剪切率增加可能会减少跨毛细血管巨噬细胞迁移和炎症。我们 结果表明，140 µg/kg 静脉注射 DRP (ED70) 可增加脑小动脉的血流速度，降低 MVS，在 TBI 大鼠模型中，静脉注射时可恢复毛细血管灌注并减少组织缺氧。注射30 侮辱后几分钟。下一个合乎逻辑的步骤，即我们的目标，是对剂量进行全面研究 以及 DRP 与时间相关的疗效，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，可以呈现出独特且 TBI 的有效疗法，早期和晚期均适用。其基本原理是，与其他 TBI 疗法不同 迄今为止的测试表明，DRP 的血液流变学效应与组织或血管方面的组织状态无关。 受体对其作用机制的反应性或敏感性。我们的长期目标是优化应用 TBI 后的 DRP 对长期恢复具有最大功效，并首次提供治疗干预 即使在受伤后延迟数小时，这也可能有效。采用大鼠侧方液体冲击损伤TBI模型， 我们将实现两个目标：1）研究 DRP 对时间进程和相对剂量的急性剂量依赖性影响 使用体内 2 光子改变脑微血管流量，即 MVS、组织氧合和代谢 中度和重度 TBI 后的激光显微镜和激光散斑成像； 2) 确定最佳剂量 DRP 的临床相关长期结果和治疗时间窗以及涉及使用的机制 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 和免疫组织化学评估调节。为了符合 NIH 的要求，研究将 对两性进行评估，以评估可能的女性/男性差异。拟议的研究意义重大，因为 它将为针对受损大脑的 TBI 提供第一种非药物流变治疗 微循环，并将揭示 TBI 中与血流相关的发病机制和恢复机制。