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.

抽象的 创伤性脑损伤（TBI）是一个主要的健康问题，代表所有与伤害有关的死亡的三分之一 美国和70％的生存疾病。数十年的TBI研究几乎完全关注 关于神经保护策略，未能开发任何用于临床治疗的治疗剂。一个少探索 潜在目标是大脑循环。在TBI中，人们越来越认识到围绕围绕的区域 TBI遭受微血管衰竭和扩散性缺氧和水肿。我们关于微血管分流的研究 （MVS）具有高颅内压（ICP）佐证的微循环衰竭。我们在这里提议调制 血液动力学与血液固体阻力还原聚合物（DRP）作为TBI的新型治疗方式 特别针对脑微循环，并基于物理但不是药物原理。 通过减少流动分离，纳摩尔量的静脉内DRP降低了动脉的血压损失 在血管分叉处的微胎面，增加毛细血管前压力和功能毛细血管的密度。 血管壁剪切速率的提高可能会减少经毛细管巨噬细胞的迁移和炎症。我们 表明140 µg/kg静脉内DRP（ED70）增加了脑小动脉的血流速度，还原 MVS，毛细血管中的灌注恢复，在静脉注射时大鼠模型中的组织缺氧减少了组织缺氧。注射30 侮辱后几分钟。我们的目标是下一个逻辑步骤，是对剂量进行全面研究 DRP的时间相关效率并检查所涉及的治疗机制。中央假设：DRP， 通过它们对脑血管微循环的一般剂量依赖性作用，可以提出独特的和 TBI的有效疗法，适用于早期和较晚时间。理由是与其他TBI疗法不同 迄今为止，在组织或血管方面进行了测试，DRP的出血作用与组织状态无关 受体反应性或对其作用机理的敏感性。我们的长期目标是优化 TBI之后的DRP可在长期恢复方面的最大效率，并首次提供治疗干预措施 即使受伤后延迟数小时，这也可能有效。使用大鼠的侧液打击乐损伤TBI模型 我们将解决两个目的：1）研究DRP对时间过程和相对的急性剂量依赖性影响 脑微血管流动的变化，即MVS，组织氧合和代谢使用体内2-光子 中度和重度TBI后激光显微镜和激光斑点成像； 2）定义最佳剂量 DRP的热时间窗口用于临床相关的长期结果和使用的机制 磁共振成像，行为测试和组织学，流变学可能的抗炎作用 调节将通过ELISA和免疫组织化学评估。为了符合NIH的要求，研究将 在两个性别上都可以评估可能的女性/男性差异。拟议的研究很重要，因为 它将为TBI靶向大脑的第一种非药理学治疗方法 微循环将揭示与血流相关的发病机理和TBI中的恢复机制。