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

摘要 创伤性脑损伤(TBI)是一个主要的健康问题，占美国所有与伤害相关的死亡人数的三分之一。 美国和70%的长期残疾幸存者。几十年来，TBI的研究几乎完全集中在 在神经保护策略上，未能开发出任何用于临床治疗的疗法。少了一次探索 潜在的目标是大脑循环。在脑损伤中，越来越多的人认识到挫伤周围地区 脑挫裂伤患者出现微血管衰竭、弥漫性缺氧和水肿。我们对微血管分流的研究 合并高颅内压的(MVS)证实微循环衰竭。我们在此建议调整 血液可溶性减阻聚合物(DRP)治疗颅脑损伤的血流动力学研究 专门针对大脑微循环和基于物理但不是药理原理的药物。 纳摩尔剂量的静脉注射DRP通过减少血流分离减少小动脉的血压损失 血管分叉处的微涡，增加了毛细血管前压力和功能毛细血管的密度。 血管壁剪切率的增加可能会减少巨噬细胞的跨毛细血管迁移和炎症。我们 结果表明，静脉注射DRP(ED70)140微克/公斤可增加脑小动脉的血流速度，降低 MVS，恢复毛细血管灌流，减少脑损伤大鼠组织缺氧。已注入30 就在侮辱发生几分钟后。下一个合乎逻辑的步骤，也是我们的目标，是对剂量进行全面研究 以及DRP的时间相关疗效，并探讨其治疗机制。中心假设：DRP， 通过其对脑血管微循环的一般剂量依赖作用，可呈现出独特的和 颅脑损伤的有效治疗方法，适用于早期和晚期。其基本原理是，与其他脑外伤疗法不同 到目前为止，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 颅脑损伤后DRP对远期康复的最大疗效并首次提供治疗干预 即使在受伤后推迟几个小时，这也可能是有效的。采用大鼠侧向液压冲击伤模型， 我们将致力于两个目标：1)研究DRP的急性剂量依赖效应的时程和相对 利用体内双光子技术研究脑微血管血流的变化，即MVS、组织氧合和代谢 中、重度颅脑损伤后的激光显微镜和激光散斑成像；2)确定最佳剂量 和DRP的治疗时间窗，用于临床相关的长期结果和机制 磁共振成像、行为测试和组织学，流变学可能的抗炎作用 通过酶联免疫吸附试验和免疫组织化学方法对其调节作用进行评价。为了遵守NIH的要求，研究将 对两种性别都进行检查，以评估可能的性别差异。拟议的研究具有重要意义，因为 它将为靶向受损的脑损伤提供首个非药物流变学治疗 并将揭示脑外伤血流相关的发病机制和恢复机制。

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.