Does perfluorocarbon attenuate the severity of SAH by limiting vasospasm and improving tissue oxygenation?

全氟化碳是否可以通过限制血管痉挛和改善组织氧合来减轻 SAH 的严重程度？

• 批准号: 10604708
• 负责人: Abdullah S Ahmad
• 金额: $ 22.8万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10604708
• 关键词: 3-Dimensional; Acute; Affect; Aftercare; Air; Air Embolism; Anatomy; Area; Attenuated; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain Injuries; Brain Pathology; Brain hemorrhage; Brain region; Caliber; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrovascular Spasm; Cerebrum; Clinical; Coagulation Process; Complex; Critical Care; Data; Development; Diffuse; Dose; Drug Kinetics; Drug usage; Early Intervention; Elements; Emulsions; Endothelium; Erythrocytes; Female; Fluorocarbons; Functional disorder; Future; Gases; Goals; Half-Life; Hemoglobin; Hour; Human; Human Resources; Hyperbaric Oxygen; Impairment; Ischemic Stroke; Lead; Lipids; Liquid substance; Methods; Mitochondria; Modeling; Molecular; Monitor; Mus; Nutrient; Outcome; Oxidative Stress; Oxygen; Oxygent; Partial Pressure; Particle Size; Pathologic; Pathology; Patient Care; Patients; Percussion; Perforation; Pharmacodynamics; Plasma; Play; Reporting; Research; Research Personnel; Residual state; Resolution; Risk; Rodent Model; Role; Safety; Severities; Solubility; Striated Muscles; Subarachnoid Hemorrhage; Supportive care; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Sample; Tissues; Training; Translating; Vasospasm; arteriole; base; care providers; cell motility; cerebral oxygenation; drug candidate; drug repurposing; efficacy testing; flexibility; functional outcomes; human data; improved; male; mitochondrial dysfunction; mortality; neuropathology; novel; optimal treatments; particle; pre-clinical; preclinical trial; pressure; prevent; primary outcome; therapeutically effective; tissue oxygenation; treatment strategy

Subarachnoid hemorrhage (SAH) is one of the deadliest of hemorrhagic stroke types; however, no effective therapeutic intervention is yet available, other than supportive care. Vasospasm is reported to trigger within the first three days after the onset of SAH and sustain for 1-2 weeks. The vasospasm results in delayed cerebral ischemia (DCI) which is considered as the main cause of mortality after SAH. Since vasospasm leads to a decrease in O2 level in the affected regions of the brain, novel methods to supply O2 to the compromised brain region could play a critical role in salvaging the area at risk. Hyperbaric oxygen/air therapy may have a beneficial effect in decreasing the pathophysiology of SAH by increasing dissolved tissue O2. However, such treatment is complex, time-limited (a few hours at a time), extensive monitoring, and trained personnel. Therefore, here we propose perfluorocarbon (PFC)-based emulsion Oxygent (referred to as PFC-Oxygent onwards), which increases dissolved O2 in blood and tissue. PFC-Oxygent is reported to have an extended half-life of about 3d. PFCs are emulsified compounds that can carry and release O2 fundamentally differently than does the hemoglobin. The particle size of these emulsions allows for PFCs to get to places where red blood cells are blocked such as capillaries affected in SAH. In a model of striated muscle and cerebral air embolism, we have shown that PFC-Oxygent increased cerebral blood flow and delivered O2 to the affected area even with little or no red cell movement. Moreover, in preclinical TBI, we showed that PFC-Oxygent augments cerebral O2 level. These data indicate the therapeutic potential of PFC-Oxygent in an acute cerebral pathology and its potential efficacy in SAH where cerebral vasospasm plays a vital role in the progression of pathological and functional outcomes. Since PFC is well tolerated in humans and the safety profile of this compound has already been tested, it is a prime candidate for drug repurposing. Here, we are testing the hypothesis that PFC-Oxygent treatment after SAH can increase O2 delivery to the compromised area after the SAH, attenuate oxidative stress, and improve pathological/functional outcomes. Aim 1: To test whether PFC rescues functional outcomes and neuropathology after SAH. This aim will test the effect of PFC-Oxygent on functional and anatomical outcomes after SAH in young and old male and female mice. Aim 2: To test whether PFC improves tissue oxygenation and cerebral blood flow following SAH. In this aim, we will test whether PFC improves local/global cerebral oxygenation, tissue sampled mitochondrial activity, and reduces oxidative stress after SAH. The proposed study will collectively provide the robustness of the therapeutic potential of this clinically used drug in SAH. Because most of the pharmacokinetics, pharmacodynamics, and safety of PFC-Oxygent is known, repurposing of this drug in regulating SAH outcomes would be expedited and of high translational value.

亚蛛网膜下腔出血（SAH）是最致命的中风类型之一。但是，无效 除支持护理外，还可以进行治疗干预。据报道，血管痉挛在 SAH发作并维持1-2周后的前三天。血管痉挛导致大脑延迟 缺血（DCI）被认为是SAH后死亡率的主要原因。由于血管痉挛导致 大脑受影响区域的O2水平降低，向损害大脑供应O2的新方法 区域在挽救面临风险的地区可能发挥关键作用。 高压氧/空气疗法可能对降低SAH的病理生理学具有有益的作用 增加溶解的组织O2。但是，这种治疗是复杂的，限时的（一次几个小时）， 广泛的监控和训练有素的人员。因此，在这里我们提出了基于全氟的（PFC） 乳液氧（称为PFC氧气开始），这会增加血液和组织中的O2溶解。 据报道，PFC氧的半衰期约为3D。 PFC是乳化化合物，可以 携带和释放的O2从根本上不同于血红蛋白。这些乳液的粒径 允许PFC到达被红细胞阻塞的地方，例如在SAH中受到影响的毛细血管。 在横纹肌肉和大脑空气栓塞模型中，我们已经表明PFC氧气增加了大脑 即使很少或没有红细胞运动，血流并将O2传递到受影响区域。而且，在临床前 TBI，我们表明pFC氧增强大脑O2水平。这些数据表明 急性脑病理学中的PFC氧及其在SAH中的潜在功效，其中大脑血管痉挛发挥作用 在病理和功能结果的进展中至关重要的作用。由于PFC在人类中的耐受性很好 而且该化合物的安全性概况已经进行了测试，它是药物重新使用的主要候选人。 在这里，我们正在测试以下假设：SAH后的PFC氧化治疗可以增加O2的递送 SAH后损害的区域，减轻氧化应激并改善病理/功能结果。 目标1：测试PFC是否在SAH后是否挽救功能结果和神经病理学。这个目标将测试 PFC氧对SAH的功能和解剖结局的影响 老鼠。 目标2：测试PFC是否改善了SAH后的组织氧合和脑血流。在这个目标中，我们 将测试PFC是否可以改善局部/全球脑充氧，组织采样线粒体活性和 SAH后减少氧化应激。 拟议的研究将共同​​提供该临床使用药物的治疗潜力的鲁棒性 在SAH。由于已知的大多数药代动力学，药物动力学和安全性，因此已知 在调节SAH结果中，将这种药物重新利用将是加快的，并且具有很高的翻译价值。