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.

蛛网膜下腔出血(SAH)是出血性中风中最致命的类型之一；然而，没有有效的治疗方法 除了支持性护理之外，目前还可以进行治疗干预。据报道，血管痉挛是在 SAH起病后三天开始治疗，持续1-2周。血管痉挛导致迟发性脑缺血 缺血(DCI)被认为是SAH后死亡的主要原因。因为血管痉挛会导致 降低大脑受影响区域的氧气水平，为受损的大脑提供氧气的新方法 该地区可以在挽救处于危险中的地区方面发挥关键作用。 高压氧/空气疗法可能通过以下方式在减轻SAH的病理生理方面起到有益作用 增加溶解组织的氧气。然而，这种治疗是复杂的、有时间限制的(一次几个小时)， 广泛的监测和训练有素的人员。因此，我们在这里提出了基于全氟碳(PFC)的 乳剂含氧剂(简称PFC-含氧剂)，可增加血液和组织中的溶解氧。 据报道，PFC-Oxygent的延长半衰期约为3d。全氟碳化物是一种乳化化合物，可以 携带和释放氧气从根本上不同于血红蛋白。这些乳剂的颗粒大小 允许PFC到达红细胞受阻的地方，例如受SAH影响的毛细血管。 在横纹肌和脑空气栓塞的模型中，我们已经表明PFC-Oxygent增加了大脑 血液流动，并将氧气输送到受影响的区域，即使红细胞很少或没有运动。此外，在临床前阶段 TBI，我们发现PFC-Oxygent可以增加大脑O2水平。这些数据表明， PFC-Oxy在急性脑病理中的作用及其对脑血管痉挛的SAH的潜在疗效 在病理和功能结果的进展中起着至关重要的作用。由于人类对PFC的耐受性很好 而且这种化合物的安全性已经过测试，它是药物再利用的首选候选药物。 在这里，我们正在验证这样的假设，即SAH后PFC-Oxy治疗可以增加向脑组织的氧气输送 SAH后受损区域，减轻氧化应激，改善病理/功能结局。 目的1：检测PFC能否挽救蛛网膜下腔出血后的功能结局和神经病理。这一目标将考验 PFC氧合剂对青年和老年男女蛛网膜下腔出血后功能和解剖结局的影响 老鼠。 目的2：检测PFC能否改善蛛网膜下腔出血后的组织氧合和脑血流量。为了实现这一目标，我们 将测试PFC是否改善局部/整体脑氧合，组织样本线粒体活性，以及 减少蛛网膜下腔出血后的氧化应激。 拟议中的研究将共同提供这种临床使用药物的治疗潜力的健壮性。 在SAH。因为PFC-Oxygent的大部分药代动力学、药效学和安全性都是已知的， 这种药物在调节SAH结果方面的重新用途将会加快，并具有很高的翻译价值。