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）是最致命的出血性中风类型之一;然而，没有有效的 除了支持性护理外，目前还可以进行治疗性干预。据报道，血管痉挛是在 在SAH发作后的前三天，并持续1-2周。脑血管痉挛导致大脑 脑缺血（DCI）是SAH后死亡的主要原因。由于血管痉挛导致 大脑受影响区域的O2水平下降，为受损大脑提供O2的新方法 该区域可以在拯救处于危险中的地区方面发挥关键作用。 高压氧/空气治疗可能通过以下方式在减少SAH的病理生理学方面具有有益效果： 增加溶解的组织O2。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，在这里，我们提出了基于全氟化碳（PFC）的 乳剂Oxygent（以后称为PFC Oxygent），可增加血液和组织中的溶解O2。 据报告，PFC-Oxygent具有约3天的延长半衰期。PFC是乳化化合物， 携带和释放氧气的方式与血红蛋白完全不同。这些乳剂的颗粒大小 允许PFC到达红细胞被阻塞的地方，如SAH中受影响的毛细血管。 在横纹肌和脑空气栓塞模型中，我们已经证明PFC-Oxygent增加了脑动脉栓塞， 即使红细胞很少或没有移动，血液流动和输送O2到受影响的区域。此外，在临床前 TBI，我们发现PFC-Oxygent增加了大脑O2水平。这些数据表明， PFC-Oxygent在急性脑病理学中的作用及其在脑血管痉挛起作用的SAH中的潜在疗效 在病理和功能结果的进展中起重要作用。由于PFC在人类中耐受良好 这种化合物的安全性已经过测试，它是药物再利用的主要候选者。 在这里，我们正在测试的假设，即PFC氧合治疗后SAH可以增加O2输送到 SAH后受损区域，减弱氧化应激，并改善病理/功能结果。 目的1：测试PFC是否挽救SAH后的功能结局和神经病理学。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果影响 小鼠 目的2：检测PFC是否改善SAH后的组织氧合和脑血流量。为此，我们 将测试PFC是否改善局部/整体脑氧合，组织采样线粒体活性， 减少SAH后的氧化应激。 拟定研究将共同提供该临床使用药物治疗潜力的稳健性 在SAH。因为PFC-Oxygent的大部分药代动力学、药效学和安全性是已知的， 这种药物在调节SAH结果中的再利用将被加速并且具有高转化价值。