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，没有效果