Repurposing Azithromycin for premature brain injury

重新利用阿奇霉素治疗过早脑损伤

• 批准号: 10580029
• 负责人: Thomas Wood
• 金额: $ 43.37万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-19 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580029
• 关键词: 37 weeks gestation; Adult; Aftercare; Animal Model; Animals; Antibiotics; Antiinflammatory Effect; Asthma; Azithromycin; Behavioral; Birth; Blood - brain barrier anatomy; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cardiovascular Diseases; Cell Death; Cells; Cerebrovascular Disorders; Cessation of life; Childhood; Chronic; Clinical; Clinical Trials; Cognitive; Communities; Complex; DNA; Development; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Encephalopathies; Epigenetic Process; Erythropoietin; Extremely low gestational age newborn; FDA approved; Ferrets; Fluorescence-Activated Cell Sorting; Glucose; Glutathione; Health; Histologic; Human; Hyperoxia; Hypertension; Hypotension; Hypoxia; Hypoxic-Ischemic Brain Injury; Image; Immunohistochemistry; In Vitro; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemia; Ischemic Brain Injury; Laboratories; Lipid Peroxidation; Lipopolysaccharides; Live Birth; Long-Term Effects; Macrolides; Macrophage; Magnetic Resonance Imaging; Metabolic syndrome; Microglia; Modeling; Morbidity - disease rate; Motor; Myeloid Cells; Neonatal; Neonatal Mortality; Nervous System Trauma; Neurocognitive Deficit; Neurodevelopmental Impairment; Neuroprotective Agents; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidative Stress; Oxygen; Pathology; Patient-Focused Outcomes; Perinatal; Phagocytes; Pharmaceutical Preparations; Phenotype; Placenta; Populations at Risk; Pregnancy; Pregnant Women; Premature Birth; Premature Infant; Preterm brain injury; Publishing; Rattus; Resource-limited setting; Risk; Rodent; Rodent Model; Schizophrenia; Shotgun Sequencing; Site; Slice; Spinal cord injury; Stroke; Structure; Survivors; Work; behavior test; behavioral outcome; clinically relevant; deprivation; disability; glial activation; high risk population; immunoregulation; improved; improved outcome; injured; insight; migration; mortality; neuroprotection; novel strategies; oxidation; oxidative damage; postnatal; premature; stroke model; transcriptome; transcriptome sequencing; white matter

PROJECT SUMMARY/ABSTRACT Globally, prematurity is the leading cause of neonatal mortality. Prematurity is also on the rise in the U.S., with 9.93% of infants born preterm in 2017. This resulted in 382,851preterm births, more than 25,800 of whom were born before 28 weeks' gestation. This group, also known as extremely low gestational age newborns (ELGANs), is at a significant risk for poor outcomes; mortality in ELGANs is 10-20%, and up to 50% of survivors will have moderate or severe neurocognitive deficits in childhood. Preterm birth is commonly initiated by maternal infection or inflammation, and is often associated with additional perinatal insults including oxidative injury due to fluctuating hypoxia, hyperoxia, as well as ischemia and hypotension. These insults contribute to significant long- term neurodevelopmental impairment, which has remained essentially unchanged over the past decades. New approaches to treating the injured premature brain that improve outcomes and reduce long-term morbidity in ELGANs therefore remains a significant unmet clinical need. Azithromycin (AZ) is a macrolide antibiotic commonly prescribed to treat community-based infections. It is easy to administer, safe to use in pregnant women, and crosses both the placenta and blood brain barrier. AZ accumulates in phagocytes, providing a form of targeted drug delivery as phagocytes migrate to the site of infection or inflammation. AZ has anti-inflammatory effects, particularly modulating macrophages and microglia to a less inflammatory or injurious phenotype. This results in significant neuroprotection in experimental rodent models of stroke, spinal cord injury, and hypoxic- ischemic brain injury in neonatal rats. AZ is an attractive neuroprotectant as it is FDA approved, inexpensive, and safe. If it were to be found effective, it could be used in both high and low resource settings to improve outcomes of premature brain injury. The overarching objective of this proposal is to determine whether AZ provides long-term neuroprotection in a ferret model of inflammation-sensitized brain injury in ELGANs. Unlike the rodent, the ferret has a gyrified brain that is very similar to the human brain in terms of both development and structure. It is also amenable to long-term behavioral testing and complex imaging, making it ideal for investigating the short- and long-term effects of premature brain injury. The first aim will evaluate how AZ alters inflammation and oxidative stress, including microglial phenotype, in organotypic brain slices taken from the P12 ferret (26-28 weeks' gestation-equivalent). The second aim will examine the pharmacokinetics and short-term neuroprotective effects of single versus multiple doses of AZ in a P12 ferret model of inflammation- sensitized hypoxic-ischemic/hyperoxic (HIH) premature brain injury developed in our laboratory. The third aim will then examine the long-term effects of AZ treatment in the ferret HIH model, including behavioral outcomes, MRI, immunohistochemistry, and microglial phenotyping. Successful completion of the aims could support a clinical trial in this at-risk population for which no specific neuroprotective therapies are currently available.

项目摘要/摘要 在全球范围内，早产是新生儿死亡率的主要原因。在美国，早产也正在上升， 9.93％的婴儿在2017年出生。 出生于28周之前。这个群体，也称为极低的胎龄新生儿（Elgans）， 面临不良结果的风险很大； Elgans的死亡率为10-20％，最多50％的幸存者将拥有 儿童期中度或严重的神经认知缺陷。早产通常是由母体感染引发的 或炎症，通常与其他围产期损伤有关，包括由于氧化损伤 波动的缺氧，高氧以及缺血和低血压。这些侮辱有助于长期 在过去的几十年中，神经发育障碍术语基本上保持不变。新的 治疗受伤的早产大脑的方法，以改善预后并降低长期发病率 因此，Elgans仍然是巨大的未满足的临床需求。阿奇霉素（AZ）是一种大环内酯类抗生素 通常以治疗社区感染的规定。它易于管理，可以安全地用于怀孕 妇女，并越过胎盘和血脑屏障。 AZ积聚在吞噬细胞中，提供形式 作为吞噬细胞迁移到感染或炎症部位的靶向药物递送。 AZ具有抗炎 效果，尤其是调节巨噬细胞和小胶质细胞，以减少炎症或有害表型。这 在实验性啮齿动物模型，脊髓损伤和缺氧的实验啮齿动物模型中导致明显的神经保护作用。 新生大鼠缺血性脑损伤。 AZ是一种有吸引力的神经保护剂，因为它经过FDA批准，便宜， 安全。如果发现有效，则可以在高资源设置和低资源设置中使用 过早脑损伤的结果。该提议的总体目标是确定AZ是否是否 在Elgans炎症敏感的脑损伤的雪貂模型中提供长期神经保护作用。 与啮齿动物不同，雪貂的大脑与人脑非常相似 发展和结构。它也适合长期行为测试和复杂的成像，使其 研究过早脑损伤的短期和长期影响的理想选择。第一个目标将评估如何 AZ在器官脑切片中改变了炎症和氧化应激，包括小胶质表型 从p12雪貂（26-28周的妊娠期等效）。第二个目标将检查药代动力学和 在炎症的p12雪貂模型中，单剂量和多剂量AZ的短期神经保护作用 - 在我们的实验室中，敏化的低氧缺血/高氧（HIH）过早脑损伤。第三个目标 然后将检查AZ治疗在雪貂HIH模型中的长期影响，包括行为结果， MRI，免疫组织化学和小胶质表型。成功完成目标可以支持 目前没有特定神经保护疗法的高危人群中的临床试验。