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.

项目总结/摘要 在全球范围内，早产是新生儿死亡的主要原因。美国的早产率也在上升，与 2017年早产儿占9.93%。这导致了382，851例早产，其中超过25，800例是早产。 在怀孕28周之前出生。这一组，也被称为极低胎龄新生儿（ELGAN）， 存在不良结局的重大风险; ELGAN的死亡率为10- 20%，高达50%的幸存者将有 儿童期中度或重度神经认知缺陷。早产通常是由母体感染引起的 或炎症，并且通常与额外的围产期损伤相关，包括由于 波动性缺氧、高氧以及缺血和低血压。这些侮辱导致了严重的长期- 长期神经发育障碍，在过去几十年中基本保持不变。新 治疗早产儿脑损伤的方法，可改善预后并降低长期发病率， 因此，ELGAN仍然是一个重要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 通常用于治疗社区感染。它易于管理，安全使用，在怀孕 妇女，并通过胎盘和血脑屏障。AZ在吞噬细胞中积累， 当吞噬细胞迁移到感染或炎症部位时，靶向药物输送的能力。AZ具有抗炎作用 作用，特别是将巨噬细胞和小胶质细胞调节为较少炎症或损伤的表型。这 在中风、脊髓损伤和缺氧的实验啮齿动物模型中产生显著的神经保护作用， 新生大鼠缺血性脑损伤。AZ是一种有吸引力的神经保护剂，因为它是FDA批准的，便宜， 和安全.如果它被认为是有效的，它可以用于高和低资源环境，以改善 过早脑损伤的后果。本提案的总体目标是确定AZ是否 在ELGAN的炎症致敏脑损伤的雪貂模型中提供长期神经保护。 与啮齿类动物不同，雪貂的脑回结构与人类的大脑非常相似， 发展和结构。它也可以进行长期的行为测试和复杂的成像， 是研究过早脑损伤的短期和长期影响的理想工具。第一个目标将评估如何 AZ改变器官型脑切片中的炎症和氧化应激，包括小胶质细胞表型 来自P12雪貂（相当于妊娠26-28周）。第二个目的是检查药代动力学， P12白鼬炎症模型中AZ单次与多次给药的短期神经保护作用- 致敏缺氧缺血/高氧（HIH）的过早脑损伤在我们的实验室发展。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细胞表型。成功完成这些目标可以支持 在目前尚无特异性神经保护疗法的高危人群中进行的临床试验。