Repurposing Azithromycin for premature brain injury

重新利用阿奇霉素治疗过早脑损伤

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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， 2017年，9.93%的婴儿早产。这导致早产儿382,851人，其中超过25,800人是早产儿妊娠28周前出生。该群体也称为极低胎龄新生儿 (ELGAN)，面临不良结果的重大风险； ELGAN 的死亡率为 10-20%，高达 50% 的幸存者将患有儿童期中度或重度神经认知缺陷。早产通常是由产妇感染引起的或炎症，并且通常与额外的围产期损伤相关，包括由于氧化损伤波动性缺氧、高氧以及缺血和低血压。这些侮辱导致了严重的长期术语“神经发育障碍”在过去几十年中基本保持不变。新的治疗早产大脑损伤的方法可以改善结果并减少长期发病率因此，ELGAN 仍然是一个重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用于治疗社区感染。服用方便，孕妇可以安全使用女性，并穿过胎盘和血脑屏障。 AZ 在吞噬细胞中积累，提供一种形式当吞噬细胞迁移到感染或炎症部位时，靶向药物输送的过程。 AZ具有抗炎作用作用，特别是调节巨噬细胞和小胶质细胞以减少炎症或损伤性表型。这在中风、脊髓损伤和缺氧的实验啮齿动物模型中产生显着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，因为它已获得 FDA 批准，价格便宜，和安全。如果发现它有效，则可以在资源丰富和资源匮乏的情况下使用它来改善过早脑损伤的结果。该提案的总体目标是确定 AZ 是否 ELGAN 为雪貂炎症敏感脑损伤模型提供长期神经保护。与啮齿动物不同，雪貂有一个回旋的大脑，在以下方面与人类大脑非常相似发展和结构。它还适合长期行为测试和复杂成像，使其非常适合研究过早脑损伤的短期和长期影响。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（26-28 周妊娠当量）。第二个目标将检查药代动力学和单剂量与多剂量 AZ 在 P12 雪貂炎症模型中的短期神经保护作用我们实验室开发了致敏性缺氧缺血/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细胞表型分析。成功完成目标可以支持针对目前尚无特定神经保护疗法的高危人群进行的临床试验。