Repurposing Azithromycin for Neonatal Neuroprotection

重新利用阿奇霉素进行新生儿神经保护

基本信息

批准号：
9766343
负责人：
JOHN D BARKS
金额：
$ 23.4万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-17 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9766343
关键词：
Adult Adverse effects Animals Antibiotics Asphyxia Neonatorum Azithromycin Blood Brain Injuries Caring Carotid Arteries Cessation of life Childhood Chronic Clinical Clinical Trials Coupled Data Diet Dietary Fats Discipline of obstetrics Disease Dose Drug Kinetics Environment Evaluation Exposure to Fatty acid glycerol esters Foundations Goals High Fat Diet Hypoxia Hypoxic-Ischemic Brain Injury Infant Infection Inflammation Inflammatory Injury International Intervention Knowledge Laboratory Finding Lesion Ligation Light Lipopolysaccharides Microglia Modeling Modernization Motor Mus Myelogenous Neonatal Neonatal Brain Injury Neonatal Intensive Care Units Newborn Infant Outcome Oxygen Performance Perinatal anoxic ischemic brain injury Pharmaceutical Preparations Population Premature Infant Procedures Prosencephalon Protocols documentation Rattus Recovery Reporting Research Resources Resuscitation Risk Rodent Rodent Model Role Safety Severities Standardization Survivors Testing Therapeutic Translations Treatment Protocols base clinical application clinical implementation clinical translation clinically relevant clinically significant disability disability-adjusted life years effective therapy experimental study functional outcomes healing improved improved outcome interest intraamniotic infection intrapartum ischemic lesion mother nutrition natural hypothermia neonatal brain neonatal hypoxic-ischemic brain injury neonatal infection neonate nervous system disorder neuroprotection novel novel therapeutics pre-clinical pregnant response standard care stem stroke model targeted treatment

项目摘要

This proposal builds upon our recent findings that treatment with a clinically available antibiotic, Azithromycin (AZ), reduces brain damage and improves functional outcomes in a neonatal rodent hypoxic-ischemic (HI) brain injury model. Our aims are to refine and extend these results, build the foundation for testing AZ in larger animal HI models, and ultimately, repurpose AZ for treatment of neonates with hypoxic-ischemic encephalopathy (HIE). Neonatal HIE remains an important cause of disability. Although wide implementation of therapeutic hypothermia in US newborn intensive care units (NICUs) has improved outcomes of HIE, many survivors develop chronic neurological disorders; thus supplemental neuroprotection interventions are greatly needed. Moreover, in low resource settings with limited access to NICU care, therapeutic hypothermia may worsen outcomes. Thus, safe and effective treatments are urgently needed for neonates at risk for HIE- associated brain injury, both in US NICUs and in settings with no current effective treatment options. Our rationale for initial evaluation of AZ stemmed from: i) interest in understanding the roles of inflammation in neonatal HI injury and recovery, coupled with evidence that AZ modulates myeloid function; ii) a recent report that AZ confers protection in a murine adult stroke model; iii) knowledge that AZ is increasingly used intra- partum in obstetric practice with many newborns exposed to AZ (by trans-placental transport) without evidence of adverse effects; iv) reports that trials of AZ for treatment of neonatal infections identified no safety concerns. Based on these factors and our initial findings that AZ regulates microglia and stimulates their healing responses in neonatal brain, we evaluated the impact of AZ treatment on the outcome of HI brain injury in neonatal rodents. We used a well-characterized model of neonatal HI brain injury elicited in 7 day old rats by unilateral carotid artery ligation and timed exposure to a reduced (8%) oxygen environment; this HI model results in quantifiable sensorimotor deficits and unilateral forebrain damage. This model has been used for over 35 years to study mechanisms of neonatal HI brain injury and to test potential treatments, including therapeutic hypothermia. Our preliminary data showed that a single dose of AZ, injected 15 min after the initiating injury, provided long-term improvements in motor function and reduced brain damage. Our goals are to build on these findings by: i) refining AZ treatment protocols (Aim 1) and ii) evaluating the impact of 3 clinically relevant variables that we are able to assess in this model, on AZ neuroprotective efficacy (Aim 2). Results of these experiments could lay the foundation for clinical trials that test AZ as a neuroprotective therapy in asphyxiated newborns.

该提议基于我们最近的发现，即使用临床可用的抗生素阿奇霉素进行治疗 (AZ)，减少新生儿啮齿动物缺氧缺血 (HI) 的脑损伤并改善功能结果脑损伤模型。我们的目标是完善和扩展这些结果，为在更大范围内测试 AZ 奠定基础动物 HI 模型，并最终将 AZ 重新用于治疗新生儿缺氧缺血脑病（HIE）。新生儿 HIE 仍然是导致残疾的重要原因。虽然广泛实施美国新生儿重症监护病房 (NICU) 的低温治疗改善了 HIE 的预后，许多人幸存者出现慢性神经系统疾病；因此补充性神经保护干预措施对需要。此外，在资源匮乏、获得 NICU 护理的机会有限的情况下，治疗性低温可能会使结果恶化。因此，对于有 HIE 风险的新生儿迫切需要安全有效的治疗。相关脑损伤，无论是在美国新生儿重症监护病房还是在目前没有有效治疗选择的环境中。我们对 AZ 进行初步评估的理由源于：i) 对了解炎症在新生儿 HI 损伤和恢复，以及 AZ 调节骨髓功能的证据； ii) 最近的报告 AZ 在小鼠成年中风模型中提供保护； iii) 了解 AZ 越来越多地在内部使用在产科实践中，许多新生儿在没有证据的情况下暴露于 AZ（通过胎盘转运）不良影响； iv) 报告称 AZ 治疗新生儿感染的试验未发现安全问题。基于这些因素和我们的初步发现，AZ 调节小胶质细胞并刺激其愈合在新生儿大脑反应中，我们评估了 AZ 治疗对 HI 脑损伤结果的影响新生啮齿动物。我们使用了 7 天大的大鼠诱发的新生儿 HI 脑损伤模型。单侧颈动脉结扎并定时暴露于低氧（8%）环境；这个HI型号导致可量化的感觉运动缺陷和单侧前脑损伤。该模型已用于超过 35 年的时间来研究新生儿 HI 脑损伤的机制并测试潜在的治疗方法，包括治疗性低温。我们的初步数据显示，在注射后 15 分钟注射单剂量的 AZ 引发损伤，提供运动功能的长期改善并减少脑损伤。我们的目标是在这些发现的基础上，通过以下方式进行：i) 完善 AZ 治疗方案（目标 1）和 ii) 评估 3 的影响我们能够在此模型中评估 AZ 神经保护功效的临床相关变量（目标 2）。这些实验的结果可以为测试 AZ 作为神经保护剂的临床试验奠定基础窒息新生儿的治疗。