Repurposing Azithromycin for Neonatal Neuroprotection

这项建议建立在我们最近的发现，治疗与临床可用的抗生素，阿奇霉素 (AZ)，减少脑损伤，改善新生啮齿动物缺氧缺血（HI）的功能结果 脑损伤模型我们的目标是改进和扩展这些结果，为在更大的范围内测试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性脑病。 脑病（HIE）。新生儿缺氧缺血性脑病仍然是一个重要的原因，残疾。虽然广泛实施 在美国新生儿重症监护病房（NICU）中，治疗性低温改善了HIE的预后，许多 幸存者发展为慢性神经系统疾病;因此， needed.此外，在低资源环境中，NICU护理有限，治疗性低温可能 恶化结果。因此，迫切需要安全有效的治疗新生儿缺氧缺血性脑病的风险， 相关脑损伤，无论是在美国NICU和在目前没有有效的治疗方案的设置。 我们对AZ进行初步评价的理由来自：i）对理解炎症在 新生儿HI损伤和恢复，加上AZ调节骨髓功能的证据; ii）最近的一份报告 AZ在小鼠成年中风模型中赋予保护作用; iii）AZ越来越多地用于脑内的知识， 在产科实践中，许多新生儿暴露于AZ（经胎盘运输），但无证据表明 不良反应; iv）报告AZ治疗新生儿感染的试验未发现安全性问题。 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 为了评估新生儿脑的反应，我们评估了AZ治疗对HI脑损伤结局的影响， 新生啮齿动物我们使用了一个充分表征的新生儿HI脑损伤模型，该模型在7日龄大鼠中引起， 单侧颈动脉结扎和定时暴露于低氧（8%）环境;该HI模型 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 35年来，研究新生儿HI脑损伤的机制，并测试潜在的治疗方法，包括 低温治疗我们的初步数据显示，在注射后15分钟注射单剂量AZ， 引发损伤，提供长期的运动功能改善和减少脑损伤。我们的目标是 在这些研究结果的基础上，通过：i）完善AZ治疗方案（目标1）和ii）评估3 我们能够在该模型中评估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临床试验奠定基础，测试AZ作为神经保护剂 窒息新生儿的治疗

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.