Repurposing Azithromycin for Neonatal Neuroprotection

这项建议建立在我们最近的发现基础上，即使用临床上可用的抗生素阿奇霉素治疗 (AZ)，减少脑损伤并改善新生啮齿动物缺氧缺血(HI)的功能结局 脑损伤模型。我们的目标是提炼和扩展这些结果，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性疾病 脑病(HIE)。新生儿缺氧缺血性脑病仍然是致残的重要原因。尽管广泛实施 美国新生儿重症监护病房(NICU)的治疗性低温治疗改善了HIE的预后，许多 幸存者会患上慢性神经疾病；因此，补充神经保护干预措施在很大程度上 需要的。此外，在获得NICU护理的机会有限的低资源环境中，治疗性低温可能会 使结果变得更糟。因此，迫切需要对HIE高危新生儿进行安全有效的治疗。 相关的脑损伤，在美国的NICU和在目前没有有效治疗选择的情况下都是如此。 我们对AZ进行初步评估的理由是：i)有兴趣了解炎症在 新生儿缺氧缺血性脑病的损伤和恢复，以及AZ调节髓系功能的证据；ii)最近的一份报告 在小鼠成年中风模型中，AZ提供了保护；iii)知道AZ在体内的使用越来越多。 产科实践中的分娩，许多新生儿在没有证据的情况下暴露于AZ(通过胎盘转移) 不良反应；iv)关于AZ治疗新生儿感染的试验没有发现安全问题的报道。 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 在新生儿脑损伤中的反应，我们评估了AZ治疗对缺氧缺血性脑损伤预后的影响。 新生啮齿动物。我们使用了一种具有良好特征的新生大鼠脑损伤模型，该模型由7日龄大鼠通过 单侧颈动脉结扎和定时暴露于低氧(8%)环境；这是一种HI模型 导致可量化的感觉运动障碍和单侧前脑损伤。这个模型已经被用于 35年来研究新生儿缺氧缺血性脑损伤的机制并测试可能的治疗方法，包括 治疗性低温。我们的初步数据显示，单次注射AZ，在15分钟后 启动损伤，提供运动功能的长期改善和减少脑损伤。我们的目标是 以这些发现为基础：i)完善AZ治疗方案(目标1)和ii)评估3 临床相关变量，我们能够在这个模型中评估AZ神经保护效果(目标2)。 这些实验的结果可能为测试AZ的神经保护作用的临床试验奠定基础 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.