Repurposing Azithromycin for premature brain injury

项目摘要/摘要 在全球范围内，早产是新生儿死亡的主要原因。美国的早产儿现象也在上升， 2017年9.93%的早产儿。这导致382,851人早产，其中超过25,800人是 在怀孕28周之前出生。这一群体也被称为极低胎龄新生儿(Elgans)， 面临着不良结局的重大风险；伊尔干人的死亡率为10%-20%，高达50%的幸存者将患有 儿童时期有中度或严重的神经认知缺陷。早产通常是由母亲感染引起的。 或炎症，通常与额外的围产期侮辱有关，包括由于以下原因造成的氧化损伤 波动的低氧、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。新的 治疗早产儿脑损伤改善预后和降低远期发病率的方法 因此，伊尔甘斯仍然是一个重要的未得到满足的临床需求。阿奇霉素是一种大环内酯类抗生素。 通常用于治疗社区感染的处方。使用方便，孕期使用安全 可以跨越胎盘和血脑屏障。AZ在吞噬细胞中积累，提供了一种形式 当吞噬细胞迁移到感染或炎症部位时，靶向药物的传递。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炎症较轻或损伤较小的表型。这 在中风、脊髓损伤和缺氧的实验性啮齿动物模型中，结果显示显著的神经保护作用。 新生大鼠缺血性脑损伤的实验研究AZ是一种有吸引力的神经保护剂，因为它是FDA批准的，廉价， 而且很安全。如果它被发现是有效的，它可以在高资源和低资源环境中使用以改进 早产儿脑损伤的后果。这项提案的首要目标是确定AZ是否 在雪貂炎症敏感性脑损伤模型中提供长期的神经保护。 与啮齿动物不同的是，雪貂有一个与人类大脑非常相似的脑回 发展和结构。它还可以接受长期的行为测试和复杂的成像，使其 是研究早产儿脑损伤的短期和长期影响的理想选择。第一个目标将评估如何 AZ改变器官型脑片中的炎症和氧化应激，包括小胶质细胞表型 来自P12雪貂(相当于怀孕26-28周)。第二个目标将检查药物动力学和 在P12雪貂炎症模型中单剂量与多剂量AZ的短期神经保护作用 致敏性缺氧缺血/高氧性(HIH)早产性脑损伤是本实验室发展起来的。第三个目标 然后将在雪貂HIH模型中检查AZ治疗的长期影响，包括行为结果， 核磁共振、免疫组织化学和小胶质细胞表型。成功完成AIMS可以支持 在这一高危人群中进行的临床试验，目前还没有针对该人群的特定神经保护疗法。

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.