Repurposing Azithromycin for premature brain injury

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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.