Reversing Inflammatory Macrophage Activation as Treatment for Neonatal Intraventricular Hemorrhage and Hydrocephalus

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Neonatal Intraventricular hemorrhage (IVH) originates from the underdeveloped germinal matrix, a site of cell rapid cell division adjacent to the lateral ventricles of the brain. IVH leads to post-hemorrhagic hydrocephalus (PHH). Within the same time frame that neonatal IVH occurs, the neonatal brain is also rapidly producing the cells needed for myelination. Oligodendrocytes, the myelin-forming cells of the brain, are derived from oligodendrocyte progenitor cells (OPCs). OPCs are fragile cells - exquisitely sensitive to many factors that are present across multiple neurological diseases such as excitotoxicity, inflammatory cytokines, and oxidative stress. Across a wide spectrum of neurological diseases, neuroinflammation causes OPC loss and failure of myelination. Infiltrating brain macrophages are implicated in many forms of neonatal brain injury. Macrophages are activated by many different stimuli in CNS injury and disease, including blood products released into the ventricular space. Understanding the role of macrophages after IVH is critical to improving outcomes, as macrophage activation mediates white matter injury in other forms of neonatal brain injury. Azithromycin is a commonly prescribed antibiotic that is safe in neonates. Besides its antibiotic properties, azithromycin is also anti-inflammatory and shifts macrophage activation into an anti-inflammatory phenotype that actually promotes tissue recovery rather than injury. Azithromycin has been used in a variety of anti-inflammatory applications including preclinical work in spinal cord injury where it improves tissue sparing and neurological function. Importantly, azithromycin has already undergone rigorous clinical trials in neonates for inflammation-induced lung injury. This study will pharmacologically block infiltrating macrophages in IVH/PHH and test azithromycin’s ability to protect OPCs from macrophage-induced injury in a rat model of neonatal IVH. I will use a combination of in vivo and in vitro experiments to examine macrophage activation, OPC death and myelination with and without azithromycin treatment. My in vivo work will allow us to use neurobehavioral outcomes to assess the efficacy of azithromycin while my in vitro model will allow for in-depth mechanistic studies of macrophage-OPC interaction. This project will support Dr. Miller’s training in studies of neuroinflammation and neurotherapeutics. If successful, this project will pave the way for clinical studies of azithromycin for improving neurological outcome after neonatal IVH.