# Reversing inflammatory macrophage activation as treatment for neonatal intraventricular hemorrhage and hydrocephalus

> **NIH NIH K08** · UNIVERSITY OF KENTUCKY · 2020 · $185,437

## Abstract

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.

## Key facts

- **NIH application ID:** 9977341
- **Project number:** 1K08NS112580-01A1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** BRANDON A MILLER
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $185,437
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977341

## Citation

> US National Institutes of Health, RePORTER application 9977341, Reversing inflammatory macrophage activation as treatment for neonatal intraventricular hemorrhage and hydrocephalus (1K08NS112580-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9977341. Licensed CC0.

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