Repurposing Azithromycin for Neonatal Neuroprotection

BACKGROUND: Inflammation contributes to neonatal hypoxic-ischemic brain injury pathogenesis. We evaluated the neuroprotective efficacy of azithromycin, a safe, widely available antibiotic with anti-inflammatory properties, in a neonatal rodent hypoxic-ischemic brain injury model. METHODS: Seven day old rats underwent right carotid artery ligation followed by 90 min 8% oxygen exposure; this procedure elicits quantifiable left forepaw functional impairment and right cerebral hemisphere damage. Sensorimotor function (vibrissae-stimulated forepaw placing, grip strength) and brain damage were compared in azithromycin- and saline-treated littermates two to four weeks later. Multiple treatment protocols were evaluated (variables included doses ranging from 15-45 mg/kg; treatment onset 15 min to 4h post-hypoxia, and comparison of 1 vs. 3 injections). RESULTS: All azithromycin doses improved function and reduced brain damage; efficacy was dose-dependent, and declined with increasing treatment delay. Three azithromycin injections, administered over 48 hours, improved performance on both function measures and reduced brain damage more than a single dose. CONCLUSION: In this neonatal rodent model, azithromycin improved functional and neuropathology outcomes. If supported by confirmatory studies in complementary neonatal brain injury models, azithromycin could be an attractive candidate drug for repurposing and evaluation for neonatal neuroprotection in clinical trials.