Basic Science Article | Published:

Repurposing azithromycin for neonatal neuroprotection

Abstract

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 2–4 weeks later. Multiple treatment protocols were evaluated (variables included doses ranging from 15 to 45 mg/kg; treatment onset 15 min to 4 h 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 h, 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.

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Acknowledgements

Research reported in this publication was supported by the Michigan Institute for Clinical & Health Research (MICHR) that is supported by the National Institutes of Health under award number UL1TR002240. Research was also supported by the National Institutes of Health under award number R21 HD096251 (to J.D.E.B. and F.S.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This research was also supported by the Neonatal Therapeutic Hypothermia Gift Fund, and The Reiter HIE Research Fund.

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Competing interests

The authors declare no competing interests.

Correspondence to John D. E. Barks.

Supplementary information

  1. Supplementary Data Table S1

  2. Supplementary Data Table S2

  3. Supplementary Data Table S3

  4. Supplementary Data Figure S1

  5. Supplementary Video

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