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Publication
Comparing neuroprotective drug efficacy in rodent neonatal brain injury models.
Authors Barks JDE, Liu Y, Sturza J, Kaciroti N, Meurer WJ, Silverstein FS
Submitted By Submitted Externally on 7/6/2026
Status Published
Journal Pediatric research
Year 2026
Date Published 6/5/2026
Volume : Pages Not Specified : Not Specified
PubMed Reference 42243503
Abstract A challenge in preclinical neonatal neuroprotection research is the
implementation of study designs that enable direct comparison of multiple
potentially effective drugs. We used adaptive design to test four FDA-approved
drugs (azithromycin, erythropoietin, caffeine, and melatonin) concurrently and
determine which best combined safety and efficacy., Seven-day-old (P7) rats
underwent hypoxia-ischemia (HI; right carotid ligation + timed 8% O2 exposure);
some experiments included pre-treatment with agents that induced inflammation,
and some included post-HI brief moderate hypothermia. Sensorimotor and
neuropathology measures were incorporated into a Composite Score that also
accounted for deaths. Outcome was initially evaluated at P21 and in confirmatory
studies at P35. A pre-specified Bayesian algorithm with futility and efficacy
stopping rules was devised to analyze emerging data and adjust subsequent animal
allocation among drug groups., In all models, either azithromycin or
erythropoietin (EPO) offered superior neuroprotection at P21, and the other was
"runner-up". Caffeine and melatonin conferred modest neuroprotection in pure HI
but were quickly eliminated in hypothermia-treated HI. At P35, azithromycin and
EPO outcomes were generally similar., These results support azithromycin as a
candidate neuroprotective agent that warrants future studies in large animal
neonatal cerebral hypoxia-ischemia models., We used adaptive design to compare
four repurposed drugs (azithromycin, caffeine, erythropoietin, and melatonin) in
neonatal rodent brain injury. Key factors differentiating our approach from
existing reports were within-litter comparisons, evaluation in multiple models,
and measurement of both function and neuropathology. Either azithromycin or
erythropoietin was the most neuroprotective in any given model, with the other a
close "runner-up". Melatonin and caffeine were neuroprotective in pure HI, but
less effective than azithromycin. In other models, they were less effective and
eliminated early by the Bayesian algorithm. This supports azithromycin as a
candidate neuroprotectant and supports future studies in large animal models.




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