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The preterm brain also displays regionally heterogeneous responses to both injury and treatment, suggesting that drug combinations may be needed to provide global neuroprotection. We developed an extremely preterm\u2010equivalent organotypic whole hemisphere (OWH) slice culture mild injury model using the gyrencephalic ferret brain to probe treatment mechanisms of promising therapeutic agents and their combination. Regional and global responses to injury and treatment were assessed by cell death quantification, machine learning\u2010augmented morphological microglia assessments, and digital transcriptomics. Using two promising therapeutic agents, azithromycin (Az) and erythropoietin (Epo), we show minimal neuroprotection by either therapy alone, but evidence of synergistic neuroprotection by Az*Epo both globally and regionally. This effect of Az*Epo involved augmentation of transcriptomic responses to injury related to neurogenesis and neuroplasticity and downregulation of transcripts involved in cytokine production, inflammation, and cell death. With the increasing need to develop therapies for extremely preterm brain injury, the ferret OWH slice culture model provides a high\u2010throughput platform to examine combinations of therapeutics as part of a preclinical therapeutic pipeline.<\/jats:p>","DOI":"10.1002\/btm2.70058","type":"journal-article","created":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T06:09:02Z","timestamp":1754114942000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Multi\u2010modal screening for synergistic neuroprotection of mild extremely preterm brain injury"],"prefix":"10.1002","volume":"11","author":[{"given":"Zheyu Ruby","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kylie A.","family":"Corry","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, 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