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We hypothesized that inhibition HIF\u2010PHD by adaptaquin reduces hypoxic\u2010ischemic brain injury in a neonatal mouse model. The pups were treated intraperitoneally immediately with adaptaquin after hypoxia\u2010ischemia (HI) and then every 24\u00a0h for 3\u00a0days. Adaptaquin treatment reduced infarction volume by an average of 26.3% at 72\u00a0h after HI compared to vehicle alone, and this reduction was more pronounced in males (34.8%) than in females (11.7%). The protection was also more pronounced in the cortex. The subcortical white matter injury as measured by tissue loss volume was reduced by 24.4% in the adaptaquin treatment group, and this reduction was also more pronounced in males (28.4%) than in females (18.9%). Cell death was decreased in the cortex as indicated by Fluoro\u2010Jade labeling, but not in other brain regions with adaptaquin treatment. Furthermore, in the brain injury area, adaptaquin did not alter the number of cells positive for caspase\u20103 activation or translocation of apoptosis\u2010inducing factor to the nuclei. Adaptaquin treatment increased <jats:italic>glutathione peroxidase 4<\/jats:italic> mRNA expression in the cortex but had no impact on 3\u2010nitrotyrosine, 8\u2010hydroxy\u20102 deoxyguanosine, or malondialdehyde production. <jats:italic>Hif1\u03b1<\/jats:italic> mRNA expression increased after HI, and adaptaquin treatment also stimulated <jats:italic>Hif1\u03b1<\/jats:italic> mRNA expression, which was also more pronounced in males than in females. However, nuclear translocation of HIF1\u03b1 protein was decreased after HI, and adaptaquin treatment had no influence on HIF1\u03b1 expression in the nucleus. These findings demonstrate that adaptaquin treatment is neuroprotective, but the potential mechanisms need further investigation.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14790-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.1111\/jnc.14822\">Read the Editorial Highlight for this article on page 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