Sex differences in neonatal mouse brain injury after hypoxia-ischemia and adaptaquin treatment

Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-PHDs) are important targets against oxidative stress. We hypothesized that inhibition HIF-PHD by adaptaquin reduces hypoxic-ischemic brain injury in a neonatal mouse model. The pups were treated intraperitoneally immediately with adaptaquin after hypoxia-ischemia (HI) and then every 24 h for 3 days. Adaptaquin treatment reduced infarction volume by an average of 26.3% at 72 h 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-Jade 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-3 activation or translocation of apoptosis-inducing factor to the nuclei. Adaptaquin treatment increased glutathione peroxidase 4 mRNA expression in the cortex but had no impact on 3-nitrotyrosine, 8-hydroxy-2 deoxyguanosine, or malondialdehyde production. Hif1α mRNA expression increased after HI, and adaptaquin treatment also stimulated Hif1α mRNA expression, which was also more pronounced in males than in females. However, nuclear translocation of HIF1α protein was decreased after HI, and adaptaquin treatment had no influence on HIF1α expression in the nucleus. These findings demonstrate that adaptaquin treatment is neuroprotective, but the potential mechanisms need further investigation. Read the Editorial Highlight for this article on page 645.