Abstract: Objective To investigate the effect of γ-secretase inhibitor (N-[N-(3,5-difluorophenacetyl)-l -alanyl]-S-phenylglycine
t-butyl ester, DAPT) on hyperoxia-induced brain white matter injury in mice. Methods Three-day-old C57BL/10J mouse pups
were divided into air control (C) group, control+DAPT (10 mg/kg, injected intraperitoneally) group, hyperoxia group (exposed
to 80% oxygen for 48 h), and hyperoxia+DAPT group. The brain and body weights of the mice were measured at postnatal
days 3, 5, 12, and 28. Real-time PCR was used to detect Notch intracellular domain (NICD) mRNA expression in the brain after
modeling, and the expressions of NG2 and myelin basic protein (MBP) were detected by double-labeled immunofluorescence
assay to verify the oligdendrocycle type at postnatal day 12. The mice in each group were bred until postnatal day 28 for
Morris water maze test. Results The brain and body weights were significantly decreased in mice in hyperoxia group
compared to the control mice, but increased significantly after DAPT treatment (P<0.05). Real-time PCR showed that a 48-hour
hyperoxia exposure significantly increased NICD mRNA expression in the brain (P<0.05), which was decreased by
co-treatment by DAPT (P<0.05). Hyperoxia also resulted in enhanced NG2 expression and lowered MBP expression in the
brain (P<0.05). Compared with the control mice, the mice exposed to hyperoxia showed prolonged escape latency (P<0.05) and
spent less time in the target quadrant with a lowered number of passing through the virtual platform (P<0.05). All these
parameters were significantly improved by co-treatment with DAPT. Conclusion Specific inhibition of Notch signaling
pathway activation in the brain by the γ-secretase inhibitor DAPT can ameliorate white matter injury and learning and
memory impairment in newborn mice with hyperoxia exposure.