Effect ofγ-secretase inhibitor on hyperoxia-induced brain white matter injury in mice

doi:10.3969/j.issn.1673-4254.2015.09.014

Abstract：Objective To investigate the effect ofγ-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.