n-(n-(3-5-difluorophenacetyl)alanyl)phenylglycine-tert-butyl-ester and Hyperoxia

Hyperoxia exposure can cause dramatic release of proinflammatory cytokines, leading to neuronal apoptosis and inducing white matter damage in newborn mouse brains. Some studies indicated that the Notch activation was provoked during inflammation and might regulate adaptive and innate immune responses. Moreover, the pathway also regulated oligodendrocyte maturation which was disrupted in neonatal mice after hyperoxia exposure. This study sought to investigate whether the Notch signalling activation contributed to immature brain damage after hyperoxia exposure. Cellular changes in the white matter (WM) of neonatal wild-type mice exposed to 80% oxygen from postnatal day 3 (P3) to day 5 (P5) were determined. Moreover, in order to further confirm the relationship between the Notch signalling pathway and hyperoxia-induced periventricular white matter injury, mice were pre-treated with a γ-secretase inhibitor (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, DAPT), which inhibits activation of the Notch pathway before exposure to hyperoxia. The results suggested that expression of myelin basic protein (MBP) increased in P12 mice subjected to hyperoxia after DAPT pretreatment. Moreover, hyperoxia could cause mature oligodendrocytes (MBP+) counts decreased with an obvious inverse increase in OPCs (NG2+) after hyperoxia on P12, DAPT pretreatment significantly ameliorated disruption of oligodendrocytes maturation induced by hyperoxia. Our results also demonstrated that DAPT could reduce memory impairment induced by hyperoxia exposure. Taken together, these results suggest that hyperoxia exposure induces both brain damage in the developing brain and behavioural abnormalities through the Notch signalling activation. And modulation of γ-secretase, selectively interfering with the Notch signalling pathway, could improve adverse outcomes induced by hyperoxia.

Topics: Animals; Animals, Newborn; Brain; Brain Injuries; Dipeptides; Hyperoxia; Learning; Mice, Inbred C57BL; Oligodendroglia; Receptor, Notch1; Signal Transduction

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.. 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.. 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.. 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.

Topics: Amyloid Precursor Protein Secretases; Animals; Body Weight; Brain; Dipeptides; Hyperoxia; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Organ Size; Receptors, Notch; Signal Transduction; White Matter