Du Min, Tan Yuting, Liu Guangjian, Liu Lan, Cao Fei, Liu Jianxia, Jiang Pu, Xu Ying
Department of Anesthesiology, Ministry of Education Key Laboratory of Child Development and Disorders, China Internatinal Science and Technology Cooperation Base of Child Development and Critical Disorders,Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
Department of Anesthesiology, Ministry of Education Key Laboratory of Child Development and Disorders, China Internatinal Science and Technology Cooperation Base of Child Development and Critical Disorders,Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; Department of Anaesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, Wuhan, 442000, China.
Neurosci Lett. 2017 Jul 13;653:220-227. doi: 10.1016/j.neulet.2017.05.065. Epub 2017 Jun 3.
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.
高氧暴露可导致促炎细胞因子的大量释放，导致新生小鼠脑内神经元凋亡并引发白质损伤。一些研究表明，Notch激活在炎症过程中被激发，可能调节适应性免疫和先天性免疫反应。此外，该信号通路还调节少突胶质细胞成熟，而高氧暴露后的新生小鼠中该过程受到破坏。本研究旨在探讨Notch信号激活是否导致高氧暴露后未成熟脑损伤。我们测定了出生后第3天（P3）至第5天（P5）暴露于80%氧气的新生野生型小鼠白质（WM）中的细胞变化。此外，为了进一步证实Notch信号通路与高氧诱导的脑室周围白质损伤之间的关系，在高氧暴露前，用γ-分泌酶抑制剂（N-[N-(3,5-二氟苯乙酰基)-L-丙氨酰基]-S-苯甘氨酸叔丁酯，DAPT）对小鼠进行预处理，该抑制剂可抑制Notch信号通路的激活。结果表明，DAPT预处理后，在高氧环境下的P12小鼠中髓鞘碱性蛋白（MBP）表达增加。此外，高氧可导致成熟少突胶质细胞（MBP+）数量减少，而P12时高氧后少突胶质前体细胞（NG2+）数量明显反向增加，DAPT预处理显著改善了高氧诱导的少突胶质细胞成熟破坏。我们的结果还表明，DAPT可减轻高氧暴露诱导的记忆障碍。综上所述，这些结果表明，高氧暴露通过Notch信号激活在发育中的大脑中诱导脑损伤和行为异常。γ-分泌酶的调节，选择性干扰Notch信号通路，可改善高氧诱导的不良后果。
