期刊
EBIOMEDICINE
卷 43, 期 -, 页码 473-486出版社
ELSEVIER
DOI: 10.1016/j.ebiom.2019.04.048
关键词
Sevoflurane; Folate; Methylation; ERMN; Myelination; Neurotoxicity
资金
- NSFC [81571028, 81771132, 81870818, 31625013, 91732302, 81720108012]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDBS01060200]
- Open Large Infrastructure Research of Chinese Academy of Sciences
- National Key R&D Programof China [2017YFA0105201]
- CAMS Innovation Fund for Medical Sciences [CIFMS 2016-I2M-2-001]
- Program of Shanghai Academic Research Leader [19XD1404300]
- Shanghai Science and Technology Committee [17ZR1416400]
- Shanghai Brain-Intelligence Project from STCSM [16JC1420501]
Background: Exposure to anesthetics during early life may impair cognitive functions. However, the underlying mechanisms remain largely unknown. We set out to determine effects of sevoflurane anesthesia on folate metabolism and myelination in young non-human primates, mice and children. Methods: Young rhesus macaque and mice received 25 to 3% sevoflurane daily for three days. DNA and RNA sequencing and immunohistochemistry among others were used in the studies. We performed unbiased transcriptome profiling in prefrontal cortex of rhesus macaques and mice after the sevoflurane anesthesia. We constructed a brain blood barrier-crossing AAV-PHP.EB vector to harbor ERMN expression in rescue studies. We measured blood folate levels in children after anesthesia and surgery. Findings: We found that thymidylate synthase (TYMS) gene was downregulated after the sevoflurane anesthesia in both rhesus macaque and mice. There was a reduction in blood folate levels in children after the anesthesia and surgery. Combined with transcriptome and genome-wide DNA methylation analysis, we identified that ERMN was the primary target of the disrupted folate metabolism. Myelination was compromised by the anesthesia in the young mice, which was rescued by systematic administration of folic acid or expression of ERMN in the brain through brain-specific delivery of the adeno-associated virus. Moreover, folic acid and expression of ERMN alleviated the cognitive impairment caused by the sevoflurane anesthesia in the mice. Interpretation: General anesthesia leads to disrupted folate metabolism and subsequently defects in myelination in the developmental brain, and ERMN is the important target affected by the anesthesia via epigenetic mechanisms. (C) 2019 The Authors. Published by Elsevier B.V.
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