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记忆基因的DNA甲基化调控参与七氟醚诱导的老年大鼠认知功能障碍

DNA Methylation Manipulation of Memory Genes Is Involved in Sevoflurane Induced Cognitive Impairments in Aged Rats.

作者信息

Ni Cheng, Qian Min, Geng Jiao, Qu Yinyin, Tian Yi, Yang Ning, Li Shuai, Zheng Hui

机构信息

Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Department of Anesthesiology, Peking University Third Hospital, Beijing, China.

出版信息

Front Aging Neurosci. 2020 Aug 18;12:211. doi: 10.3389/fnagi.2020.00211. eCollection 2020.

DOI:10.3389/fnagi.2020.00211
PMID:33013350
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7461785/
Abstract

DNA methylation is an essential epigenetic mechanism involving in gene transcription modulation. An age-related increase in promoter methylation has been observed for neuronal activity and memory genes, and participates in neurological disorders. However, the position and precise mechanism of DNA methylation for memory gene modulation in anesthesia related cognitive impairment remained to be determined. Here, we studied the effects of sevoflurane anesthesia on the transcription of memory genes in the aged rat hippocampus. Then, we investigated changes in DNA methylation of involved genes and verified whether dysregulated DNA methylation would contribute to anesthesia induced cognitive impairment. The results indicated that sevoflurane anesthesia down-regulated the mRNA and protein levels of three memory genes, , , and , which were accompanied with promoter hypermethylation and increased , , and expression, and finally impaired hippocampus dependent memory. Furthermore, inhibition of DNA hypermethylation by 5-Aza rescued sevoflurane induced memory gene expression decrease and cognitive impairment. These findings provide an epigenetic understanding for the pathophysiology of cognitive impairment induced by general anesthesia in aged brain.

摘要

DNA甲基化是一种涉及基因转录调控的重要表观遗传机制。已观察到神经元活动和记忆基因的启动子甲基化随年龄增长而增加，并参与神经疾病。然而，在麻醉相关认知障碍中，记忆基因调控的DNA甲基化位置和精确机制仍有待确定。在此，我们研究了七氟醚麻醉对老年大鼠海马体中记忆基因转录的影响。然后，我们研究了相关基因的DNA甲基化变化，并验证了失调的DNA甲基化是否会导致麻醉诱导的认知障碍。结果表明，七氟醚麻醉下调了三个记忆基因（此处原文未给出具体基因名称）的mRNA和蛋白质水平，同时伴有启动子高甲基化以及（此处原文未给出具体基因名称）表达增加，最终损害了海马体依赖性记忆。此外，5-氮杂胞苷抑制DNA高甲基化可挽救七氟醚诱导的记忆基因表达下降和认知障碍。这些发现为老年大脑中全身麻醉诱导认知障碍的病理生理学提供了表观遗传学理解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b595/7461785/cdfc6bf96b94/fnagi-12-00211-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b595/7461785/26a65c841452/fnagi-12-00211-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b595/7461785/cdfc6bf96b94/fnagi-12-00211-g008.jpg
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