中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (4): 863-868.doi: 10.4103/1673-5374.353494

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

抑制DNA甲基化可促进脑缺血再灌注模型大鼠恢复学习和记忆功能

  

  • 出版日期:2023-04-15 发布日期:2022-10-29
  • 基金资助:
    国家自然科学基金项目（82101567）；辽宁省博士创业基金项目（2021-BS-111）；中国医科大学盛京医院345人才工程（M0673）

DNA hypomethylation promotes learning and memory recovery in a rat model of cerebral ischemia/reperfusion injury

Guang Shi1, 2, Juan Feng1, Ling-Yan Jian3, Xin-Yu Fan3, *   

  1. 1Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China;  2Department of Neurology, The People’s Hospital of Liaoning Province, Shenyang, Liaoning Province, China;  3Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
  • Online:2023-04-15 Published:2022-10-29
  • Contact: Xin-Yu Fan, PhD, fanxy@sj-hospital.org.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 82101567; Doctoral Start-up Foundation of Liaoning Province, No. 2021-BS-111; and 345 Talent Project of Shengjing Hospital of China Medical University, No. M0673 (all to XYF).

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摘要：

脑缺血再灌注可导致患者学习记忆损伤。研究表明，突触功能可参与学习记忆的形成和发展；DNA甲基化在调节学习记忆方面发挥着关键作用。为探索DNA甲基化在脑缺血再灌注中的作用，实验以大脑中动脉闭塞方法建立了脑缺血再灌注大鼠模型，腹腔注射DNA甲基化抑制剂5-氮杂-2'-脱氧胞苷进行治疗。结果发现5-氮杂-2'-脱氧胞苷可显著改善脑缺血再灌注损伤大鼠的神经功能、认知、社会和空间记忆能力，同时能剂量依赖性地提高海马内突触密度以及SYP和SHANK2蛋白的表达。5-氮杂-2'-脱氧胞苷的作用与其降低脑缺血再灌注损伤大鼠中基因组DNA甲基化以及Syp和Shank2基因特定位点DNA甲基化水平密切相关。提示以5-氮杂-2'-脱氧胞苷抑制DNA甲基化可促进脑缺血再灌注模型大鼠的学习和记忆功能恢复，这一结果在实验动物水平上为基于表观遗传学手段治疗脑卒中提供了理论证据。 

https://orcid.org/0000-0003-4537-4834 (Xin-Yu Fan)

关键词: DNA甲基化, DNA甲基转移酶1, 海马, 脑缺血再灌注, 认知记忆, 社会记忆, 空间记忆, 瞬时大脑中动脉闭塞, 甲基胞嘧啶双加氧酶1, 5-氮杂-2'-脱氧胞苷

Abstract: Cerebral ischemia/reperfusion injury impairs learning and memory in patients. Studies have shown that synaptic function is involved in the formation and development of memory, and that DNA methylation plays a key role in the regulation of learning and memory. To investigate the role of DNA hypomethylation in cerebral ischemia/reperfusion injury, in this study, we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery and then treated the rats with intraperitoneal 5-aza-2′-deoxycytidine, an inhibitor of DNA methylation. Our results showed that 5-aza-2′-deoxycytidine markedly improved the neurological function, and cognitive, social and spatial memory abilities, and dose-dependently increased the synaptic density and the expression of SYP and SHANK2 proteins in the hippocampus in a dose-dependent manner in rats with cerebral ischemia/reperfusion injury. The effects of 5-aza-2′-deoxycytidine were closely related to its reduction of genomic DNA methylation and DNA methylation at specific sites of the Syp and Shank2 genes in rats with cerebral ischemia/reperfusion injury. These findings suggest that inhibition of DNA methylation by 5-aza-2′-deoxycytidine promotes the recovery of learning and memory impairment in a rat model of cerebral ischemia/reperfusion injury. These results provide theoretical evidence for stroke treatment using epigenetic methods.

Key words: cognitive memory, DNA methylation, DNMT1, hippocampus, ischemia/reperfusion, social memory, spatial memory, TET1, transient middle cerebral artery occlusion, 5-aza-2′-deoxycytidine