葛根素通过调节肥胖相关蛋白介导的N6-甲基腺苷去甲基化，抑制氧化应激并激活酒精戒断所致抑郁症中的环磷酸腺苷（cAMP）/cAMP反应元件结合蛋白/脑源性神经营养因子信号通路。

Puerarin suppresses the oxidative stress and activates the cyclic AMP (cAMP)/cAMP response element binding protein/brain-derived neurotrophic factor signaling pathway in alcohol withdrawal-induced depressive disorder via regulating obesity-associated protein-mediated N6-methyladenosine demethylation.

作者信息

Li Yazhong, Liu Zhong, Ma Jianhua, Tian Aizhao, Wang Jia, Xu Yang, Yang Jie, Yan Xin

机构信息

Department of Psychiatry.

Department of Psychosomatic, Tangshan Fifth Hospital.

出版信息

Neuroreport. 2025 Aug 6;36(11):589-598. doi: 10.1097/WNR.0000000000002179. Epub 2025 Jun 3.

DOI:10.1097/WNR.0000000000002179

PMID:40470634

Abstract

OBJECTIVE

Puerarin, a bioactive isoflavone glycoside predominantly extracted from the root of the kudzu plant ( Pueraria lobata ), is a traditional Chinese medicinal herb widely used for centuries. Alcohol withdrawal-induced depression (AWIDD), a serious psychiatric disorder, is prevalent in society. This study aimed to investigate the role of puerarin in oxidative stress and cyclic AMP (cAMP)/cAMP response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway in AWIDD, as well as the underlying mechanism.

METHODS

An alcohol withdrawal rat model was established. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-px) were measured using commercial kits. The cAMP level was detected by ELISA. CREB and phospho-CREB protein levels were analyzed by Western blot. BDNF level was assessed by reverse transcription-quantitative PCR. Dot blot was used to assess the total N6-methyladenosine (m 6 A) level. The interaction between obesity-associated protein (FTO) and prostaglandin-endoperoxide synthase 1 (PTGS1) was examined through RNA immunoprecipitation and dual-luciferase reporter assays.

RESULTS

Puerarin decreased oxidative stress and increased the cAMP, p-CREB, and BDNF levels. Besides, puerarin increased FTO-mediated m 6 A demethylation in alcohol withdrawal rats. FTO inhibition increased oxidative stress and decreased the activation of cAMP/CREB/BDNF signaling pathway. Mechanistically, FTO weakened the stability of PTGS1 mRNA via m 6 A demethylation. Overexpression of PTGS1 reversed the reduction in oxidative stress and the activation of the cAMP/CREB/BDNF signaling pathway induced by FTO overexpression.

CONCLUSION

Puerarin suppressed oxidative stress and activated the cAMP/CREB/BDNF signaling pathway in AWIDD via regulating FTO-mediated m 6 A demethylation.

摘要

目的

葛根素是一种主要从葛根植物（野葛）根中提取的生物活性异黄酮苷，是一种数百年来广泛使用的传统中草药。酒精戒断所致抑郁（AWIDD）是一种严重的精神疾病，在社会中普遍存在。本研究旨在探讨葛根素在AWIDD中氧化应激和环磷酸腺苷（cAMP）/cAMP反应元件结合蛋白（CREB）/脑源性神经营养因子（BDNF）信号通路中的作用及其潜在机制。

方法

建立酒精戒断大鼠模型。使用商用试剂盒测量超氧化物歧化酶（SOD）、丙二醛（MDA）和谷胱甘肽过氧化物酶（GSH-px）的水平。通过酶联免疫吸附测定（ELISA）检测cAMP水平。通过蛋白质免疫印迹法分析CREB和磷酸化CREB蛋白水平。通过逆转录定量聚合酶链反应评估BDNF水平。斑点印迹法用于评估总N6-甲基腺苷（m6A）水平。通过RNA免疫沉淀和双荧光素酶报告基因测定法检测肥胖相关蛋白（FTO）与前列腺素内过氧化物合酶1（PTGS1）之间的相互作用。

结果

葛根素降低了氧化应激并提高了cAMP、p-CREB和BDNF水平。此外，葛根素增加了酒精戒断大鼠中FTO介导的m6A去甲基化。FTO抑制增加了氧化应激并降低了cAMP/CREB/BDNF信号通路的激活。机制上，FTO通过m6A去甲基化削弱了PTGS1 mRNA的稳定性。PTGS1的过表达逆转了FTO过表达诱导的氧化应激降低和cAMP/CREB/BDNF信号通路的激活。