"7,8-Dihydroxyflavone ameliorates cognitive impairment induced by repeated neonatal sevoflurane exposures in mice through increasing tau O-GlcNAcylation"

作者全名："Xu, Mingliang; Xia, Lei; Li, Junjie; Du, Yehong; Dong, Zhifang"

作者地址："[Xu, Mingliang; Xia, Lei; Li, Junjie; Du, Yehong; Dong, Zhifang] Chongqing Med Univ, Childrens Hosp, Growth Dev & Mental Hlth Children & Adolescence Ct, Pediat Res Inst,Natl Clin Res Ctr Child Hlth & Dis, Chongqing 400014, Peoples R China; [Xu, Mingliang] Southwest Med Univ, Affiliated Hosp, Dept Anesthesiol, Luzhou, Sichuan, Peoples R China"

通信作者："Dong, ZF (通讯作者)，Chongqing Med Univ, Childrens Hosp, Growth Dev & Mental Hlth Children & Adolescence Ct, Pediat Res Inst,Natl Clin Res Ctr Child Hlth & Dis, Chongqing 400014, Peoples R China."

来源：NEUROSCIENCE LETTERS

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001124531800001

JCR分区：Q3

影响因子：2.5

年份：2024

卷号：818

期号：　

开始页：　

结束页：　

文献类型：Article

关键词："7,8-Dihydroxyflavone; Learning and memory; TrkB; Tau; O-GlcNAcylation"

摘要："Background: Sevoflurane, one of the most commonly used general anesthetics for pediatric anesthesia, has recently gained significant attention in both preclinical and clinical settings due to its potential neurotoxicity in the developing brain. Tau phosphorylation, induced by sevoflurane, is recognized as one of the major causes of neurotoxicity. 7,8-dihydroxyflavone (DHF), a TrkB receptor agonist, has been reported to exhibit potential neuroprotective effects against tauopathies. In this study, our objective was to investigate whether DHF could provide neuroprotective effects against sevoflurane-induced neurotoxicity and explore the underlying molecular mechanisms.Methods: Six-day-old mice were subjected to 2 h of anesthesia with 3 % sevoflurane, with or without pretreatment of DHF (5 mg/kg/day, i.p.) for 3 consecutive days. Autonomic motor ability was assessed by open-field test, while learning and memory abilities were evaluated by the fear conditioning test. Western blotting was con-ducted to measure the levels of t-TrkB, p-TrkB, tau, and phosphorylated tau. Additionally, a co-immunoprecipitation assay was performed to investigate the interaction between O-GlcNAcylation and tau.Results: Repeated neonatal sevoflurane exposures resulted in reduced freezing time during the context and cued fear conditioning tests in adulthood. However, pretreatment with DHF restored the freezing time to the level of the control group, indicating that DHF effectively alleviated cognitive impairments induced by neonatal sevoflurane exposure. We also observed that repeated neonatal sevoflurane exposures increased tau phosphorylation while decreasing tau O-GlcNAcylation. However, DHF pretreatment rebalanced the tau O-GlcNAcylation/ phosphorylation ratio by enhancing the interaction between tau and O-GlcNAcylation.Conclusion: Our findings demonstrate that DHF effectively ameliorates sevoflurane-induced cognitive impairment in developing mice by restoring the balance between tau O-GlcNAcylation and phosphorylation. Therefore, this study suggests that DHF has the potential to be a therapeutic agent for treating cognitive impairment associated with anesthetics, such as sevoflurane."

基金机构："National Natural Science Foundation of China [32371030, 82371194, 82071395, 82001158]; Natural Science Foundation of Chongqing [CSTB2022NSCQ-LZX0010, cstc2021ycjh-bgzxm0186]; CQMU Program for Youth Innovation in Future Medicine [W0044]"

基金资助正文："This work was supported by grants from the National Natural Science Foundation of China (32371030, 82371194, 82071395 and 82001158) , the Natural Science Foundation of Chongqing (CSTB2022NSCQ-LZX0010 and cstc2021ycjh-bgzxm0186) and CQMU Program for Youth Innovation in Future Medicine (W0044) . Ethics Approval Animal ethics approval is approved by the Animal Ethics Committee of Children's Hospital of Chongqing Medical University (approval number: CHCMU-IACUC20210114017) ."