中国病理生理杂志2026，Vol.42Issue(3)：477-486,10.DOI:10.3969/j.issn.1000-4718.2026.03.007
异甘草素通过抑制BRD4激活BDNF信号通路并缓解脓毒症大鼠认知障碍
Isoliquiritigenin inhibits BRD4 to activate BDNF signaling pathway and alleviate cognitive impairment in septic rats
摘要
Abstract
AIM:To investigate whether isoliquiritigenin alleviates sepsis-associated cognitive impairment in rats by regulating bromodomain-containing protein 4(BRD4)and subsequently activating the brain-derived neurotrophic factor(BDNF)signaling pathway.METHODS:In vitro,BV2 microglial cells were randomly divided into four groups:control,lipopolysaccharide(LPS;1 mg/L)model,isoliquiritigenin intervention(20 µmol/L),and positive control(JQ1,a BRD4 inhibitor;0.05 µmol/L).After 24 h of intervention,cell viability was assessed using the CCK-8 assay.Microgli-al activation was evaluated by immunofluorescence staining for ionized calcium-binding adapter molecule 1(Iba-1).Levels of tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)in the supernatant were measured by ELISA.The mRNA and protein expression levels of BRD4,BDNF and nuclear factor-κB(NF-κB)p65 were detected via RT-qPCR and Western blot,respectively.The physical interaction between BRD4 and NF-κB p65 was analyzed by co-immunopre-cipitation.In vivo,forty male SD rats were randomly assigned to four groups(n=10 per group):Sham,Model[cecal liga-tion and puncture(CLP)],isoliquiritigenin and positive control.Following treatment,spatial learning and memory,as well as motor coordination,were evaluated using the Morris water maze,Y-maze,and rotarod tests.Hippocampal neuro-nal morphology was observed via Nissl staining.Inflammatory cytokines,key protein expressions,and the colocalization of BRD4 and NF-κB p65 in hippocampal tissues were assessed using ELISA,RT-qPCR,Western blot,and immunofluores-cence.RESULTS:In vitro,compared with the LPS group,isoliquiritigenin significantly inhibited LPS-induced microgli-al hyperproliferation(P<0.01),reduced Iba-1 fluorescence intensity,and markedly decreased the secretion of pro-inflam-matory cytokines TNF-α and IL-6(P<0.01).Mechanistically,isoliquiritigenin significantly down-regulated the mRNA and protein expression of BRD4 and NF-κB p65(P<0.01),up-regulated BDNF expression(P<0.01),and effectively disrupted the binding and colocalization of BRD4 with NF-κB p65(P<0.01).In vivo,behavioral tests demonstrated that isoliquiritigenin treatment significantly shortened the escape latency in the Morris water maze,increased the number of platform crossings and the time/frequency of exploring the novel arm in the Y-maze(P<0.01),and prolonged the retention time on the rotarod(P<0.01).Histopathological analysis revealed a marked improvement in the disordered arrangement of hippocampal neurons.Biochemical assays confirmed that isoliquiritigenin similarly down-regulated BRD4 and NF-κB p65 expression in the hippocampus,inhibited their colocalization,and significantly activated the BDNF signaling path-way.CONCLUSION:Isoliquiritigenin alleviates sepsis-induced cognitive dysfunction by inhibiting BRD4 expression and its interaction with NF-κB p65,thereby relieving the suppression of the BDNF signaling pathway.关键词
异甘草素/含溴结构域蛋白4/脑源性神经营养因子/脓毒症/认知障碍Key words
isoliquiritigenin/bromodomain-containing protein 4/brain-derived neurotrophic factor/sepsis/cognitive impairment分类
医药卫生引用本文复制引用
肖俊锋,朱宣蓉,徐秀梅,黄绍芳..异甘草素通过抑制BRD4激活BDNF信号通路并缓解脓毒症大鼠认知障碍[J].中国病理生理杂志,2026,42(3):477-486,10.基金项目
江西省中医药管理局科技计划(No.2024B0544) （No.2024B0544）
