Research on the mechanism of antidepressive effect of Suanzaoren Decoction through TLR4/MyD88/NF-κB pathway and Wnt/β-catenin pathway.
Research on the mechanism of antidepressive effect of Suanzaoren Decoction through TLR4/MyD88/NF-κB pathway and Wnt/β-catenin pathway.
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基于TLR4/MyD88/NF-κB通路及Wnt/β-catenin通路探讨酸枣仁汤抗抑郁作用机制的研究
DOI：
10.1016/j.jep.2023.117190
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发表时间：
2023-09
影响因子：
5.4
通讯作者：
Yiyang Du;Tingxu Yan;Bo Wu;Bosai He;Ying Jia
中科院分区：
文献类型：
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作者：
Yiyang Du;Tingxu Yan;Bo Wu;Bosai He;Ying Jia
炎症反应增强和神经可塑性破坏是抑郁症发病机制假说的重要机制。因此，这两个方面都有利于抑郁症治疗方法的发展。酸枣仁汤是治疗失眠症的经典中药复方，临床上可缓解抑郁症状，但其抗抑郁药理机制尚待阐明。本研究旨在探讨SZRD对慢性轻度不可预见性应激的抗抑郁作用及其分子机制。材料与方法采用SZRD灌胃或不灌胃治疗4周，观察SZRD对SD大鼠BV 2细胞神经炎症模型的影响，并比较SZRD对BV 2细胞神经炎症模型的影响。苏木精-伊红染色观察脑组织病理学改变。TUNEL法观察神经元凋亡情况。采用免疫荧光、ELISA试剂盒和Western blotting检测炎症指标Iba-1和炎症因子，以及重要的炎症途径TLR 4/MyD 88/NF-κB。采用酶联免疫吸附试验（ELISA）和蛋白质印迹法检测神经可塑性指标脑源性神经营养因子（BDNF）、突触前膜蛋白突触素（SYP）、突触后蛋白95（PSD 95）和关键通路Wnt/β-catenin。结果SZRD能明显逆转抑郁模型大鼠的抑郁样行为，降低炎症因子水平，增加BDNF、SYP、PSD 95的表达。SZRD可抑制TLR 4/MyD 88/NF-κB和Wnt/β-catenin通路的激活，减少NF-κB和β-catenin的大量核转位。SZRD对Wnt通路的抑制作用可部分被NF-κB通路激动剂所抵消，而Wnt通路激动剂可部分被SZRD对TLR 4通路的抑制作用所抵消。结论SZRD可能通过联合调节TLR 4/MyD 88/NF-κB通路和Wnt/β-catenin通路发挥抗抑郁作用。
Ethnopharmacological relevanceIncreased inflammatory response and disruption of neuroplasticity are important mechanisms in the hypothesis of the pathogenesis of depression. Thus, these two aspects are conducive to the development of treatments for depression. Suanzaoren Decoction (SZRD) is a classic traditional Chinese medicine compound for the treatment of insomnia, which can clinically relieve depression symptoms, but its antidepressant pharmacological mechanism remains to be elucidated.Aim of this studyBased on the hypothesis of inflammation and neuroplasticity in depression, this study aimed to investigate the antidepressant effect of SZRD and its specific molecular mechanism through chronic unpredictable mild stress (CUMS) induced SD rat model and lipopolysaccharide (LPS) induced BV2 cell neuroinflammation model.Materials and methodsThe body weight and behavioral indexes of CUMS model rats treated with orally or without oral SZRD for 4 weeks were detected. Hematoxylin and eosin staining was used to observe brain pathological damage. Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) staining was used to observe neuronal apoptosis. Immunofluorescence, ELISA kit and Western blotting were used to detect the inflammatory index Iba-1 and inflammatory factors, as well as the important inflammatory pathway TLR4/MyD88/NF-κB. Enzyme linked immunosorbent assay (ELISA) and western blotting were used to detect neuroplasticity indexes proteins-brain-derived neurotrophic factor (BDNF), presynaptic membrane protein-synaptophysin (SYP), and postsynaptic protein- 95(PSD95), and the key pathway Wnt/β-catenin. The possible mechanism of SZRD antidepressant was further explored in LPS-induced BV2 cells.ResultsIn vivoandin vitroexperiments showed that SZRD treatment significantly reversed the depression-like behaviors in rats, decreased the levels of inflammatory factors and increased the expression levels of BDNF, SYP, PSD95 in depression model rats. Furthermore, SZRD treatment inhibited the activation of TLR4/MyD88/NF-κB and Wnt/β-catenin pathways and reduced the massive nuclear translocation of NF-κB and β-catenin. The addition of NF-κB pathway agonists could partially offset the inhibitory effect of SZRD on the Wnt pathway, and the addition of Wnt pathway agonists could also partially offset the inhibitory effect of SZRD on the TLR4 pathway.ConclusionThis study suggestted that SZRD may exert its antidepressant effect by regulating TLR4/MyD88/NF-κB pathway and Wnt/β-catenin pathway in combination.