The effect of geniposide on chronic unpredictable mild stress‐induced depressive mice through BTK/TLR4/NF‐κB and BDNF/TrkB signaling pathways

Abstract

The purpose of this study was to estimate the pharmacological effect of geniposide (GEN) on depression, caused by chronic unpredictable mild stress (CUMS), and explore its potential mechanism. During the 6 week CUMS procedure, the mice were treated with GEN (10, 40 mg/kg) by gavage once daily for 3 weeks. As a result, the GEN treatment remarkably improved the behavioral manifestations and suppressed the generations of inflammatory cytokines both in vivo and in vitro. The MDA level was significantly increased, while the activities of SOD, GSH‐PX were decreased in CUMS‐challenged mice and corticosterone‐stimulated PC12 cells. GEN administration significantly inhibited those changes. Moreover, GEN treatment could downregulate the expressions of p‐BTK, TLR4, MyD88, p‐NF‐κB proteins, and upregulate BDNF, p‐TrkB generations in CUMS‐induced mice. Moreover, GEN administration inhibited the protein levels of p‐BTK, TLR4, MyD88, p‐NF‐κB in corticosterone‐induced PC12 cell. In summary, the results suggested that GEN exerted a therapeutic effect on CUMS‐induced depressive mice possibly through the regulation of BTK/TLR4/NF‐κB and BDNF/TrkB signaling pathways.

Alpinia oxyphylla Miq. volatile oil ameliorates depressive behaviors and inhibits neuroinflammation in CUMS-exposed mice by inhibiting the TLR4-medicated MyD88/NF-κB signaling pathway

“…Relevant studies have shown that NF-κB is pivotal for modulating the TLR4-mediated proin ammatory cascade (Chen et al, 2021;Xu et al, 2020). Moreover, the NF-κB activation is correlated with IKKdependent IκBα phosphorylation and the translocation of cytosolic NF-κB p65 to the nucleus (Qu et al, 2021).…”

Discovery of Novel Potent and Fast BTK PROTACs for the Treatment of Osteoclasts-Related Inflammatory Diseases

“…To date, six BTK inhibitors have been approved for treating hematologic malignancies: Ibrutinib, Accalabrutinib, Zanubrutinib, Tirabrutinib, Orelabutinib, and Pirtobrutinib (Figure ). In addition to B cells, BTK is also expressed in other myeloid cells and regulates their development and immune responses through multiple signaling pathways − (e.g., FcγR, CXCR, and TLR pathways). Recent studies have elucidated that BTK acts as a key upstream regulator of the PLCγ2-Ca 2+ -NFAT signaling pathway, , which regulates the formation of osteoclasts from hemato­poietic monocyte precursors and ultimately leads to bone resorption and osteolytic bone damage .…”

Role of BDNF–TrkB signaling in the antidepressant‐like actions of loganin, the main active compound of Corni Fructus

“…For example, clinical autopsy analyses found that patients with depression have lower level of TrkB in brain, whereas patients treated with some antidepressants (e.g., fluoxetine) have higher level of TrkB 4,5 . For another, preclinical results showed that the level of TrkB in the hippocampus of depression was low, which was reversed after the treatment of antidepressants (such as iridoid glycoside compound geniposide) 6,7 . TrkB was a specific binding site for brain derived neurotrophic factor (BDNF) and BDNF was considered a potential neurobiological marker for depression 8,9 .…”

“…4,5 For another, preclinical results showed that the level of TrkB in the hippocampus of depression was low, which was reversed after the treatment of antidepressants (such as iridoid glycoside compound geniposide). 6,7 TrkB was a specific binding site for brain derived neurotrophic factor (BDNF) and BDNF was considered a potential neurobiological marker for depression. 8,9 Clinical autopsy data shown that decreased levels of BDNF and increased levels of proBDNF in brain samples from depressed patients.…”