Geniposide protects depression through BTK/JAK2/STAT1 signaling pathway in lipopolysaccharide-induced depressive mice

The purpose of this study was to investigate the antidepressant mechanism of GEN (geniposide) on depression mice induced by LPS. The mice were intragastrically treated with GEN (10 mg/kg/d or 40 mg/kg/d) or ibrutinib for continuous 7 days prior to LPS injection. The anxiety- and depression-like behaviors of mice were assessed via behavioral tests (sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and open-field test (OFT)). Microglial BV2 cells were treated with GEN or/and ibrutinib and stimulated with LPS. The productions of pro-inflammatory cytokines IL-6 and TNF-α in hippocampus, serum, and supernatant were detected by ELISA. The correlative proteins Btk, p-BTK, JAK2, p-JAK2, STAT1, p-STAT1, BDNF, TrkB, and p-TrkB were assessed through western blot. As a result, GEN ameliorated the anxiety- and depression-like behaviors of mice in behavioral tests. GEN treatment also regulated microglia polarization towards anti-inflammatory phenotype M2 and inhibited the production of pro-inflammatory cytokines IL-6 and TNF-α. In addition, with the application of ibrutinib, the selective inhibitor of Btk, it was proclaimed that the administration of GEN restrained the activation of JAK2/STAT1 pathway via attenuating the hyperphosphorylation of Btk both in mice and BV2 cells. Furthermore, it was also found that GEN activated BDNF/TrkB neuroprotective signaling pathway through the reduction of Btk phosphorylation. From the overall results, we suggested that GEN exerted a beneficial effect on LPS-induced depression in mice possibly through the modulation of Btk/JAK2/STAT1 signaling.