Standardized rice bran supplement ameliorates depressive behaviors via FKBP5 mediated glucocorticoid receptor signaling

Chronic stress-induced dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and glucocorticoid receptor (GR) signaling is central to the development of depression. This study investigated the antidepressant effects of a standardized rice bran supplement (RBS) in a corticosterone (CORT)-induced mouse model and explored the underlying molecular mechanisms, with a focus on GR regulation. Male ICR mice were administered CORT (40 mg/kg, intraperitoneally) for 6 weeks to induce depression-like behaviors. RBS (250, 500, and 100 mg/kg/day) or fluoxetine (FLU, 20 mg/kg/day) was orally administered. Behavioral assessments were performed using the sucrose preference test, tail suspension test, forced swim test, and open field test. RBS significantly ameliorated CORT-induced depression-like behaviors, with effects comparable to FLU. RBS restored brain monoamine neurotransmitter levels and suppressed HPA axis hyperactivity, evidenced by reduced serum corticotropin-releasing hormone, adrenocorticotropic hormone, and CORT levels. Moreover, RBS inhibited GR nuclear translocation in the hippocampus and HT-22 cells. It also decreased FKBP5 expression and disrupted GR/FKBP5/HSP90 complex formation. Furthermore, RBS treatment reduced GRE-luciferase activity in CORT-treated HT-22 cells, indicating decreased GR binding affinity to GREs. Consistently, the expression of GR downstream target genes, Sgk1 and Mkp1, was significantly downregulated by RBS treatment. These effects were similar to those observed with RU486 (GR antagonist) and GR siRNA knockdown. Additionally, RBS restored ERK–CREB–BDNF signaling pathway in HT-22 cells and in the hippocampus of the CORT-injected mice hippocampus. RBS exerts antidepressant-like effects by modulating HPA axis activity, inhibiting GR signaling and its downstream pathway, highlighting its potential as a natural therapeutic agent for stress-related depression.