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 1000 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-FKBP 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 MKP-1, 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. RBS exerts antidepressant-like effects by modulating HPA axis activity and inhibiting GR signaling and its downstream pathway, thereby highlighting its potential as a natural therapeutic agent for stress-related depression.