Glucocorticoid antagonist RU486 attenuates microglial activation and ameliorates post-traumatic stress disorder via NLRP3/JAK1/STAT3 pathway.

BACKGROUND

Post-traumatic stress disorder (PTSD) is a severe mental health condition characterized by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and neuroinflammation. RU486, a glucocorticoid receptor (GR) antagonist, has been proposed as a potential modulator of neuroinflammation, but its precise mechanisms in PTSD remain unclear.

METHODS

We established both in vivo single-prolonged stress (SPS) rat models and in vitro lipopolysaccharide (LPS)-stimulated BV-2 microglial models to evaluate the effects of RU486. Transcriptomic sequencing, quantitative PCR (qPCR), Western blot, and immunofluorescence assays were employed to analyze variations in inflammatory markers and signaling pathway molecules, as well as to evaluate therapeutic outcomes.

RESULTS

In the SPS rat model, glucocorticoid receptor (GR) expression was upregulated, and the levels of NLRP3, Caspase-1, IL-1β, TNF-α, and IL-6 were elevated, while IL-10 levels were reduced. RU486 treatment alleviated the behavioral abnormalities induced by SPS, decreased serum corticosterone and pro-inflammatory cytokines, and increased IL-10 levels. In BV-2 cells, RU486 downregulated GR expression, modulated inflammatory responses, and inhibited NLRP3 inflammasome-related pathways.

CONCLUSION

Our study demonstrates that RU486 significantly suppresses microglial activation and effectively reduces neuroinflammation by modulating the NLRP3/JAK1/STAT3 signaling pathway, thereby alleviating PTSD-like symptoms. These findings highlight RU486 as a promising therapeutic candidate for stress-related inflammatory disorders such as PTSD.