Cystathionine-β-synthase-derived hydrogen sulfide contributes to glucocorticoid-induced depressive-like behaviors in rats by modulating neuroinflammation

Long-term treatment of glucocorticoids (GCs) may lead to depressive adverse effect. Hydrogen sulfide (H2S) is implicated in the pathophysiology of depression and has an ability to modulate neuroinflammatory, which underlies the pathogenesis of depression. The aim of this study was to investigate whether H2S signaling contributed to dexamethasone (DEX)-induced depression in a rat model. Rats were subcutaneously injected with DEX (5mg/kg) once daily for 28 days. The behavioral performances were examined by social interaction test (SIT), sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST). The expressions of cystathionine-β-synthase (CBS) and inducible nitric oxide synthase (iNOS) were measured by western blotting and immunofluorescence assay. Cytokine levels were examined by enzyme-linked immunosorbent assay (ELISA) kits. The morphological changes of neurons in rat hippocampal CA1 region were observed using H.E. staining. We found that chronic DEX treatment caused obvious depressive-like behaviors in rats, and the levels of H2S and CBS, the predominant H2S-producing enzyme in the brain, were significantly reduced in the hippocampus of DEX-treated rats. Overexpression of CBS increased the levels of H2S and CBS protein in the hippocampus and attenuated the depressive-like behaviors in DEX-treated rats, whereas inhibition of CBS activity abolished the beneficial effects of CBS elevation. Mechanismly, chronic DEX treatment reduced the levels of anti-inflammatory cytokines IL-10 and TGF-β, increased the levels of pro-inflammatory cytokines IL-1β and TNF-α, and caused neuronal damage in the hippocampus of rats, while CBS overexpression reversed these changes caused by DEX treatment. Furthermore, the increased protein level of iNOS, a marker of microglia polarizing to M1 phenotype to produce pro-inflammatory effects, in the hippocampus of DEX-treated rats was also restored by CBS overexpression. These results indicate that CBS-derived H2S contributes to glucocorticoid-induced depressive-like behaviors in rats, and the effects of H2S signaling might involve the regulation of neuroinflammation.