Hydrogen sulfide (H₂S) is a crucial signaling molecule with a wide range of physiological functions. Previously, we confirmed that stress-induced depression is accompanied with disturbance of H₂S generation in hippocampus. The present work attempted to investigate the inhibitory effect of H₂S on chronic unpredictable mild stress-induced depressive-like behaviors and the underlying mechanism. We established the rat model of chronic unpredictable mild stress to simulate depression. Open field test, forced swim test, and tail suspension test were used to assess depressive-like behaviors. The expression of Sirt-1 and three marked proteins related to endoplasmic reticulum stress (GRP-78, CHOP, and cleaved caspase-12) were detected by western blot. We found that chronic unpredictable mild stress-exposed rats exhibit depression-like behavior responses, including significantly increased immobility time in the forced swim test and tail suspension test, and decreased climbing time and swimming time in the forced swim test. In parallel, chronic unpredictable mild stress-exposed rats showed elevated levels of hippocampal endoplasmic reticulum stress and reduced levels of Sirt-1. However, NaHS (a donor of H₂S) not only alleviated chronic unpredictable mild stress-induced depressive-like behaviors and hippocampal endoplasmic reticulum stress, but it also increased the expression of hippocampal Sirt-1 in chronic unpredictable mild stress-exposed rats. Furthermore, Sirtinol, an inhibitor of Sirt-1, reversed the protective effects of H₂S against chronic unpredictable mild stress-induced depression-like behaviors and hippocampal endoplasmic reticulum stress. These results demonstrated that H₂S has an antidepressant potential, and the underlying mechanism is involved in the inhibition of hippocampal endoplasmic reticulum stress by upregulation of Sirt-1 in hippocampus. These findings identify H₂S as a novel therapeutic target for depression.

Hydrogen sulfide ameliorates cognitive dysfunction in streptozotocin-induced diabetic rats: involving suppression in hippocampal endoplasmic reticulum stress Hydrogen sulfide ameliorates cognitive dysfunction in streptozotocin-induced diabetic rats: involving suppression in hippocampal endoplasmic reticulum stress

Chronic unpredictable mild stress (CUMS) induces hippocampal oxidative stress. H₂S functions as a neuroprotectant against oxidative stress in brain. We have previously shown the upregulatory effect of H₂S on BDNF protein expression in the hippocampus of rats. Therefore, we hypothesized that H₂S prevents CUMS‐generated oxidative stress by upregulation of BDNF‐TrkB pathway. We showed that NaHS (0.03 or 0.1 mmol/kg/day) ameliorates the level of hippocampal oxidative stress, including reduced levels of malondialdehyde (MDA) and 4‐hydroxy‐2‐trans‐nonenal (4‐HNE), as well as increased level of glutathione (GSH) and activity of superoxide dismutase (SOD) in the hippocampus of CUMS‐treated rats. We also found that H₂S upregulated the level of BDNF and p‐TrkB protein in the hippocampus of CUMS rats. Furthermore, inhibition of BDNF signaling by K252a, an inhibitor of the BDNF receptor TrkB, blocked the antioxidant effects of H₂S on CUMS‐induced hippocampal oxidative stress. These results reveal the inhibitory role of H₂S in CUMS‐induced hippocampal oxidative stress, which is through upregulation of BDNF/TrkB pathway.