Hydrogen Sulfide Inhibits Chronic Unpredictable Mild Stress-Induced Depressive-Like Behavior by Upregulation of Sirt-1: Involvement in Suppression of Hippocampal Endoplasmic Reticulum Stress

摘要

Background 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. Methods 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. Results 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. Conclusion 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. chronic unpredictable mild stress , depression , endoplasmic reticulum stress , hydrogen sulfide , silent mating type information regulation 2 homolog 1 Significance Statement Depression is a chronic and recurrent serious mental disorder that affects about 10% of the world population and imposes a substantial societal burden. Therefore, understanding the prevention bases and looking for a future therapeutic target on depression are extremely urgent. The present work is to investigate the inhibitory action of H₂S in CUMS-induced depression-like behaviors and the underlying mechanisms. In our study, we found that H₂S ameliorated CUMS-induced depression-like behaviors, involving inhibition of hippocampal ER stress, by upregulation of hippocampal Sirt-1. Findings from our present work identify H₂S as a potential target for therapeutic intervention in depression.