Hydrogen Sulfide Prevents LPS-Induced Depression-like Behavior through the Suppression of NLRP3 Inflammasome and Pyroptosis and the Improvement of Mitochondrial Function in the Hippocampus of Mice

SIMPLE SUMMARY: Depression is a significant public health problem, and its pathogenesis is associated with inflammation in the central nervous system. In this study, we investigated the effects of H(2)S donor NaHS treatment on depression-like behavior caused by lipopolysaccharide (LPS) and its potential mechanisms. It was found that H(2)S treatment prevented LPS-induced depression-like behavior. LPS resulted in NF-κB and NLRP3 inflammasome activation and pyroptosis in the hippocampus and led to hippocampal mitochondrial dysfunction, which could be reversed with H(2)S treatment. Our data indicate that H(2)S prevents LPS-induced depression-like behaviors via the inhibition of neuroinflammation and pyroptosis and improving mitochondrial function. H(2)S could be a promising therapeutic reagent for depression. ABSTRACT: Hydrogen sulfide (H(2)S) has been implicated to have antidepressive effects. We sought to investigate the prevention effects of H(2)S donor NaHS on depression-like behavior induced by lipopolysaccharide (LPS) in mice and its potential mechanisms. Sucrose preference, force swimming, open field, and elevate zero maze were used to evaluate depression-like behavior. NF-κB and NLRP3 inflammasome activation and mitochondrial function in the hippocampus were determined. It was found that depression-like behavior induced by LPS was prevented by NaHS pretreatment. LPS caused NF-κB and NLRP3 inflammasome activation in the hippocampus as evidenced by increased phosphorylated-p65 levels and increased NLRP3, ASC, caspase-1, and mature IL-1β levels in the hippocampus, which were also blocked by NaHS. LPS increased GSDMD-N levels and TUNEL-positive cells in the hippocampus, which was prevented by NaHS. Abnormal mitochondrial morphology in the hippocampus was found in LPS-treated mice. Mitochondrial membrane potential and ATP production were reduced, and ROS production was increased in the hippocampus of LPS-treated mice. NaHS pretreatment improved impaired mitochondrial morphology and increased membrane potential and ATP production and reduced ROS production in the hippocampus of LPS-treated mice. Our data indicate that H(2)S prevents LPS-induced depression-like behaviors by inhibiting NLRP3 inflammasome activation and pyroptosis and improving mitochondrial function in the hippocampus.