Hydrogen Sulfide Reverses LPS-Induced Behavioral Deficits by Suppressing Microglial Activation and Promoting M2...

Activation of microglia is a hallmark of neuroinflammation and has been implicated in the development of many psychiatric disorders. Hydrogen sulfide (H₂S); a gasotransmitter has recently emerged as a potent antioxidant and anti-inflammatory molecule. However, the protective potential of H₂S and its underpin molecular mechanisms in neuroinflammation associated behavioral deficits are still unknown. The present study has been designed to investigate the effect of sodium hydrogen sulfide (NaHS; a source of H₂S) on microglial activation and associated behavior phenotype in response to lipopolysaccharide (LPS)-induced neuroinflammation. LPS treatment decreased H₂S levels with a concomitant increase in reactive oxygen species (ROS) in the cortex and hippocampus. However, NaHS administration restored the endogenous H₂S levels to the normal and decreased ROS levels. NaHS supplementation reduced the number of active microglia in the cortex and hippocampus of LPS treated animals. Morphological analysis of microglia showed significant increase in microglial density, span ratio and soma area in the cortex and hippocampus of LPS treated animals which was decreased by NaHS supplementation. Moreover, NaHS administration reduced the expression of microglial M1 phenotype markers (IL-1β, TNF-α and nitrite) and concomitantly increased the expression of M2 phenotype markers (IL-4 and TGF-β) in the brain regions of LPS treated animals. Furthermore, LPS-induced anxiety-like behavior assessed by open field test and elevated plus maze was reversed by NaHS supplementation. Taken together, these findings suggest that H₂S supplementation ameliorates LPS-induced behavioral deficits by suppressing pro-inflammatory and promoting anti-inflammatory microglial response. Therefore, H₂S releasing drugs may be potential therapeutics to treat neuroinflammation associated psychiatric disorders. Graphical abstract.