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

Abstract

Activation of microglia is ahallmark ofneuroinflammationand has been implicated in thedevelopment of manypsychiatric disorders. Hydrogen sulfide (H2S); a gasotransmitter has recently emerged as a potent antioxidant and anti-inflammatory molecule. However, the protective potential of H2Sandits underpin molecularmechanisms in neuroinflammation associated behavioral deficits arestill 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 thenormal 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 byNaHS supplementation. Moreover, NaHS administration reduced the expression of microglialM1 phenotype markers (IL-1β, TNF-α and nitrite) and concomitantlyincreased 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 fieldtest 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.