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Innate immune and inflammatory responses are important factors in the pathophysiology of secondary brain injury following intracerebral hemorrhage(ICH).The NLRP3 inflammasome,the most characterized pattern recognition receptor(PRR)in innate immune response initiation,is strongly involved in ICH-induced acute inflammation and produces pro-inflammatory factors such as IL-1β.Hydrogen sulfide(H2S)increasingly recognized as the third signaling gasotransmitter after carbon monoxide(CO)and nitric oxide(NO)was demonstrated to play a key role in inflammatory responses of neurological diseases including Alzheimers disease,Parkinsons disease,traumatic brain injury,subarachnoid hemorrhage and ischemia stroke.However,the potential effect of H2S on NLRP3 inflammasome activation following ICH is not well known.Previous study found that blockading the P2X7 receptor,could prevent the NLRP3 inflammasome activation and the subsequent brain injury afer ICH.In the current study,we tested the hypothesis that H2S alleviates acute inflammatory injury mediated by NLRP3 inflammasome activation after ICH and explored whether P2X7 receptor involved its underlying mechanisms.ICH model was established by injecting bacterial collagenase into the striatum in male Sprague–Dawley rats.S-adenosyl-L-methionine(SAM)as cerebral predominant H2S generating enzymes cystathionine-β-synthase(CBS)specific activator and sodium hydrosulfide(NaHS),a common donor of H2S were administered to evaluate both the endogenous and exogenous effects of H2S after ICH.Adenoviruses was intracerebroventricularly injected to upregulate P2X7 receptor expression before ICH.In vitro,rat primary microglial cells was treated with SAM and NaHS to verified the effect of H2S under lipopolysaccharide(LPS)and ATP stimulation.H2S content,neurological function,hemorrhagic volume,brain water content,cell viability were evaluated,and western blot,Real-Time-PCR,Fluoro-Jade C staining,immunofluorescence,and terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)were carried out.The H2S level and protein expression of CBS reduced to a minimum at 24 hours post-ICH and administration of both SAM and NaHS showed attenuated H2S content,functional impairment,brain edema,neutrophils infiltration and microglia accumulation.NLRP3 inflammasome activation and the number of P2X7 receptor-positive microglia were significantly reduced after SAM or NaHS treatment post-ICH.Similar outcomes were observed that an adverse effect after overexpression of P2X7 receptor by adenoviruses treatment following ICH was also inhibited by SAM or NaHS treatment.Furthermore,LPS and ATP stimulation reduced cell viability and increased NLRP3 inflammasome activation and P2X7 receptor protein levels,whereas both SAM and NaHS normalized these effects.Our results suggest that both stimulating endogenous H2S production and exogenous H2S administration could significantly reduce NLRP3 inflammasome activation and brain injury induced by ICH through suppressing P2X7 Receptor expression.