Endogenous hydrogen sulphide attenuates NLRP3 inflammasome-mediated neuroinflammation by suppressing the P2X7 receptor after intracerebral haemorrhage in rats

Emerging studies have demonstrated the important physiological and pathophysiological roles of hydrogen sulphide (H 2 S) as a gasotransmitter for NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-associated neuroinflammation in the central nervous system. However, the effects of H 2 S on neuroinflammation after intracerebral haemorrhage (ICH), especially on the NLRP3 inflammasome, remain unknown. We employed a Sprague–Dawley rat of collagenase-induced ICH in the present study. The time course of H 2 S content and the spatial expression of cystathionine-β-synthase (CBS) after ICH, the effects of endogenous and exogenous H 2 S after ICH, the effects of endogenous and exogenous H 2 S on NLRP3 inflammasome activation under P2X7 receptor (P2X7R) overexpression after ICH, and the involvement of the P2X7R in the mechanism by which microglia-derived H 2 S prevented NLRP3 inflammasome activation were investigated. We found ICH induced significant downregulation of endogenous H 2 S production in the brain, which may be the result of decreasing in CBS, the predominant cerebral H 2 S-generating enzyme. Administration of S -adenosyl- l -methionine (SAM), a CBS-specific agonist, or sodium hydrosulfide (NaHS), a classical exogenous H 2 S donor, not only restored brain and plasma H 2 S content but also attenuated brain oedema, microglial accumulation and neurological deficits at 1 day post-ICH by inhibiting the P2X7R/NLRP3 inflammasome cascade. Endogenous H 2 S production, which was derived mainly by microglia and above treatments, was verified by adenovirus-overexpressed P2X7R and in vitro primary microglia studies. These results indicated endogenous H 2 S synthesis was impaired after ICH, which plays a pivotal role in the P2X7R/NLRP3 inflammasome-associated neuroinflammatory response in the pathogenesis of secondary brain injury. Maintaining appropriate H 2 S concentrations in the central nervous system may represent a potential therapeutic strategy for managing post-ICH secondary brain injury and associated neurological deficits.