Abstract
BackgroundEmerging studies have demonstrated the important physiological and pathophysiological roles of hydrogen sulphide (H2S) 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 H2S on neuroinflammation after intracerebral haemorrhage (ICH), especially on the NLRP3 inflammasome, remain unknown.MethodsWe employed a Sprague–Dawley rat of collagenase-induced ICH in the present study. The time course of H2S content and the spatial expression of cystathionine-β-synthase (CBS) after ICH, the effects of endogenous and exogenous H2S after ICH, the effects of endogenous and exogenous H2S on NLRP3 inflammasome activation under P2X7 receptor (P2X7R) overexpression after ICH, and the involvement of the P2X7R in the mechanism by which microglia-derived H2S prevented NLRP3 inflammasome activation were investigated.ResultsWe found ICH induced significant downregulation of endogenous H2S production in the brain, which may be the result of decreasing in CBS, the predominant cerebral H2S-generating enzyme. Administration of S-adenosyl-l-methionine (SAM), a CBS-specific agonist, or sodium hydrosulfide (NaHS), a classical exogenous H2S donor, not only restored brain and plasma H2S content but also attenuated brain oedema, microglial accumulation and neurological deficits at 1 day post-ICH by inhibiting the P2X7R/NLRP3 inflammasome cascade. Endogenous H2S production, which was derived mainly by microglia and above treatments, was verified by adenovirus-overexpressed P2X7R and in vitro primary microglia studies.ConclusionsThese results indicated endogenous H2S 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 H2S concentrations in the central nervous system may represent a potential therapeutic strategy for managing post-ICH secondary brain injury and associated neurological deficits.
Highlights
Emerging studies have demonstrated the important physiological and pathophysiological roles of hydrogen sulphide (H2S) as a gasotransmitter for NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomeassociated neuroinflammation in the central nervous system
The western blotting results indicated that CBS, a key enzyme involved in endogenous Hydrogen sulphide (H2S) synthesis, exhibited the same trend in its protein levels as H2S concentrations in the ipsilateral/ right hemisphere after intracerebral haemorrhage (ICH) (Fig. 1b)
Our data indicated that both SAM administration and Sodium hydrosulfide (NaHS) administration significantly increased H2S content in the brain striatum (p < 0.05 vs. vehicle, Fig. 1d) and blood plasma (p < 0.05 vs. vehicle, Fig. 1e) at 1 day after ICH
Summary
Emerging studies have demonstrated the important physiological and pathophysiological roles of hydrogen sulphide (H2S) as a gasotransmitter for NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomeassociated neuroinflammation in the central nervous system. The effects of H2S on neuroinflammation after intracerebral haemorrhage (ICH), especially on the NLRP3 inflammasome, remain unknown. H2S has been considered a toxic and potentially lethal gas for centuries, but emerging studies have demonstrated its important physiological and pathophysiological roles as a gasotransmitter in the central nervous system and in other tissues [7]. H2S plays a significant neuroprotective role in central nervous system diseases, including Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, subarachnoid haemorrhage and ischaemic stroke, as a result of its anti-inflammatory and anti-oxidative effects [7, 9, 10]. The effects of H2S on neuroinflammation after ICH, especially its effects on the NLRP3 inflammasome, remain unknown
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