Exogenous Hydrogen Sulfide Offers Neuroprotection on Intracerebral Hemorrhage Injury Through Modulating Endogenous H2S Metabolism in Mice.

Hydrogen sulfide (H₂S), an important endogenous signaling molecule, has a significant neuroprotective role in the central nervous system. In this study, we examined the protective effects of exogenous H₂S against intracerebral hemorrhage (ICH), as well as its underlying mechanisms. We investigated the effects of exogenous H₂S on ICH using Western blotting, injury volume, measurement of brain edema, propidium iodide (PI) staining, and behavior assessment, respectively. We found that endogenous H₂S production was downregulated in the brain after ICH, which is caused by the decrease in cystathionine β-synthase (CBS) as the predominant cerebral H₂S-generating enzyme in the brain. Treatment with sodium hydrosulfide (NaHS; an H₂S producer) could restore the H₂S production and the expression of CBS. NaHS could also attenuate brain edema, injury volume, and neurological deficits in the Morris water maze test after ICH. Western blotting results indicated that H₂S pretreatment reversed the increase in caspase 3 cleavage and the decrease in Bcl-2, suppressed the activation of autophagy marker (LC3II and Beclin-1), and maintained the p62 level in injured striatum post-ICH. However, H₂S could not restore brain CBS expression and H₂S content, reduce brain edema, and improve motor performance and memory function after ICH through modulating autophagy and apoptosis when pretreated with the CBS inhibitor aminooxyacetic acid (AOAA). We also found that AOAA reduced the endogenous H₂S production through inhibiting the enzyme activity of CBS rather than modulating the expression of CBS protein level. These present results indicate that H₂S may possess potential therapeutic value in the treatment of brain injury after ICH, and the protective effect of exogenous H₂S against ICH may be not a direct action but an indirect effect through inducing endogenous H₂S metabolism responses.