Abstract
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.
Highlights
Intracerebral hemorrhage (ICH) is the second most common subtype of stroke leading to high mortality and morbidity throughout the world (van Asch et al, 2010; Kim and Bae, 2017)
The post-ICH brain injury can be distinguished into primary brain injury caused by disruption and mechanical deformation of brain tissue due to hematoma growth, and secondary brain injury induced by microglia activation, mitochondrial dysfunction, and neurotransmitter and inflammatory mediator release, which lead to cell death, including apoptosis and autophagy (Bobinger et al, 2018)
We found that ICH induced the activation of autophagy, and inhibition of autophagy was recognized as a therapeutic strategy of brain injury after hemorrhage in an ICH model (Shen et al, 2016)
Summary
Intracerebral hemorrhage (ICH) is the second most common subtype of stroke (up to 15% of all strokes) leading to high mortality and morbidity throughout the world (van Asch et al, 2010; Kim and Bae, 2017). The post-ICH brain injury can be distinguished into primary brain injury caused by disruption and mechanical deformation of brain tissue due to hematoma growth, and secondary brain injury induced by microglia activation, mitochondrial dysfunction, and neurotransmitter and inflammatory mediator release, which lead to cell death, including apoptosis and autophagy (Bobinger et al, 2018). These cell death pathways lead to the removal of inactivated and damaged cells and result in neuronal cell damage and poor neurological outcome (Lin et al, 2018). Based on the findings mentioned above, a mouse model of ICH was established to evaluate therapeutic efficacy and neuroprotective mechanism of H2S against brain injury
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