Abstract
Hydrogen sulfide (H2S) has been proposed as a novel neuromodulator, which plays critical roles in the central nervous system affecting both neurons and glial cells. However, its relationship with neurodegenerative diseases is unexplored. The present study was undertaken to investigate the effects of H2S on cell injury induced by rotenone, a commonly used toxin in establishing in vivo and in vitro Parkinson's disease (PD) models, in human-derived dopaminergic neuroblastoma cell line (SH-SY5Y). We report here that sodium hydrosulfide (NaHS), an H2S donor, concentration-dependently suppressed rotenone-induced cellular injury and apoptotic cell death. NaHS also prevented rotenone-induced p38- and c-Jun NH2-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) phosphorylation and rotenone-mediated changes in Bcl-2/Bax levels, mitochondrial membrane potential (ΔΨm) dissipation, cytochrome c release, caspase-9/3 activation and poly(ADP-ribose) polymerase cleavage. Furthermore, 5-hydroxydecanoate, a selective blocker of mitochondrial ATP-sensitive potassium (mitoKATP) channel, attenuated the protective effects of NaHS against rotenone-induced cell apoptosis. Thus, we demonstrated for the first time that H2S inhibited rotenone-induced cell apoptosis via regulation of mitoKATP channel/p38- and JNK-MAPK pathway. Our data suggest that H2S may have potential therapeutic value for neurodegenerative diseases, such as PD.
Footnotes
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This work was supported by research grants from Singapore National Medical Research Council (1057/2006) and Singapore Biomedical Research Council (07/1/21/19/509).
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ABBREVIATIONS: MAPK, mitogen-activated protein kinase; 5-HD, 5-hydroxydecanoate; mitoKATP channel, mitochondrial ATP-sensitive potassium channel; ΔΨm, mitochondrial membrane potential; PD, Parkinson's disease; PARP, poly(ADP-ribose) polymerase; JNK, c-Jun NH2-terminal kinase; ERK, extracellular signal-regulated kinase; DMSO, dimethyl sulfoxide; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; PBS, phosphate-buffered saline; PAGE, polyacrylamide gel electrophoresis; TBST, Tris-buffered saline/Tween 20; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; SP600125, anthra(1,9-cd)pyrazol-6(2H)-one 1,9-pyrazoloanthrone.
- Received April 15, 2008.
- Accepted October 2, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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