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Hydrogen Sulfide Inhibits Rotenone-Induced Apoptosis via Preservation of Mitochondrial Function

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

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 (_m) 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 (mitoK_ATP) 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 mitoK_ATP channel/p38- and JNK-MAPK pathway. Our data suggest that H₂S may have potential therapeutic value for neurodegenerative diseases, such as PD.

Address correspondence to: Dr. Jin-Song Bian, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597. E-mail: phcbjs{at}nus.edu.sg.