Hydrogen sulfide inhibits rotenone-induced apoptosis via preservation of mitochondrial function.
Hydrogen sulfide (H(2)S) 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 H(2)S 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 H(2)S donor, concentration-dependently suppressed rotenone-induced cellular injury and apoptotic cell death. NaHS also prevented rotenone-induced p38- and c-Jun NH(2)-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) phosphorylation and rotenone-mediated changes in Bcl-2/Bax levels, mitochondrial membrane potential (DeltaPsi(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 H(2)S inhibited rotenone-induced cell apoptosis via regulation of mitoK(ATP) channel/p38- and JNK-MAPK pathway. Our data suggest that H(2)S may have potential therapeutic value for neurodegenerative diseases, such as PD.
Hu
Li-Fang
LF
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Lu
Ming
M
Wu
Zhi-Yuan
ZY
Wong
Peter T-H
PT
Bian
Jin-Song
JS
D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000378:metabolism; D002232:Carbocyanines / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005456:Fluorescent Dyes / Q000378:metabolism; D005562:Formazans / Q000378:metabolism; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D012402:Rotenone / Q000633:toxicity*; D013778:Tetrazolium Salts / Q000378:metabolism; D014475:Uncoupling Agents / Q000633:toxicity*
D001562:Benzimidazoles; D002232:Carbocyanines; D005456:Fluorescent Dyes; D005562:Formazans; D013778:Tetrazolium Salts; D014475:Uncoupling Agents; D012402:Rotenone; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; C079782:MTT formazan; C017807:bisbenzimide ethoxide trihydrochloride; D006862:Hydrogen Sulfide