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Title: Protective effects of hydrogen sulfide against 6-hydroxydopamine-induced cell injury - implication for treatment of Parkinson's disease
Keywords: H2S, 6-OHDA, Parkinson's disease, SH-SY5Y, ER stress, neurodegeneration
Issue Date: 3-Aug-2011
Citation: TIONG CHI XIN (2011-08-03). Protective effects of hydrogen sulfide against 6-hydroxydopamine-induced cell injury - implication for treatment of Parkinson's disease. ScholarBank@NUS Repository.
Abstract: Parkinson's disease (PD), the second most common neurodegenerative disease, is caused by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by an alteration in the dopamine concentration in the striatum. Hydrogen sulfide (H2S), the newest member of the gasotransmitter family, serves as an important neuromodulator in regulation of the brain functions. The present study aimed to investigate the protective effect of H2S against cell injury induced by 6-hydroxydopamine (6-OHDA), a selective dopaminergic neurotoxin often used to establish a model of PD. The effect of H2S on neurotoxin, 6-OHDA was first examined. It was found that the exposure to 6-OHDA at 50-200 ?M for 12 h decreased cell viability of SH-SY5Y cells. Exogenous application of NaHS (an H2S donor) at 100-1000 ?M or overexpression of cystathionine ?-synthase (a predominant enzyme to produce endogenous H2S in SH-SY5Y cells) protected cells against 6-OHDA-induced cell apoptosis and death. NaHS (100 ?M) also reversed the up-regulation of cleaved poly (ADP-ribose) polymerase (PARP) in 6-OHDA (50 ?M)-treated cells. Furthermore, NaHS reversed 6-OHDA-induced loss of tyrosine hydroxylase, the rate-limiting enzyme for dopamine production. The underlying signaling mechanisms for H2S protection are associated with the activation of PKCa,e and PI3K/Akt pathway. In addition, blockade of PKCa and e with their specific inhibitors significantly attenuated NaHS-induced Akt phosphorylation, suggesting that activation of Akt by NaHS is PKCa, e-dependent. As endoplasmic reticulum (ER) stress has been indicated as a potential mediator of PD, the effect of H2S on 6-OHDA-induced ER stress was also examined in this study. Consistent with its cytoprotection, NaHS markedly reduced 6-OHDA- induced ER stress responses, including up-regulation of phospho-eIF2a, BiP mRNA level and CHOP protein expression level. The protective effect of NaHS against ER stress was mediated by Akt and Hsp90. Interestingly, a decrease in the levels of Hsp90 upon inhibition of Akt activity was observed, suggesting that activation of Akt by NaHS may stimulate Hsp90 protein expression. In conclusion, the present study demonstrate for the first time that H2S may protect against cell injury and ER stress induced by 6-OHDA neurotoxin via multiple signaling mechanisms and therefore has the potential therapeutic value for PD treatment.
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