Inhibition of Hydrogen Sulfide Generation Contributes to 1-Methy-4-Phenylpyridinium Ion-Induced Neurotoxicity
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Reactive oxygen species (ROS) overproduction contributes to the neurotoxicity of 1-methy-4-phenylpyridinium ion (MPP+). Increasing studies have shown that hydrogen sulfide (H2S) is an endogenous antioxidant gas. We have hypothesized that MPP+-caused neurotoxicity may involve the imbalance of proportion to this endogenous protective antioxidant gas. The aim of this study is to evaluate whether MPP+ disturbs H2S synthesis in PC12 cells, a clonal rat pheochromocytoma cell line, and whether disturbance of H2S generation induced by MPP+ is an underlying mechanism of MPP+-induced neurotoxicity. We show that exposure of PC12 cells to MPP+ causes a significant decrease in H2S generation and results in remarkable cell damage. We find that cystathionine-β-synthetase (CBS) is catalyzed in PC12 cells to generate H2S, and that both expression and activity of CBS are inhibited by MPP+ treatment. Exposure of sodium hydrosulfide (NaHS), a donor of H2S, extenuates MPP+-induced cytotoxicity and ROS accumulation in PC12 cells, while inhibition of CBS by amino-oxyacetate (AOAA) exacerbates the effects of MPP+. These results indicate that MPP+ neurotoxicity involves reduction of H2S production, which is caused by inhibition of CBS. This study provides novel insights into cell death observed in neurodegenerative disease such as Parkinson’s disease.