Inhibition of Hydrogen Sulfide Generation Contributes to 1-Methy-4-Phenylpyridinium Ion-Induced Neurotoxicity.

Reactive oxygen species (ROS) overproduction contributes to the neurotoxicity of 1-methy-4-phenylpyridinium ion (MPP). Increasing studies have shown that hydrogen sulfide (HS) 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 HS synthesis in PC12 cells, a clonal rat pheochromocytoma cell line, and whether disturbance of HS 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 HS generation and results in remarkable cell damage. We find that cystathionine-β-synthetase (CBS) is catalyzed in PC12 cells to generate HS, and that both expression and activity of CBS are inhibited by MPP treatment. Exposure of sodium hydrosulfide (NaHS), a donor of HS, 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 HS 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. [ABSTRACT FROM AUTHOR]