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

Abstract

Reactive oxygen species (ROS) overproduction contributes to the neurotoxicity of 1-methy-4-phenylpyridinium ion (MPP(+)). Increasing studies have shown that hydrogen sulfide (H(2)S) 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 H(2)S synthesis in PC12 cells, a clonal rat pheochromocytoma cell line, and whether disturbance of H(2)S 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 H(2)S generation and results in remarkable cell damage. We find that cystathionine-β-synthetase (CBS) is catalyzed in PC12 cells to generate H(2)S, and that both expression and activity of CBS are inhibited by MPP(+) treatment. Exposure of sodium hydrosulfide (NaHS), a donor of H(2)S, 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 H(2)S 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.

Endogenous Hydrogen Sulfide is Involved in Asymmetric Dimethylarginine-induced Protection Against Neurotoxicity of 1-Methyl-4-phenyl-pyridinium Ion

“…-induced cytotoxcity and apoptosis in PC12 cells [7] and that inhibition of H 2 S by MPP ? is responsible for its neurotoxicity [19]. The present work shows that treatment of PC12 cells with It has been demonstrated that ROS play a central role in MPP ?…”

“…We have found that PC12 cells generate H 2 S by cystathionine-b-synthetase (CBS), not by cystathionine-c-lyase (CSE) [19]. Thus, knockdown of CBS in PC12 cells was accomplished using shRNA CBS (the shRNA target sequences is TGACCAGGCACCTGTGGTCAACGAGTC TG).…”

“…-induced Down-regulation of CBS Expression and Activity in PC12 Cells CBS is the major enzyme responsible for endogenous H 2 S generation in PC12 cells [19]. We determined the effect of ADMA on the expression and activity of CBS in MPP ?…”

“…We have found that PC12 cells generate H 2 S by cystathionine-b-synthetase (CBS) [19]. Therefore, in the present study, we used PC12 cells to assess the potential role of endogenous H 2 S in ADMA-exerted protection against the neurotoxicity of MPP ?…”

“…inhibits the generation of endogenous H 2 S [19], and that H 2 S has protective effects against MPP ? -induced cytotoxicity and apoptosis [19,20]. Thus, we speculated that the protective effect of ADMA on MPP ?…”