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

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Abstract

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is profoundly protective against 1-methy-4-phenylpyridinium ion (MPP+)-induced neurotoxicity. Reactive oxygen species (ROS) overproduction contributes to the neurotoxicity of MPP+; while hydrogen sulfide (H2S) is a pivotal endogenous antioxidant. This study is to assess the potential role of endogenous H2S in the neuroprotection of ADMA against MPP+-induced toxicity in PC12 cells. We showed that ADMA prevented MPP+-induced inhibition of endogenous H2S generation through inhibiting the down-regulation of cystathionine-β-synthetase (CBS, the major enzyme responsible for endogenous H2S generation in PC12 cells) expression and activity elicited by MPP+. ADMA obviously attenuated MPP+-triggered accumulation of intracellular ROS, dissipation of mitochondrial membrane potential (MMP), release of cytochrome c (Cyt-c), and downregulation of Bcl-2 protein expression in PC12 cells. Inhibition of CBS activity by amino-oxyacetate and CBS silencing with a short hairpin RNA vector targeting rat CBS gene reversed the protective action of ADMA against MPP+-caused cytotoxicity, ROS overproduction, and MMP loss in PC12 cells. These results indicate that the protection of ADMA against MPP+-mediated neurotoxicity involves the melioration of MPP+-induced inhibition of endogenous H2S generation. Our findings suggest that modulation of H2S production provide new therapeutic targets for the treatment of neurodegenerative disease, such as Parkinson’s disease.

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Acknowledgments

This study was supported by Natural Science Foundation of China (81071005, 30770740), Natural Science Foundation of Hunan Province, China (06JJ2074).

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Authors and Affiliations

  1. Department of Physiology, Medical College, University of South China, 28 W Changsheng Road, Hengyang, 421001, Hunan, People’s Republic of China

    Xiao-Qing Tang, Heng-Rong Fang, Yu-Juan Li, Cheng-Fang Zhou, Yan-Kai Ren, Rong-Qian Chen & Bi Hu

  2. Institute of Cognition and Nervous systems disease, Medical College, University of south China, Hengyang, 421001, Hunan, People’s Republic of China

    Xiao-Qing Tang, Heng-Rong Fang, Yu-Juan Li, Cheng-Fang Zhou, Yan-Kai Ren, Rong-Qian Chen & Bi Hu

  3. Department of Pathphysiology, Medical College, University of South China, Hengyang, 421001, Hunan, People’s Republic of China

    Chun-Yan Wang

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  1. Xiao-Qing Tang
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Correspondence to Xiao-Qing Tang or Chun-Yan Wang.

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Tang, XQ., Fang, HR., Li, YJ. et al. Endogenous Hydrogen Sulfide is Involved in Asymmetric Dimethylarginine-induced Protection Against Neurotoxicity of 1-Methyl-4-phenyl-pyridinium Ion. Neurochem Res 36, 2176–2185 (2011). https://doi.org/10.1007/s11064-011-0542-y

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