Endogenous Hydrogen Sulfide is Involved in Asymmetric Dimethylarginine-induced Protection Against Neurotoxicity of 1-Methyl-4-phenyl-pyridinium Ion |
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Authors: | Tang Xiao-Qing Fang Heng-Rong Li Yu-Juan Zhou Cheng-Fang Ren Yan-Kai Chen Rong-Qian Wang Chun-Yan Hu Bi |
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Institution: | (1) Department of Physiology, Medical College, University of South China, 28 W Changsheng Road, Hengyang, 421001, Hunan, People’s Republic of China;(2) Institute of Cognition and Nervous systems disease, Medical College, University of south China, Hengyang, 421001, Hunan, People’s Republic of China;(3) Department of Pathphysiology, Medical College, University of South China, Hengyang, 421001, Hunan, People’s Republic of China |
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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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