title: Endogenous hydrogen sulfide is involved in asymmetric dimethylarginine-induced protection against neurotoxicity of 1-methyl-4-phenyl-pyridinium ion.
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.
authors: Department of Physiology, Medical College, University of South China, 28 W Changsheng Road, Hengyang, 421001 Hunan, People's Republic of China. txq01001@gmail.com
authors: Xiao-Qing
authors: XQ
authors: Tang
authors: Heng-Rong
authors: HR
authors: Fang
authors: Yu-Juan
authors: YJ
authors: Li
authors: Cheng-Fang
authors: CF
authors: Zhou
authors: Yan-Kai
authors: YK
authors: Ren
authors: Rong-Qian
authors: RQ
authors: Chen
authors: Chun-Yan
authors: CY
authors: Wang
authors: Bi
authors: B
authors: Hu
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology / Q000633:toxicity*; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019938:Cyclin D1 / Q000096:biosynthesis; D003541:Cystathionine beta-Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000378:metabolism* / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D019938:Cyclin D1; D000625:Aminooxyacetic Acid; C018524:N,N-dimethylarginine; D045304:Cytochromes c; D001120:Arginine; D003541:Cystathionine beta-Synthase; D015655:1-Methyl-4-phenylpyridinium; D006862:Hydrogen Sulfide