title: Role of paraoxonase-1 in the protection of hydrogen sulfide-donating sildenafil (ACS6) against homocysteine-induced neurotoxicity.
abstract: ACS6, a novel hydrogen sulfide (H2S)-releasing sildenafil, has been demonstrated to inhibit superoxide formation through donating H2S. We have previously found that ACS6 antagonizes homocysteine-induced apoptosis and cytotoxicity. The aim of the present study is to explore the molecular mechanisms underlying ACS6-exerted protective action against the neurotoxicity of homocysteine. In the present work, we used PC12 cells to explore whether paraoxonase-1 (PON-1) is implicated in ACS6-induced neuroprotection against homocysteine neurotoxicity. We show that ACS6 treatment results in prevention of homocysteine-caused neurotoxicity and overproduction of reactive oxygen species (ROS). Homocysteine downregulates the expression and activity of PON-1; however, this effect is significantly blocked by co-treatment with ACS6. The specific inhibitor of PON-1 2-hydroxyquinoline reverses the inhibitory effect of ACS6 on homocysteine-induced neurotoxicity and intracellular ROS accumulation. These results indicate that ACS6 protects PC12 cells against homocysteine-induced neurotoxicity by upregulating PON-1 and suggest a promising role of PON-1 as a novel therapeutic strategy for homocysteine-induced toxicity.
authors: Institute of Cognition and Nervous System Diseases, Medical College, University of South China, 28 W Changsheng Road, Hengyang 421001, Hunan, People's Republic of China. txq01001@163.com
authors: Xiao-Qing
authors: XQ
authors: Tang
authors: Rong-Qian
authors: RQ
authors: Chen
authors: Ling
authors: L
authors: Dong
authors: Yan-Kai
authors: YK
authors: Ren
authors: Piero
authors: P
authors: Del Soldato
authors: Anna
authors: A
authors: Sparatore
authors: Duan-Fang
authors: DF
authors: Liao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D043303:Aryldialkylphosphatase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006710:Homocysteine / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*
chemical_list: C534144:1-piperazineacetic acid 4-((3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo(4,3-d)pyrimidin-5-yl)-4-ethoxyphenyl)sulfonyl)-4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl ester; D018696:Neuroprotective Agents; D010879:Piperazines; D017382:Reactive Oxygen Species; D013450:Sulfones; D006710:Homocysteine; C572204:Pon1 protein, rat; D043303:Aryldialkylphosphatase