title: Nitric oxide-mediated toxicity in paraquat-exposed SH-SY5Y cells: a protective role of 7-nitroindazole.
abstract: The precise mechanism underlying the role of nitric oxide (NO) or nitric oxide synthases (NOSs) in paraquat-mediated toxicity is yet to be fully elucidated. The importance of the NADPH-diaphorase activity of NOSs in paraquat toxicity, in addition to the production of NO, has previously been reported as a mechanism of toxicity. However, other studies have highlighted the toxicity of NO alone and, conversely a protective role of NO in paraquat-mediated toxicity has also been described. The goal of this study was to clarify the involvement of NO and NOS in paraquat-mediated toxicity in an SH-SY5Y cell system, and to evaluate the putative role of 7-nitroindazole as a protective agent in human neural cells. Our results indicate that the three previously described isoforms of NOS are expressed in SH-SY5Y cells, with the data showing that these synthases act as paraquat diaphorases. While this process could occur at the expense of NO production, NO alone does play a toxic role, with its production leading to the formation of the toxicant peroxynitrite. Although the efficacies of the different inhibitors tested cannot be directly compared because the various NOS forms were probably inhibited to differing extents, the results support the idea that endogenous and inducible NO is a neurotoxic mediator of the effects of paraquat. The NADPH-diaphorase activity of NOS and NO production are therefore factors implicated in the toxicity mediated by the herbicide paraquat.
authors.affiliation: Departamento de Bioquímica y Biología Molecular y Genética, EU Enfermería y TO, Universidad de Extremadura, CIBER de Enfermedades Neurodegenerativas (CIBERNED), Avda Universidad s/n, Cáceres, 10071, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Ortiz-Ortiz
authors.forename: José M
authors.initials: JM
authors.lastname: Morán
authors.forename: Rosa A
authors.initials: RA
authors.lastname: González-Polo
authors.forename: Mireia
authors.initials: M
authors.lastname: Niso-Santano
authors.forename: Germán
authors.initials: G
authors.lastname: Soler
authors.forename: José M
authors.initials: JM
authors.lastname: Bravo-San Pedro
authors.forename: José M
authors.initials: JM
authors.lastname: Fuentes
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D009252:NADPH Dehydrogenase / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009447:Neuroblastoma; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010269:Paraquat / Q000633:toxicity*; D030421:Peroxynitrous Acid / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D004533:Egtazic Acid; D004791:Enzyme Inhibitors; D006540:Herbicides; D007191:Indazoles; D009252:NADPH Dehydrogenase; D019331:NG-Nitroarginine Methyl Ester; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009687:Nuclear Proteins; D010269:Paraquat; D030421:Peroxynitrous Acid; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C495901:TP53 protein, human; C022616:thiazolyl blue; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C080122:7-nitroindazole