title: A superoxide anion-scavenger, 1,3-selenazolidin-4-one suppresses serum deprivation-induced apoptosis in PC12 cells by activating MAP kinase.
abstract: Synthetic organic selenium compounds, such as ebselen, may show glutathione peroxidase-like antioxidant activity and have a neurotrophic effect. We synthesized 1,3-selenazolidin-4-ones, new types of synthetic organic selenium compounds (five-member ring compounds), to study their possible applications as antioxidants or neurotrophic-like molecules. Their superoxide radical scavenging effects were assessed using the quantitative, highly sensitive method of real-time kinetic chemiluminescence. At 166μM, the O(2)(-) scavenging activity of 1,3-selenazolidin-4-ones ranged from 0 to 66.2%. 2-[3-(4-Methoxyphenyl)-4-oxo-1,3-selenazolidin-2-ylidene]malononitrile (compound b) showed the strongest superoxide anion-scavenging activity among the 6 kinds of 2-methylene-1,3-selenazolidin-4-ones examined. Compound b had a 50% inhibitory concentration (IC(50)) at 92.4μM and acted as an effective and potentially useful O(2)(-) scavenger in vitro. The effect of compound b on rat pheochromocytome cell line PC12 cells was compared with that of ebselen or nerve growth factor (NGF) by use of the MTT [3-(4, 5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] assay. When ebselen was added at 100μM or more, toxicity toward PC12 cells was evident. On the contrary, compound b suppressed serum deprivation-induced apoptosis in PC12 cells more effectively at a concentration of 100μM. The activity of compound b to phosphorylate mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK) 1/2 (MAP kinase) in PC12 cells was higher than that of ebselen, and the former at 100μM induced the phosphorylation of MAP kinase to a degree similar to that induced by NGF. From these results, we conclude that this superoxide anion-scavenger, compound b, suppressed serum deprivation-induced apoptosis by promoting the phosphorylation of MAP kinase.
authors: Yonezawa Women's Junior College, 6-15-1 Tohrimachi, Yonezawa, Yamagata 992-0025, Japan. nishina@yone.ac.jp
authors: Atsuyoshi
authors: A
authors: Nishina
authors: Hirokazu
authors: H
authors: Kimura
authors: Kunihisa
authors: K
authors: Kozawa
authors: Geoffroy
authors: G
authors: Sommen
authors: Takao
authors: T
authors: Nakamura
authors: Heinz
authors: H
authors: Heimgartner
authors: Mamoru
authors: M
authors: Koketsu
authors: Shoei
authors: S
authors: Furukawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D054833:Isoindoles; D008163:Luminescent Measurements; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism*
chemical_list: D001393:Azoles; D016166:Free Radical Scavengers; D054833:Isoindoles; D016566:Organoselenium Compounds; D013481:Superoxides; C042986:ebselen; D020932:Nerve Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3