Metal sulfate-mediated induction of pathogenic genes and repression by phenyl butyl nitrone and Feralex-G.
Neurotoxic metal-induced oxidative damage to nervous tissue has been implicated in several progressive neurodegenerative disorders including Alzheimer's disease. In this study, using human brain cells in primary culture, the quenching of metal sulfate-induced reactive oxygen species (ROS) and ROS-sensitive gene expression was studied using the antioxidants ascorbate, folic acid, phenyl butyl nitrone and the chelators desferrioxamine and Feralex-G. Antioxidants ascorbate, folic acid, phenyl butyl nitrone, desferrioxamine or Feralex-G were found to quench ROS and cPLA2 and COX-2 gene induction to various degrees, and a synergism was observed when certain combinations of them were used. These findings support the idea that specific antioxidants and metal ion chelators when used together can effectively and synergistically quench ROS-mediated induction of pathogenic gene expression.
Kruck
Theodore P A
TP
Neurogenetics Laboratory, Surrey Place Centre and Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Percy
Maire E
ME
Lukiw
Walter J
WJ
D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D003497:Cyclic N-Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D051546:Cyclooxygenase 2 / Q000235:genetics; D004357:Drug Synergism; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use; D008670:Metals / Q000037:antagonists & inhibitors* / Q000633:toxicity; D009005:Monosaccharides / Q000494:pharmacology* / Q000627:therapeutic use; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D054467:Phospholipases A2 / Q000235:genetics; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013431:Sulfates / Q000037:antagonists & inhibitors / Q000633:toxicity; D015533:Transcriptional Activation
D000975:Antioxidants; D003497:Cyclic N-Oxides; D007502:Iron Chelating Agents; D008670:Metals; D009005:Monosaccharides; D011728:Pyridones; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013431:Sulfates; C447640:feralex; C029217:phenyl-N-tert-butylnitrone; D051546:Cyclooxygenase 2; D054467:Phospholipases A2