title: Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes.
abstract: Peroxynitrite has been suggested to be the potent oxidant causing toxicity to neurons and oligodendrocytes (OLs). Our previous studies have illustrated that intracellular zinc liberation contributes to peroxynitrite toxicity to mature OLs. In this study, we further investigated the signaling pathways involved in this event and identified protein kinase C (PKC) as an important early signaling molecule. We found that a non-selective PKC inhibitor bisindolylmaleimide-1 blocked OL toxicity induced by a peroxynitrite generator SIN-1 and exogenous zinc. The protective effects were due to its inhibition on ERK1/2 phosphorylation and ROS generation. The same phenomenon was also observed in OLs following prolonged treatment with phorbol 12 myristate 13 acetate (PMA), which downregulates the conventional and the novel PKC isoforms (cPKCs and nPKCs). To determine the role of specific PKC isoforms, we found that a specific nPKC inhibitor rottlerin significantly reduced SIN-1- or zinc-induced toxicity, whereas Go6976, a cPKC inhibitor, reduced OL toxicity triggered by zinc, but not by SIN-1 at high concentrations. Rottlerin was more potent than Go6976 to attenuate ERK1/2 phosphorylation and ROS generation induced by SIN-1 or zinc. Surprisingly, zinc only induced phosphorylation of PKCθ, but not PKCδ. Knockdown of PKCθ using lentiviral shRNA attenuated SIN-1- or zinc-induced toxicity. These results suggest that PKCθ might be the major PKC isoform involved in peroxynitrite and zinc toxicity to mature OLs, and provide a rationale for development of specific inhibitors of PKCθ in the treatment of multiple sclerosis and other neurodegenerative diseases, in which peroxynitrite formation plays a pathogenic role.
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
authors.forename: Shihe
authors.initials: S
authors.lastname: Li
authors.forename: Wen
authors.initials: W
authors.lastname: Lin
authors.forename: Flaubert
authors.initials: F
authors.lastname: Tchantchou
authors.forename: Ruby
authors.initials: R
authors.lastname: Lai
authors.forename: Jie
authors.initials: J
authors.lastname: Wen
authors.forename: Yumin
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D002712:Chlorides / Q000633:toxicity; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000633:toxicity; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008301:Maleimides / Q000378:metabolism; D008981:Molsidomine / Q000031:analogs & derivatives / Q000633:toxicity; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000633:toxicity*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D017967:Zinc Compounds / Q000633:toxicity
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D002227:Carbazoles; D002712:Chlorides; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D017382:Reactive Oxygen Species; D017967:Zinc Compounds; C081021:Go 6976; D030421:Peroxynitrous Acid; C002385:linsidomine; C016837:zinc chloride; D008981:Molsidomine; C085746:rottlerin; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; C088060:bisindolylmaleimide; D013755:Tetradecanoylphorbol Acetate