title: Distinct role of nitric oxide and peroxynitrite in mediating oligodendrocyte toxicity in culture and in experimental autoimmune encephalomyelitis.
abstract: Nitric oxide has been implicated in the pathogenesis of multiple sclerosis. However, it is still unclear whether nitric oxide plays a protective role or is deleterious. We have previously shown that peroxynitrite, a reaction product of nitric oxide and superoxide, is toxic to mature oligodendrocytes (OLs). The toxicity is mediated by intracellular zinc release, phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), activation of 12-lipoxygenase (12-LOX) and the formation of reactive oxygen species (ROS). In this study, we found that the donors of nitric oxide, dipropylenetriamine NONOate (DPT NONOate) and diethylenetriamine NONOate (DETA NONOate), protected OLs from peroxynitrite or zinc-induced toxicity. The protective mechanisms appear to be attributable to their inhibition of peroxynitrite- or zinc-induced ERK1/2 phosphorylation and 12-LOX activation. In cultures of mature OLs exposed to lipopolysaccharide (LPS), induction of inducible nitric oxide synthase (iNOS) generated nitric oxide and rendered OLs resistant to peroxynitrite-induced toxicity. The protection was eliminated when 1400W, a specific inhibitor of iNOS, was co-applied with LPS. Using MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, we found that nitrotyrosine immunoreactivity, an indicator of peroxynitrite formation, was increased in the spinal cord white matter, which correlated with the loss of mature OLs. Targeted gene deletion of the NADPH oxidase component gp91phox reduced clinical scores, the formation of nitrotyrosine and the loss of mature OLs. These results suggest that blocking the formation specifically of peroxynitrite, rather than nitric oxide, may be a protective strategy against oxidative stress induced toxicity to OLs.
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Science, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: A C
authors.initials: AC
authors.lastname: Vana
authors.forename: R
authors.initials: R
authors.lastname: Ribeiro
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020030:Nitric Oxide Donors; D030421:Peroxynitrous Acid; D009569:Nitric Oxide