Contrasting potential of nitric oxide and peroxynitrite to mediate oligodendrocyte injury in multiple sclerosis.
Nitric oxide (NO) and peroxynitrite (ONOO(-)) are potential mediators of the injury and cytotoxicity occurring over time to oligodendrocytes in multiple sclerosis (MS) lesions. Our in vitro results indicate that human adult CNS-derived oligodendrocytes are relatively resistant to NO-mediated damage. In contrast, human oligodendrocytes are highly susceptible to peroxynitrite-mediated injury. In situ, we found that inducible nitric oxide synthase (iNOS) was expressed in astrocytes and macrophages in all active demyelinating and remyelinating MS lesions examined, yet no correlation was found between numbers of glial cells expressing iNOS and the extent of oligodendrocyte cell death. Nitrotyrosine groups, indicative of the presence of peroxynitrite in vivo, could be detected on astrocytes, macrophages, and oligodendrocytes in MS lesions. High numbers of nitrotyrosine-positive oligodendrocytes were found in one MS case that featured extensive oligodendrocyte cell death. Our results indicate that NO alone is unlikely to induce oligodendrocyte injury, whereas its more potent byproduct peroxynitrite is a potential mediator of injury to oligodendrocytes in MS.
Jack
Carolyn
C
Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Antel
Jack
J
Brück
Wolfgang
W
Kuhlmann
Tanja
T
D001253:Astrocytes / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000503:physiopathology; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism* / Q000633:toxicity; D020030:Nitric Oxide Donors / Q000633:toxicity; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism* / Q000633:toxicity; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D020030:Nitric Oxide Donors; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II