Demyelination: the role of reactive oxygen and nitrogen species.
This review summarises the role that reactive oxygen and nitrogen species play in demyelination, such as that occurring in the inflammatory demyelinating disorders multiple sclerosis and Guillain-Barré syndrome. The concentrations of reactive oxygen and nitrogen species (e.g. superoxide, nitric oxide and peroxynitrite) can increase dramatically under conditions such as inflammation, and this can overwhelm the inherent antioxidant defences within lesions. Such oxidative and/or nitrative stress can damage the lipids, proteins and nucleic acids of cells and mitochondria, potentially causing cell death. Oligodendrocytes are more sensitive to oxidative and nitrative stress in vitro than are astrocytes and microglia, seemingly due to a diminished capacity for antioxidant defence, and the presence of raised risk factors, including a high iron content. Oxidative and nitrative stress might therefore result in vivo in selective oligodendrocyte death, and thereby demyelination. The reactive species may also damage the myelin sheath, promoting its attack by macrophages. Damage can occur directly by lipid peroxidation, and indirectly by the activation of proteases and phospholipase A2. Evidence for the existence of oxidative and nitrative stress within inflammatory demyelinating lesions includes the presence of both lipid and protein peroxides, and nitrotyrosine (a marker for peroxynitrite formation). The neurological deficit resulting from experimental autoimmune demyelinating disease has generally been reduced by trial therapies intended to diminish the concentration of reactive oxygen species. However, therapies aimed at diminishing reactive nitrogen species have had a more variable outcome, sometimes exacerbating disease.
Smith
K J
KJ
Department of Clinical Neurological Sciences, Guy's, King's and St. Thomas' School of Medicine, London. k.smith@umds.ac.uk
Kapoor
R
R
Felts
P A
PA
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015227:Lipid Peroxidation; D009420:Nervous System / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D016877:Oxidants / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000502:physiology*