title: Inhibition of 5-lipoxygenase activity in mice during cuprizone-induced demyelination attenuates neuroinflammation, motor dysfunction and axonal damage.
abstract: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Increased expression of 5-lipoxygenase (5-LO), a key enzyme in the biosynthesis of leukotrienes (LTs), has been reported in MS lesions and LT levels are elevated in the cerebrospinal fluid of MS patients. To determine whether pharmacological inhibition of 5-LO attenuates demyelination, MK886, a 5-LO inhibitor, was given to mice fed with cuprizone. Gene and protein expression of 5-LO were increased at the peak of cuprizone-induced demyelination. Although MK886 did not attenuate cuprizone-induced demyelination in the corpus callosum or in the cortex, it attenuated cuprizone-induced axonal damage and motor deficits and reduced microglial activation and IL-6 production. These data suggest that during cuprizone-induced demyelination, the 5-LO pathway contributes to microglial activation and neuroinflammation and to axonal damage resulting in motor dysfunction. Thus, 5-LO inhibition may be a useful therapeutic treatment in demyelinating diseases of the CNS.
authors.affiliation: Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National Institute on Aging, National Institute of Health, Bethesda, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: S
authors.initials: S
authors.lastname: Palumbo
authors.forename: C D
authors.initials: CD
authors.lastname: Toscano
authors.forename: F
authors.initials: F
authors.lastname: Bosetti
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001259:Ataxia / Q000517:prevention & control*; D015415:Biomarkers / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003337:Corpus Callosum / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003471:Cuprizone / Q000633:toxicity*; D003711:Demyelinating Diseases / Q000139:chemically induced; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007211:Indoles / Q000627:therapeutic use; D015850:Interleukin-6 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009443:Neuritis / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D002722:Chlorobenzenes
chemical_list: D001094:Arachidonate 5-Lipoxygenase; D015415:Biomarkers; D003471:Cuprizone; D007211:Indoles; D015850:Interleukin-6; D016859:Lipoxygenase Inhibitors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C060893:MK-886; D002722:Chlorobenzenes