title: Cause and prevention of demyelination in a model multiple sclerosis lesion.
abstract: OBJECTIVE
  Demyelination is a cardinal feature of multiple sclerosis, but it remains unclear why new lesions form, and whether they can be prevented. Neuropathological evidence suggests that demyelination can occur in the relative absence of lymphocytes, and with distinctive characteristics suggestive of a tissue energy deficit. The objective was to examine an experimental model of the early multiple sclerosis lesion and identify pathogenic mechanisms and opportunities for therapy.
  
  
  METHODS
  Demyelinating lesions were induced in the rat spinal dorsal column by microinjection of lipopolysaccharide, and examined immunohistochemically at different stages of development. The efficacy of treatment with inspired oxygen for 2 days following lesion induction was evaluated.
  
  
  RESULTS
  Demyelinating lesions were not centered on the injection site, but rather formed 1 week later at the white-gray matter border, preferentially including the ventral dorsal column watershed. Lesion formation was preceded by a transient early period of hypoxia and increased production of superoxide and nitric oxide. Oligodendrocyte numbers decreased at the site shortly afterward, prior to demyelination. Lesions formed at a site of inherent susceptibility to hypoxia, as revealed by exposure of naive animals to a hypoxic environment. Notably, raising the inspired oxygen (80%, normobaric) during the hypoxic period significantly reduced or prevented the demyelination.
  
  
  CONCLUSIONS
  Demyelination characteristic of at least some early multiple sclerosis lesions can arise at a vascular watershed following activation of innate immune mechanisms that provoke hypoxia, and superoxide and nitric oxide formation, all of which can compromise cellular energy sufficiency. Demyelination can be reduced or eliminated by increasing inspired oxygen to alleviate the transient hypoxia.
authors.affiliation: Department of Neuroinflammation and Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Roshni A
authors.initials: RA
authors.lastname: Desai
authors.affiliation: Department of Neuroinflammation and Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Davies
authors.affiliation: Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Tachrount
authors.affiliation: Department of Neuroinflammation and Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Marianne
authors.initials: M
authors.lastname: Kasti
authors.affiliation: Department of Neuroinflammation and Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Frida
authors.initials: F
authors.lastname: Laulund
authors.affiliation: Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Xavier
authors.initials: X
authors.lastname: Golay
authors.affiliation: Department of Neuroinflammation and Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Smith
mesh_terms: D000818:Animals; D003711:Demyelinating Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D000860:Hypoxia / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008070:Lipopolysaccharides; D008297:Male; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010102:Oxygen Inhalation Therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D008070:Lipopolysaccharides
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