Cause and prevention of demyelination in a model multiple sclerosis lesion

Roshni A. Desai, Andrew L. Davies, Mohamed Tachrount, Marianne Kasti, Frida Laulund, Xavier Golay, Kenneth J. Smith

Research output: Contribution to journalArticle

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. Interpretation 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.

Original languageEnglish (US)
Pages (from-to)591-604
Number of pages14
JournalAnnals of neurology
Volume79
Issue number4
DOIs
StatePublished - Apr 1 2016

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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  • Cite this

    Desai, R. A., Davies, A. L., Tachrount, M., Kasti, M., Laulund, F., Golay, X., & Smith, K. J. (2016). Cause and prevention of demyelination in a model multiple sclerosis lesion. Annals of neurology, 79(4), 591-604. https://doi.org/10.1002/ana.24607