BACKGROUND: 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.
OBJECTIVE: 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 two days following lesion induction was evaluated.
RESULTS: Demyelinating lesions were not centred on the injection site, but rather formed one week later at the white-grey 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 afterwards, prior to demyelination. Lesions formed at a site of inherent susceptibility to hypoxia, as revealed by exposure of naïve 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, 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.
Prof G addendum: We are in discussion with Prof Ken Smith to see if we can help him test this treatment in MSers with acute optic neuritis. If you had optic neuritis would you volunteer for an oxygen therapy trial?