Acute intermittent hypoxia alters disease course and promotes CNS repair including resolution of inflammation and remyelination in the experimental autoimmune encephalomyelitis model of MS

Author:

Tokarska Nataliya12ORCID,Naniong Justin M. A.12,Johnston Jayne M.12,Salapa Hannah E.234ORCID,Muir Gillian D.25,Levin Michael C.234ORCID,Popescu Bogdan F.12,Verge Valerie M. K.12ORCID

Affiliation:

1. Department of Anatomy, Physiology and Pharmacology University of Saskatchewan Saskatoon Saskatchewan Canada

2. Cameco MS Neuroscience Research Centre University of Saskatchewan Saskatoon Saskatchewan Canada

3. Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair University of Saskatchewan Saskatoon Saskatchewan Canada

4. College of Medicine, Neurology Division University of Saskatchewan Saskatoon Saskatchewan Canada

5. Department of Biomedical Sciences, WCVM University of Saskatchewan Saskatoon Saskatchewan Canada

Abstract

AbstractRemyelination and neurodegeneration prevention mitigate disability in Multiple Sclerosis (MS). We have shown acute intermittent hypoxia (AIH) is a novel, non‐invasive and effective therapy for peripheral nerve repair, including remyelination. Thus, we posited AIH would improve repair following CNS demyelination and address the paucity of MS repair treatments. AIH's capacity to enhance intrinsic repair, functional recovery and alter disease course in the experimental autoimmune encephalomyelitis (EAE) model of MS was assessed. EAE was induced by MOG35‐55 immunization in C57BL/6 female mice. EAE mice received either AIH (10 cycles—5 min 11% oxygen alternating with 5 min 21% oxygen) or Normoxia (control; 21% oxygen for same duration) once daily for 7d beginning at near peak EAE disease score of 2.5. Mice were followed post‐treatment for an additional 7d before assessing histopathology or 14d to examine maintenance of AIH effects. Alterations in histopathological correlates of multiple repair indices were analyzed quantitatively in focally demyelinated ventral lumbar spinal cord areas to assess AIH impacts. AIH begun at near peak disease significantly improved daily clinical scores/functional recovery and associated histopathology relative to Normoxia controls and the former were maintained for at least 14d post‐treatment. AIH enhanced correlates of myelination, axon protection and oligodendrocyte precursor cell recruitment to demyelinated areas. AIH also effected a dramatic reduction in inflammation, while polarizing remaining macrophages/microglia toward a pro‐repair state. Collectively, this supports a role for AIH as a novel non‐invasive therapy to enhance CNS repair and alter disease course following demyelination and holds promise as a neuroregenerative MS strategy.

Funder

Canadian Institutes of Health Research

Multiple Sclerosis Society of Canada

University of Saskatchewan

Publisher

Wiley

Subject

Cellular and Molecular Neuroscience,Neurology

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