The cuprizone model: regional heterogeneity of pathology

Authors

  • Stig Wergeland,

    Corresponding author
    1. Department of Clinical medicine, University of Bergen, Bergen, Norway
    • Department of Neurology, Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital, Bergen, Norway
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  • Øivind Torkildsen,

    1. Department of Neurology, Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital, Bergen, Norway
    2. Department of Clinical medicine, University of Bergen, Bergen, Norway
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  • Kjell-Morten Myhr,

    1. Department of Neurology, Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital, Bergen, Norway
    2. Department of Clinical medicine, University of Bergen, Bergen, Norway
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  • Sverre Jarl Mørk,

    1. Department of Pathology, Haukeland University Hospital, Bergen, Norway
    2. The Gade Institute, University of Bergen, Bergen
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  • Lars Bø

    1. Department of Neurology, Norwegian Multiple Sclerosis Competence Centre, Haukeland University Hospital, Bergen, Norway
    2. Department of Clinical medicine, University of Bergen, Bergen, Norway
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Stig Wergeland, Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, N-5021 Bergen, Norway. e-mail: stig.wergeland@gmail.com

Abstract

The cuprizone model is a model of de- and remyelination secondary to oligodendrocyte death, likely to be mediated by an inhibition of mitochondrial function. The aim of this study was to characterize histopathological changes associated with de/remyelination in grey and white matter at different disease stages in C57Bl/6 mice after per oral administration of cuprizone. Oligodendrocyte loss, astrocytosis and complement activation was detected in areas of demyelination. Demyelination, astrocytosis and complement activation occurred earlier in the cerebral cortex than in the corpus callosum. There was no perivascular lymphocyte infiltration. Microglia- and macrophage activation was observed in the corpus callosum, but not in the cerebral cortex. After cuprizone exposure was stopped, remyelination was extensive in the corpus callosum, but scarce in the cortex. In conclusion, cortical demyelination and oligodendrocyte loss in the cuprizone model may be due to a direct effect on oligodendrocyte mitochondrial function, as it occurs in the absence of microglial activation. The histopathology of de/remyelination in the cuprizone treated mice show regional heterogeneities which suggest differences in the underlying pathophysiology. Cuprizone-induced demyelination is a relevant model for the study of regional heterogeneity of demyelination and lesion pathology in multiple sclerosis.

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