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Cuprizone Administration Alters the Iron Metabolism in the Mouse Model of Multiple Sclerosis

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Abstract

Cuprizone (CZ) is a widely used copper chelating agent to develop non-autoimmune animal model of multiple sclerosis, characterized by demyelination of the corpus callosum (CC) and other brain regions. The exact mechanisms of CZ action are still arguable, but it seems that the only affected cells are the mature oligodendrocytes, possibly via metabolic disturbances caused by copper deficiency. During the pathogenesis of multiple sclerosis, high amount of deposited iron can be found throughout the demyelinated areas of the brain in the form of extracellular iron deposits and intracellularly accumulated iron in microglia. In the present study, we used the accepted experimental model of 0.2% CZ-containing diet with standard iron concentration to induce demyelination in the brain of C57BL/6 mice. Our aim was to examine the changes of iron homeostasis in the CC and as a part of the systemic iron regulation, in the liver. Our data showed that CZ treatment changed the iron metabolism of both tissues; however, it had more impact on the liver. Besides the alterations in the expressions of iron storage and import proteins, we detected reduced serum iron concentration and iron stores in the liver, together with elevated hepcidin levels and feasible disturbances in the Fe–S cluster biosynthesis. Our results revealed that the CZ-containing diet influences the systemic iron metabolism in mice, particularly the iron homeostasis of the liver. This inadequate systemic iron regulation may affect the iron homeostasis of the brain, eventually indicating a relationship among CZ treatment, iron metabolism, and neurodegeneration.

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Acknowledgements

The project has been supported by the Social Renewal Operational Programme [TÁMOP-4.2.2.A-11/1/KONV-2012-0017], the Economic Development and Innovation Operational Programme [GINOP-2.3.2-15], and the European Union, co-financed by the European Social Fund [EFOP-3.6.1-16-2016-0004].

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Authors and Affiliations

  1. Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Pécs, Rókus str. 2., Pécs, 7624, Hungary

    E. Varga, E. Pandur & K. Sipos

  2. Department of Medical Biology and Central Electron Microscope Laboratory, Medical School, University of Pécs, Szigeti str. 12., Pécs, 7624, Hungary

    H. Abrahám

  3. Department of Neurosurgery, Medical School, University of Pécs, Rét str. 2., Pécs, 7623, Hungary

    A. Horváth

  4. Department of Neurology, Medical School, University of Pécs, Rét str. 2., Pécs, 7623, Hungary

    P. Ács & S. Komoly

  5. Department of Laboratory Medicine, Medical School, University of Pécs, Ifjúság str. 13., Pécs, 7624, Hungary

    A. Miseta

  6. Szigeti str. 12., Pécs, 7624, Hungary

    K. Sipos

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  1. E. Varga
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  6. S. Komoly
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Contributions

K. Sipos, S. Komoly designed the concept of the work. E. Varga and E. Pandur performed the gene expression analysis experiments. H. Abrahám performed the electron microscopy and immunohistochemistry experiments. A. Horváth carried out the MRI measurements. P. Ács and A. Miseta participated in data analysis and interpretation. All authors helped to draft and revise the manuscript.

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Correspondence to K. Sipos.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Animals were maintained under SPF conditions under permits BAI/01/1390-003/2013 (issued by the Baranya County Government Office) and SF/688-18/2013 and SF/27-1/2014 (issued by the Ministry of Agriculture).

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Varga, E., Pandur, E., Abrahám, H. et al. Cuprizone Administration Alters the Iron Metabolism in the Mouse Model of Multiple Sclerosis. Cell Mol Neurobiol 38, 1081–1097 (2018). https://doi.org/10.1007/s10571-018-0578-5

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  • DOI: https://doi.org/10.1007/s10571-018-0578-5

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