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Cited by 346Multiple Sclerosis Research StudiesNeurogenesis and neuroplasticity mechanismsNeuroinflammation and Neurodegeneration Mechanisms

The cuprizone model for demyelination

Open access
Torkildsen, Ø., Brunborg, L. A., Myhr, K.-M., Bø, L.·2008·Acta Neurologica Scandinavica
DOI 10.1111/j.1600-0404.2008.01036.x
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Abstract

BACKGROUND: Important advances in multiple sclerosis (MS) research have been made as a direct or indirect result of experiments in animal models for the disease, although MS is a disease only affecting humans. The cuprizone model is a model for toxic demyelination. In this model, young mice are fed with the copper chelator cuprizone, leading to oligodendrocyte death and a subsequent reversible demyelination. Spontaneous remyelination can be seen as early as 4 days after withdrawal of cuprizone. MATERIALS AND METHODS: This article reviews previous research on this model and discusses the potential of the model for future application in MS research. DISCUSSION: The cuprizone model correlates with newer histopathological data in MS and is a valuable tool for studies on de- and remyelination. The use of the C57BL/6 strain offers the potential for future studies on transgene and knockout mice.

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Crossref · 10.1111/j.1600-0404.2008.01036.x

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  • The cuprizone model involves administration of cuprizone to induce oligodendrocyte apoptosis.

    “The cuprizone model involves administration of the toxin cuprizone to induce oligodendrocyte apoptosis [4, 5].”

    From Strain differences in cuprizone induced demyelination (2017) · cites this paper as [4]

    The “Mice strain and cuprizone administration” section says mice are fed cuprizone, leading to oligodendrocyte death. “Effects of cuprizone administration” describes apoptosis as a plausible hypothesis for that death, rather than establishing it as the mechanism. The claim states apoptosis without that qualification. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Features common to both cuprizone-induced and type 3 MS lesions include mitochondrial stress, selective loss of myelin-associated glycoprotein (MAG), lesions with indistinct borders that are not perivascular, pronounced glial activation, and lymphocyte infiltration.

    “Other features common to both cuprizone-induced and type 3 MS lesions are mitochondrial stress, selective loss of myelin-associated glycoprotein (MAG), lesions with indistinct borders that are not perivascular, pronounced glial activation, and lymphocyte infiltration [43, 46, 65, 69–71].”

    From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [43]

    The sections “Effects of cuprizone administration” and “Areas of demyelination and correlation to MS” support mitochondrial dysfunction, a microglial/macrophage response, and a possible resemblance to type 3 MS lesions. They do not establish selective MAG loss or indistinct, non-perivascular lesion borders. The latter section also says T cells are almost completely absent during cuprizone-induced demyelination, contrary to lymphocyte infiltration as a shared feature. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Upon treatment with cuprizone, mice typically exhibit profound demyelination in the corpus callosum, the cortex and the superior cerebellar peduncles.

    “Upon treatment with cuprizone, mice typically exhibit profound demyelination in the corpus callosum, the cortex and the superior cerebellar peduncles [4, 5].”

    From Strain differences in cuprizone induced demyelination (2017) · cites this paper as [4]

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Cites

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Research works printed but not linked: 23

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  3. Lindner M, Heine S, Haastert K et al. Sequential myelin protein expression during remyelination reveals fast and efficient repair after central nervous system demyelination. Neuropathol Appl Neurobiol 2008;34:105-14.
  4. Carlton WW. Studies on the induction of hydrocephalus and spongy degeneration by cuprizone feeding and at- tempts to antidote the toxicity. Life Sci 1967;6:11-19.
  5. Irvine K-A, Blakemore WF. Age increased axon loss associated with primary demyelination in cuprizone-in- duced demyelination in C57BL ⁄ 6 mice. J Neuroimmunol 2006;175:69-76.
  6. Morell P, Barrett CV, Mason JL et al. Gene expression in brain during cuprizone-induced demyelination and remyelination. Mol Cell Neurosci 1998;12:220-7.
  7. Mason Jones JJ, Taniike M, Morell P, Suzuki K, Matsushima GKMature oligodendrocyte apoptosis precedes IGF-1 production and oligodendrocyte progenitor accumulation and differentiation during demyelination ⁄ remyelination. J Neurosci Res 2000, Aug. 1;61:251-62.
  8. Venturini G. Enzymic activity and sodium, potassium and copper concentrations in mouse brain and liver after cuprizone treatment in vivo. J Neurochem 1973;21:1147-51.
  9. Kesterson JW, Carlton WW. Aqueductal stenosis as the cause of hydrocephalus in mice fed the substituted hydra- zine, cuprizone. Exp Mol Pathol 1970;13:281-94.
  10. Suzuki K, Kikkawa Y. Status spongiosus of CNS and hepatic changes induced by cuprizone (biscyclohexanone oxalyldihydrazone). Am J Pathol 1969;54:307-25.
  11. Bø L, Vedeler CA, Nyland HI, Trapp BD, Mørk SJ. Sub- pial demyelination in the cerebral cortex of multiple scle- rosis patients. J Neuropathol Exp Neurol 2003;62:723-32.
  12. Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47:707-17.
  13. McMahon EJ, Suzuki K, Matsushima GK. Peripheral macrophage recruitment in cuprizone-induced CNS demyelination despite an intact blood-brain barrier. J Neuroimmunol 2002;130:32-45.
  14. Barnett MH, Prineas JW. Relapsing and remitting multi- ple sclerosis: pathology of the newly forming lesion. Ann Neurol 2004;55:458-68.
  15. Lassmann H. Multiple sclerosis: is there neurodegeneration independent from inflammation? J Neurol Sci 2007;259:3-6.
  16. Franco-Pons N, Torrente M, Colomina MT, Viella EBehavioral deficits in the cuprizone-induced murine model of demyelination ⁄ remyelination. Toxicol Let 2007;169:205-13.
  17. Liebetanz D, Merkler D. Effects of commissural de-and remyelination on motor skill behaviour in the cuprizone mouse model of multiple sclerosis. Exp Neurol 2006;202:217-24.
  18. Armstrong RC, Le TQ, Flint NC, Vana AC, Zhou YX. Endogenous cell repair of chronic demyelination. J Neu- ropathol Exp Neurol 2006;65:245-56.
  19. Chen JT, Kuhlmann T, Jansen GH et al. Voxel-based analysis of the evolution of magnetization transfer ratio to quantify remyelination and demyelination with histopath- ological validation in a multiple sclerosis lesion. Neuro- image 2007;36:1152-8.
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Cited by

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Authors
Torkildsen, Ø., Brunborg, L. A., Myhr, K.-M., & Bø, L.
Affiliations
Haukeland University Hospital (NO)
Corresponding author
Torkildsen, Ø.
ORCID
Venue
Acta Neurologica Scandinavica
Publisher
Hindawi Limited
Published
2008-05
Volume
117
Issue
s188
Pages
72-76
ISSN
  • 0001-6314 (ISSN-L)
  • 1600-0404
DOI
10.1111/j.1600-0404.2008.01036.x
OpenAlex
W2075819003
Cited by
346
References
3
Citations by year
2026: 17 · 2025: 21 · 2024: 28 · 2023: 28 · 2022: 34 · 2021: 31 · 2020: 21 · 2019: 30 · 2018: 20 · 2017: 25 · 2016: 19 · 2015: 9 · 2014: 11 · 2013: 12 · 2012: 5
FWCI
1.36
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 2679 d)
Locations
  • Acta Neurologica Scandinavica (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
cuprizone model, multiple sclerosis, oligodendrocyte death, remyelination, demyelination, C57BL/6 mice, knockout mice, transgenic mice, animal models of multiple sclerosis
MeSH terms
Animals, Chelating Agents, Cuprizone, Disease Models, Animal, Multiple Sclerosis, Myelin Sheath, Mice

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