Abstract
An elegant model to study mechanisms operant during oligodendrocyte degeneration and subsequent demyelination is the cuprizone model. In that model, mice are intoxicated with the copper chelation agent cuprizone which results in early oligodendrocyte stress, oligodendrocyte apoptosis, and, finally, demyelination. Here, we systematically investigated to what extent the animals’ weight at the beginning of the cuprizone intoxication period is critical for the reproducibility of the cuprizone-induced pathology. We can demonstrate that a negative correlation exists between the two variables “extent of cuprizone-induced demyelination” and “starting weight.” Demyelination and microglia activation were more severe in low weight compared to heavy weight mice. These findings are highly relevant for the experimental design using the cuprizone model.
Similar content being viewed by others
References
Acs P, Kipp M, Norkute A, Johann S, Clarner T, Braun A, Berente Z, Komoly S, Beyer C (2009) 17beta-estradiol and progesterone prevent cuprizone provoked demyelination of corpus callosum in male mice. Glia 57:807–814. https://doi.org/10.1002/glia.20806
Behrangi N, Fischbach F, Kipp M (2019) Mechanism of siponimod: anti-inflammatory and neuroprotective mode of action Cells 8 doi:https://doi.org/10.3390/cells8010024
Chrzanowski U, Schmitz C, Horn-Bochtler A, Nack A, Kipp M (2019) Evaluation strategy to determine reliable demyelination in the cuprizone model. Metab Brain Dis 34:681–685. https://doi.org/10.1007/s11011-018-0375-3
Clarner T, Diederichs F, Berger K, Denecke B, Gan L, van der Valk P, Beyer C, Amor S, Kipp M (2012) Myelin debris regulates inflammatory responses in an experimental demyelination animal model and multiple sclerosis lesions. Glia 60:1468–1480. https://doi.org/10.1002/glia.22367
Clarner T, Janssen K, Nellessen L, Stangel M, Skripuletz T, Krauspe B, Hess FM, Denecke B, Beutner C, Linnartz-Gerlach B, Neumann H, Vallières L, Amor S, Ohl K, Tenbrock K, Beyer C, Kipp M (2015) CXCL10 triggers early microglial activation in the cuprizone model. Journal of immunology (Baltimore, Md : 1950) 194:3400–3413. https://doi.org/10.4049/jimmunol.1401459
Fischbach F, Nedelcu J, Leopold P, Zhan J, Clarner T, Nellessen L, Beißel C, van Heuvel Y, Goswami A, Weis J, Denecke B, Schmitz C, Hochstrasser T, Nyamoya S, Victor M, Beyer C, Kipp M (2018) Cuprizone-induced graded oligodendrocyte vulnerability is regulated by the transcription factor DNA damage-inducible transcript 3. Glia 67:263–276. https://doi.org/10.1002/glia.23538
Funfschilling U et al (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485:517–521. https://doi.org/10.1038/nature11007
Genain CP, Cannella B, Hauser SL, Raine CS (1999) Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 5:170–175. https://doi.org/10.1038/5532
Goldberg J, Daniel M, van Heuvel Y, Victor M, Beyer C, Clarner T, Kipp M (2013) Short-term cuprizone feeding induces selective amino acid deprivation with concomitant activation of an integrated stress response in oligodendrocytes. Cell Mol Neurobiol 33:1087–1098. https://doi.org/10.1007/s10571-013-9975-y
Hesse A, Wagner M, Held J, Brück W, Salinas-Riester G, Hao Z, Waisman A, Kuhlmann T (2010) In toxic demyelination oligodendroglial cell death occurs early and is FAS independent. Neurobiol Dis 37:362–369. https://doi.org/10.1016/j.nbd.2009.10.016
Hochstrasser T, Exner GL, Nyamoya S, Schmitz C, Kipp M (2017) Cuprizone-containing pellets are less potent to induce consistent demyelination in the corpus callosum of C57BL/6 mice. J Mol Neurosci 61:617–624. https://doi.org/10.1007/s12031-017-0903-3
Kipp M, Nyamoya S, Hochstrasser T, Amor S (2017) Multiple sclerosis animal models: a clinical and histopathological perspective. Brain pathology (Zurich, Switzerland) 27:123–137. https://doi.org/10.1111/bpa.12454
Lassmann H (1983) Comparative neuropathology of chronic experimental allergic encephalomyelitis and multiple sclerosis. Schriftenreihe Neurologie 25:1–135
Lassmann H, van Horssen J (2016) Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions. Biochim Biophys Acta 1862:506–510. https://doi.org/10.1016/j.bbadis.2015.09.018
Licht-Mayer S, Wimmer I, Traffehn S, Metz I, Brück W, Bauer J, Bradl M, Lassmann H (2015) Cell type-specific Nrf2 expression in multiple sclerosis lesions. Acta Neuropathol 130:263–277. https://doi.org/10.1007/s00401-015-1452-x
Love S (1988) Cuprizone neurotoxicity in the rat: morphologic observations. J Neurol Sci 84:223–237
Mahad D, Ziabreva I, Lassmann H, Turnbull D (2008) Mitochondrial defects in acute multiple sclerosis lesions. Brain : a journal of neurology 131:1722–1735. https://doi.org/10.1093/brain/awn105
Moore S, Patel R, Hannsun G, Yang J, Tiwari-Woodruff SK (2013) Sex chromosome complement influences functional callosal myelination. Neuroscience 245:166–178. https://doi.org/10.1016/j.neuroscience.2013.04.017
Nack A, Brendel M, Nedelcu J, Daerr M, Nyamoya S, Beyer C, Focke C, Deussing M, Hoornaert C, Ponsaerts P, Schmitz C, Bartenstein P, Rominger A, Kipp M (2019) Expression of translocator protein and [18F]-GE180 ligand uptake in multiple sclerosis animal models. Cells 8. https://doi.org/10.3390/cells8020094
Nyamoya S, Leopold P, Becker B, Beyer C, Hustadt F, Schmitz C, Michel A, Kipp M (2018) G-protein-coupled receptor Gpr17 expression in two multiple sclerosis remyelination models. Mol Neurobiol 56:1109–1123. https://doi.org/10.1007/s12035-018-1146-1
Omotoso GO, Gbadamosi IT, Afolabi TT, Abdulwahab AB, Akinlolu AA (2018) Ameliorative effects of Moringa on cuprizone-induced memory decline in rat model of multiple sclerosis. Anatomy & cell biology 51:119–127. https://doi.org/10.5115/acb.2018.51.2.119
Pasquini LA, Calatayud CA, Bertone Una AL, Millet V, Pasquini JM, Soto EF (2007) The neurotoxic effect of cuprizone on oligodendrocytes depends on the presence of pro-inflammatory cytokines secreted by microglia. Neurochem Res 32:279–292. https://doi.org/10.1007/s11064-006-9165-0
Patel R, Moore S, Crawford DK, Hannsun G, Sasidhar MV, Tan K, Molaie D, Tiwari-Woodruff SK (2013) Attenuation of corpus callosum axon myelination and remyelination in the absence of circulating sex hormones. Brain pathology (Zurich, Switzerland) 23:462–475. https://doi.org/10.1111/bpa.12029
Raine CS, Scheinberg L, Waltz JM (1981) Multiple sclerosis. Oligodendrocyte survival and proliferation in an active established lesion. Laboratory investigation; a journal of technical methods and pathology 45:534–546
Schmidt T, Awad H, Slowik A, Beyer C, Kipp M, Clarner T (2013) Regional heterogeneity of cuprizone-induced demyelination: topographical aspects of the midline of the corpus callosum. J Mol Neurosci 49:80–88. https://doi.org/10.1007/s12031-012-9896-0
Scolding NJ, Jones J, Compston DA, Morgan BP (1990) Oligodendrocyte susceptibility to injury by T-cell perforin. Immunology 70:6–10
Taylor LC, Gilmore W, Matsushima GK (2009) SJL mice exposed to cuprizone intoxication reveal strain and gender pattern differences in demyelination. Brain pathology (Zurich, Switzerland) 19:467–479. https://doi.org/10.1111/j.1750-3639.2008.00230.x
Valeiras B, Rosato Siri MV, Codagnone M, Reines A, Pasquini JM (2014) Gender influence on schizophrenia-relevant abnormalities in a cuprizone demyelination model. Glia 62:1629–1644. https://doi.org/10.1002/glia.22704
van der Valk P, De Groot CJ (2000) Staging of multiple sclerosis (MS) lesions: pathology of the time frame of MS. Neuropathol Appl Neurobiol 26:2–10
Xing B, Brink LE, Maers K, Sullivan ML, Bodnar RJ, Stolz DB, Cambi F (2018) Conditional depletion of GSK3b protects oligodendrocytes from apoptosis and lessens demyelination in the acute cuprizone model. Glia 66:1999–2012. https://doi.org/10.1002/glia.23453
Zendedel A, Beyer C, Kipp M (2013) Cuprizone-induced demyelination as a tool to study remyelination and axonal protection. J Mol Neurosci 51:567–572. https://doi.org/10.1007/s12031-013-0026-4
Acknowledgements
The technical support from S. Wübbel, B. Aschauer, and A. Baltruschat is acknowledged.
Funding
This study was financially supported by the Deutsche Forschungsgemeinschaft (KI 1469/8-1).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
All experiments were formally approved by the Regierung Oberbayern (reference number 55.2-154-2532-73-15).
Conflict of Interest
The authors declare that they have no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Leopold, P., Schmitz, C. & Kipp, M. Animal Weight Is an Important Variable for Reliable Cuprizone-Induced Demyelination. J Mol Neurosci 68, 522–528 (2019). https://doi.org/10.1007/s12031-019-01312-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-019-01312-0