Demyelination and remyelination in anatomically distinct regions of the corpus callosum following cuprizone intoxication
Open accessAbstract
Multiple sclerosis is a chronic demyelinating disease of the central nervous system. Spontaneous remyelination during early disease stages is thought to preserve and partially restore function. However, this process ceases in later stages despite the presence of pre-oligodendrocytes. Cuprizone-induced demyelination is a useful model with which to study the remyelination process. Previous studies have demonstrated heterogeneities in demyelination in individual animals. Here we investigated regional differences in demyelination and remyelination within the corpus callosum. C57BL/6 mice were fed 0.2% cuprizone for 5 weeks to induce demyelination. Remyelination was examined 2-5 weeks after cuprizone withdrawal. Immunohistochemistry and electron microscopy were used to quantify regional differences in demyelination, gliosis, and remyelination. We found that, while demyelination was limited in the rostral region of corpus callosum, nearly complete demyelination occurred in the caudal callosum, beginning at approximately -0.5mm from bregma. Astrogliosis and microgliosis were correlated with demyelination and differed between the rostral and caudal callosal structures. Remyelination upon cessation of cuprizone ensued at different rates with splenium remyelinating faster than dorsal hippocampal commissure. Our data show anatomical differences of cuprizone-induced demyelination and remyelination in the corpus callosum and the importance of examining specific callosal regions in myelin repair studies using this model.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Cuprizone-dependent demyelination is massive within the corpus callosum but also occurs within additional brain regions such as the cortex and hippocampus.
“cuprizone-dependent demyelination is massive within the corpus callosum but also occurs within additional brain regions such as the cortex and hippocampus (Koutsoudaki et al. 2009; Skripuletz et al. 2008; Steelman et al. 2012).”
From Cuprizone-Dependent De/Remyelination Responses and Functional Correlates in Mouse Strains Adopted to Model Relapsing, Chronic and Progressive Experimental Autoimmune Encephalomyelitis (2021) · cites this paper as Steelman et al. 2012
The Results report prominent demyelination in the cerebral cortex, and the Discussion reports nearly complete demyelination in caudal regions of the corpus callosum. But the paper says rostral callosal regions are less affected, so it does not support massive demyelination throughout the corpus callosum. It examines the dorsal hippocampal commissure, not demyelination of the hippocampus itself (Results; Discussion; page numbers unavailable). (LLM, conf=0.87)
Experimental — accuracy not yet measuredAlternative methods, such as provision of cuprizone-containing pellets, mixing cuprizone into drinking water, or oral gavage of dissolved cuprizone, have successfully been applied.
“Alternative methods, such as the provision of cuprizone-containing pellets [103,104,105], mixing of cuprizone into the drinking water [106], or oral gavage of dissolved cuprizone (personal communication) have successfully been applied.”
From The Cuprizone Model: Dos and Do Nots (2020) · cites this paper as [103]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
TNFα promotes proliferation of oligodendrocyte progenitors and remyelination
Arnett, H. A., Mason, J., Marino, M., Suzuki, K., Matsushima, G. K., & Ting, J. P.-Y. (2001) · Nature Neuroscience · doi:10.1038/nn738 · Cited by 1,012 · see citing works
Matsushima, G. K., & Morell, P. (2001) · Brain Pathology · doi:10.1111/j.1750-3639.2001.tb00385.x · Cited by 984 · see citing works
Blakemore, W. F. (1972) · Journal of Neurocytology · doi:10.1007/bf01102943 · Cited by 217 · see citing works
Liu, L., Belkadi, A., Darnall, L., Hu, T., Drescher, C., Cotleur, A. C., Padovani-Claudio, D., He, T., Choi, K., Lane, T. E., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2491 · Cited by 214 · see citing works
Demyelination of the superior cerebellar peduncle in the mouse induced by cuprizone
Blakemore, W. F. (1973) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(73)90118-4 · Cited by 207 · see citing works
Taylor, L. C., Gilmore, W., & Matsushima, G. K. (2009) · Brain Pathology · doi:10.1111/j.1750-3639.2008.00230.x · Cited by 84 · cited 3× · see citing works
“…in other animal models, the degree of demyelination depends on mouse strain (Skripuletz et al., 2008; Taylor et al., 2009; Taylor et al., 2010), anatomic location (Gudi et al., 2009; Stidworthy et al., 2003a), age (Kipp et al., 2009), dose (Hiremath et al., 1998), and gender (Taylor et al., 2009).”
Flagged first, then by citations
Research works printed but not linked: 39
- Bando Y Takakusaki K Ito S Terayama R Kashiwayanagi M Yoshida S 2008 Differential changes in axonal conduction following CNS demyelination in two mouse models Eur J Neurosci 28 1731 1742 18973589
- Barnett MH Prineas JW 2004 Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion Ann Neurol 55 458 468 15048884
- Binder MD Cate HS Prieto AL Kemper D Butzkueven H Gresle MM Cipriani T Jokubaitis VG Carmeliet P Kilpatrick TJ 2008 Gas6 deficiency increases oligodendrocyte loss and microglial activation in response to cuprizone-induced demyelination J Neurosci 28 5195 5206 18480276 PMC3844801
- Breij EC Brink BP Veerhuis R van den Berg C Vloet R Yan R Dijkstra CD van der Valk P Bo L 2008 Homogeneity of active demyelinating lesions in established multiple sclerosis Ann Neurol 63 16 25 18232012
- Carlton WW Kreutzberg G 1966 Isonicotinic acid hydrazide-induced spongy degeneration of the white matter in the brains of Pekin ducks Am J Pathol 48 91 105 5902838 PMC1916406
- Compston A Coles A 2008 Multiple sclerosis Lancet 372 1502 1517 18970977
- Duncan ID Brower A Kondo Y Curlee JF Jr Schultz RD 2009 Extensive remyelination of the CNS leads to functional recovery Proc Natl Acad Sci U S A 106 6832 6836 19342494 PMC2672502
- Franklin BJ Paxinos G 2008 The mouse brain in stereotaxic coordinates 3 Academic Press New York
- Ge Y Law M Johnson G Herbert J Babb JS Mannon LJ Grossman RI 2004 Preferential occult injury of corpus callosum in multiple sclerosis measured by diffusion tensor imaging J Magn Reson Imaging 20 1 7 15221802
- Gean-Marton AD Vezina LG Marton KI Stimac GK Peyster RG Taveras JM Davis KR 1991 Abnormal corpus callosum: a sensitive and specific indicator of multiple sclerosis Radiology 180 215 221 2052698
- Groebe A Clarner T Baumgartner W Dang J Beyer C Kipp M 2009 Cuprizone treatment induces distinct demyelination, astrocytosis, and microglia cell invasion or proliferation in the mouse cerebellum Cerebellum 8 163 174 19259754
- Gudi V Moharregh-Khiabani D Skripuletz T Koutsoudaki PN Kotsiari A Skuljec J Trebst C Stangel M 2009 Regional differences between grey and white matter in cuprizone induced demyelination Brain Res 1283 127 138 19524552
- Hiremath MM Saito Y Knapp GW Ting JP Suzuki K Matsushima GK 1998 Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice J Neuroimmunol 92 38 49 9916878
- Irvine KA Blakemore WF 2008 Remyelination protects axons from demyelination-associated axon degeneration Brain 131 1464 1477 18490361
- Kipp M Clarner T Dang J Copray S Beyer C 2009 The cuprizone animal model: new insights into an old story Acta Neuropathol 118 723 736 19763593
- Koutsoudaki PN Skripuletz T Gudi V Moharregh-Khiabani D Hildebrandt H Trebst C Stangel M 2009 Demyelination of the hippocampus is prominent in the cuprizone model Neurosci Lett 451 83 88 19084049
- Linares D Taconis M Mana P Correcha M Fordham S Staykova M Willenborg DO 2006 Neuronal nitric oxide synthase plays a key role in CNS demyelination J Neurosci 26 12672 12681 17151270 PMC6674851
- Lou X Jiang W Ma L Ma N Cai Y Huang D Wong EH 2009 Lower fractional anisotropy at the anterior body of the normal-appearing corpus callosum in multiple sclerosis versus symptomatic carotid occlusion Neuroradiology 51 557 561 19504090
- Lucchinetti C Bruck W Parisi J Scheithauer B Rodriguez M Lassmann H 2000 Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination Ann Neurol 47 707 717 10852536
- Ludwin SK 1978 Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity Lab Invest 39 597 612 739762
- Mi S Miller RH Tang W Lee X Hu B Wu W Zhang Y Shields CB Miklasz S Shea D Mason J Franklin RJ Ji B Shao Z Chedotal A Bernard F Roulois A Xu J Jung V Pepinsky B 2009 Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells Ann Neurol 65 304 315 19334062
- Ozturk A Smith SA Gordon-Lipkin EM Harrison DM Shiee N Pham DL Caffo BS Calabresi PA Reich DS MRI of the corpus callosum in multiple sclerosis: association with disability Mult Scler 16 166 177 20142309 PMC2820126
- 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 17063394
- Patel JR McCandless EE Dorsey D Klein RS 2010 CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination Proc Natl Acad Sci U S A 107 11062 11067 20534485 PMC2890706
- Plant SR Arnett HA Ting JP 2005 Astroglial-derived lymphotoxin-alpha exacerbates inflammation and demyelination, but not remyelination Glia 49 1 14 15382206
- Poppenga RH Trapp AL Braselton WE Louden CG Gumbs JM Dalley JB 1990 Hexachlorophene toxicosis in a litter of Doberman pinschers J Vet Diagn Invest 2 129 131 2094434
- Pott F Gingele S Clarner T Dang J Baumgartner W Beyer C Kipp M 2009 Cuprizone effect on myelination, astrogliosis and microglia attraction in the mouse basal ganglia Brain Res 1305 137 149 19799876
- Raybaud C 2010 The corpus callosum, the other great forebrain commissures, and the septum pellucidum: anatomy, development, and malformation Neuroradiology 52 447 477 20422408
- Skripuletz T Bussmann JH Gudi V Koutsoudaki PN Pul R Moharregh-Khiabani D Lindner M Stangel M 2010 Cerebellar cortical demyelination in the murine cuprizone model Brain Pathol 20 301 312 19371354 PMC8094790
- Skripuletz T Lindner M Kotsiari A Garde N Fokuhl J Linsmeier F Trebst C Stangel M 2008 Cortical demyelination is prominent in the murine cuprizone model and is strain-dependent Am J Pathol 172 1053 1061 18349131 PMC2276412
- Smith AB Smirniotopoulos JG Imaging evaluation of demyelinating processes of the central nervous system Postgrad Med J 86 218 229 20354045
- Stidworthy MF Genoud S Suter U Mantei N Franklin RJ 2003a Quantifying the early stages of remyelination following cuprizone-induced demyelination Brain Pathol 13 329 339 12946022 PMC8095752
- Suzuki K Kikkawa Y 1969 Status spongiosus of CNS and hepatic changes induced by cuprizone (biscyclohexanone oxalyldihydrazone) Am J Pathol 54 307 325 5765567 PMC2013472
- Taylor LC Gilmore W Ting JP Matsushima GK 2010 Cuprizone induces similar demyelination in male and female C57BL/6 mice and results in disruption of the estrous cycle J Neurosci Res 88 391 402 19746424
- Tobin JE Xie M Le TQ Song S-K Armstrong RC 2011 Reduced Axonopathy and Enhanced Remyelination After Chronic Demyelination in Fibroblast Growth Factor 2 (Fgf2)-Null Mice: Differential Detection With Diffusion Tensor Imaging Journal of Neuropathology & Experimental Neurology 70 157 165 110.1097/NEN.1090b1013e31820937e31820934 21343885 PMC3072283 · DOI
- Williams A Piaton G Lubetzki C 2007 Astrocytes - Friends or foes in multiple sclerosis? Glia 55 1300 1312 17626262
- Wu QZ Yang Q Cate HS Kemper D Binder M Wang HX Fang K Quick MJ Marriott M Kilpatrick TJ Egan GF 2008 MRI identification of the rostral-caudal pattern of pathology within the corpus callosum in the cuprizone mouse model J Magn Reson Imaging 27 446 453 17968901
- Xie M Tobin JE Budde MD Chen CI Trinkaus K Cross AH McDaniel DP Song SK Armstrong RC 2010 Rostrocaudal analysis of corpus callosum demyelination and axon damage across disease stages refines diffusion tensor imaging correlations with pathological features J Neuropathol Exp Neurol 69 704 716 20535036 PMC2901930
- Yang HJ Wang H Zhang Y Xiao L Clough RW Browning R Li XM Xu H 2009a Region-specific susceptibilities to cuprizone-induced lesions in the mouse forebrain: Implications for the pathophysiology of schizophrenia Brain Research 1270 121 130 19306847
Cited by
Sorted by citations
Jelescu, I. O., Zurek, M., Winters, K. V., Veraart, J., Rajaratnam, A., Kim, N. S., Babb, J. S., Shepherd, T. M., Novikov, D. S., Kim, S. G., et al. (2016) · NeuroImage · doi:10.1016/j.neuroimage.2016.02.004 · Cited by 188 · see citing works
The Cuprizone Model: Dos and Do Nots
Zhan, J., Mann, T., Joost, S., Behrangi, N., Frank, M., & Kipp, M. (2020) · Cells · doi:10.3390/cells9040843 · Cited by 171 · see citing works
Spatio-Temporal Patterns of Demyelination and Remyelination in the Cuprizone Mouse Model
Tagge, I., O’Connor, A., Chaudhary, P., Pollaro, J., Berlow, Y., Chalupsky, M., Bourdette, D., Woltjer, R., Johnson, M., & Rooney, W. (2016) · PLOS ONE · doi:10.1371/journal.pone.0152480 · Cited by 81 · see citing works
Guglielmetti, C., Le Blon, D., Santermans, E., Salas-Perdomo, A., Daans, J., De Vocht, N., Shah, D., Hoornaert, C., Praet, J., Peerlings, J., et al. (2016) · Glia · doi:10.1002/glia.23053 · Cited by 76 · see citing works
Butti, E., Bacigaluppi, M., Chaabane, L., Ruffini, F., Brambilla, E., Berera, G., Montonati, C., Quattrini, A., & Martino, G. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.0227-18.2019 · Cited by 67 · see citing works
McMurran, C. E., Guzman de la Fuente, A., Penalva, R., Ben Menachem-Zidon, O., Dombrowski, Y., Falconer, J., Gonzalez, G. A., Zhao, C., Krause, F. N., Young, A. M. H., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1905787116 · Cited by 39 · see citing works
Animal models to investigate the effects of inflammation on remyelination in multiple sclerosis
Gharagozloo, M., Mace, J. W., & Calabresi, P. A. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.995477 · Cited by 38 · see citing works
Cuprizone Administration Alters the Iron Metabolism in the Mouse Model of Multiple Sclerosis
Varga, E., Pandur, E., Abrahám, H., Horváth, A., Ács, P., Komoly, S., Miseta, A., & Sipos, K. (2018) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-018-0578-5 · Cited by 27 · see citing works
Yamate-Morgan, H., Lauderdale, K., Horeczko, J., Merchant, U., & Tiwari-Woodruff, S. K. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.01.038 · Cited by 27 · see citing works
Palavra, F., Viana, S. D., Henriques, S., Dinis, J., Martins, J., Madeira, M. H., Santiago, R., Petrella, L., Sereno, J., Castelo-Branco, M., et al. (2022) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2022.103886 · Cited by 14 · see citing works
Buonvicino, D., Ranieri, G., & Chiarugi, A. (2021) · Neurotoxicity Research · doi:10.1007/s12640-021-00331-3 · Cited by 8 · see citing works
Multifaceted response of microglia in the cuprizone model of demyelination
Shanahan, A., Eichfeld, G., Todd, L., & Niraula, A. (2026) · PLOS One · doi:10.1371/journal.pone.0355981
“The microglial response to cuprizone-induced demyelination has largely been studied weeks into cuprizone administration, when demyelination reaches peak levels [21,22].”
- Authors
- Steelman, A. J., Thompson, J. P., & Li, J.
- Affiliations
- Texas A&M University (US)
- Corresponding author
- Li, Jianrong
- Venue
- Neuroscience Research
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 72
- Issue
- 1
- Pages
- 32-42
- ISSN
- 0168-0102 (ISSN-L)
- PMC
- PMC3230728
- OpenAlex
- W2090519295
- Cited by
- 183
- References
- 6
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 12 · 2023: 17 · 2022: 13 · 2021: 14 · 2020: 22 · 2019: 20 · 2018: 12 · 2017: 15 · 2016: 16 · 2015: 10 · 2014: 6 · 2013: 7 · 2012: 1
- FWCI
- 3.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Multiple Sclerosis Society
- Texas A and M University
- University of Regina
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS060017)
- 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, demyelination, remyelination, corpus callosum, multiple sclerosis model, regional heterogeneity, astrocyte activation, microglial activation, splenium, oligodendrocytes
- MeSH terms
- Animals, Axons, Brain, Corpus Callosum, Cuprizone, Demyelinating Diseases, Disease Models, Animal, Glial Fibrillary Acidic Protein, Gliosis, Male, Mice, Inbred C57BL, Myelin Sheath, Nerve Tissue Proteins, Oligodendroglia, Weight Loss, Microglia, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
