Skip to main content

Advertisement

SpringerLink
Log in

The cuprizone animal model: new insights into an old story

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease that affects the central nervous system and represents the most common neurological disorder in young adults in the Western hemisphere. There are several well-characterized experimental animal models that allow studying potential mechanisms of MS pathology. While experimental allergic encephalomyelitis is one of the most frequently used models to investigate MS pathology and therapeutic interventions, the cuprizone model reflects a toxic experimental model. Cuprizone-induced demyelination in animals is accepted for studying MS-related lesions and is characterized by degeneration of oligodendrocytes rather than by a direct attack on the myelin sheet. The present article reviews recent data concerning the cuprizone model and its relevance for MS. Particular focus is given to the concordance and difference between human MS patterns (types I–IV lesions) and cuprizone-induced histopathology, including a detailed description of the sensitive brain regions extending the observations to different white and grey matter structures. Similarities between pattern III lesions and cuprizone-induced demyelination and dissimilarities, such as inflamed blood vessels or the presence of CD3+ T cells, are outlined. We also aim to distinguish acute and chronic demyelination under cuprizone including processes such as spontaneous remyelination during acute demyelination. Finally, we point at strain and gender differences in this animal model and highlight the contribution of some growth factors and cytokines during and after cuprizone intoxication, including LIF, IGF-1, and PDGFα.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Acs P, Kipp M, Norkute A et al (2009) 17beta-estradiol and progesterone prevent cuprizone provoked demyelination of corpus callosum in male mice. Glia 57:807–814

    Article  PubMed  Google Scholar 

  2. Allen IV, McQuaid S, Mirakhur M, Nevin G (2001) Pathological abnormalities in the normal-appearing white matter in multiple sclerosis. Neurol Sci 22:141–144

    Article  CAS  PubMed  Google Scholar 

  3. Antonio M, Patrizia F, Ilaria I, Paolo F (2008) A rational approach on the use of sex steroids in multiple sclerosis. Recent Pat CNS Drug Discov 3:34–39

    Article  CAS  PubMed  Google Scholar 

  4. Armstrong RC (2007) Growth factor regulation of remyelination: behind the growing interest in endogenous cell repair of the CNS. Future Neurol 2:689–697

    Article  CAS  PubMed  Google Scholar 

  5. Armstrong RC, Le TQ, Flint NC, Vana AC, Zhou YX (2006) Endogenous cell repair of chronic demyelination. J Neuropathol Exp Neurol 65:245–256

    PubMed  Google Scholar 

  6. Arnold S, Beyer C (2009) Neuroprotection by estrogen in the brain: the mitochondrial compartment as presumed therapeutic target. J Neurochem 110:1–11

    Article  CAS  PubMed  Google Scholar 

  7. Back SA, Tuohy TM, Chen H et al (2005) Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nat Med 11:966–972

    CAS  PubMed  Google Scholar 

  8. Baer AS, Syed YA, Kang SU et al (2009) Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling. Brain 132:465–481

    Article  PubMed  Google Scholar 

  9. Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55:458–468

    Article  PubMed  Google Scholar 

  10. Barres BA, Schmid R, Sendnter M, Raff MC (1993) Multiple extracellular signals are required for long-term oligodendrocyte survival. Development 118:283–295

    CAS  PubMed  Google Scholar 

  11. Blakemore WF, Franklin RJ (2008) Remyelination in experimental models of toxin- induced demyelination. Curr Top Microbiol Immunol 318:193–212

    Article  CAS  PubMed  Google Scholar 

  12. Braun A, Dang J, Johann S, Beyer C, Kipp M (2009) Selective regulation of growth factor expression in cultured cortical astrocytes by neuro-pathological toxins. Neurochem Int

  13. Bruck W (2005) Inflammatory demyelination is not central to the pathogenesis of multiple sclerosis. J Neurol 252(Suppl 5):v10–v15

    Article  PubMed  Google Scholar 

  14. Cammer W (1999) The neurotoxicant, cuprizone, retards the differentiation of oligodendrocytes in vitro. J Neurol Sci 168:116–120

    Article  CAS  PubMed  Google Scholar 

  15. Cammer W, Zhang H, Tansey FA (1995) Effects of carbonic anhydrase II (CAII) deficiency on CNS structure and function in the myelin-deficient CAII-deficient double mutant mouse. J Neurosci Res 40:451–457

    Article  CAS  PubMed  Google Scholar 

  16. Carlton WW (1966) Response of mice to the chelating agents sodium diethyldithiocarbamate, alpha-benzoinoxime, and biscyclohexanone oxaldihydrazone. Toxicol Appl Pharmacol 8:512–521

    Article  CAS  PubMed  Google Scholar 

  17. Carlton WW (1967) Studies on the induction of hydrocephalus and spongy degeneration by cuprizone feeding and attempts to antidote the toxicity. Life Sci 6:11–19

    Article  CAS  PubMed  Google Scholar 

  18. Chang A, Tourtellotte WW, Rudick R, Trapp BD (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 346:165–173

    Article  PubMed  Google Scholar 

  19. Cho KH, Kim MW, Kim SU (1997) Tissue culture model of Krabbe’s disease: psychosine cytotoxicity in rat oligodendrocyte culture. Dev Neurosci 19:321–327

    Article  CAS  PubMed  Google Scholar 

  20. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T (1998) Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 339:285–291

    Article  CAS  PubMed  Google Scholar 

  21. Copray S, Balasubramaniyan V, Levenga J, de Bruijn J, Liem R, Boddeke E (2006) Olig2 overexpression induces the in vitro differentiation of neural stem cells into mature oligodendrocytes. Stem Cells 24:1001–1010

    Article  CAS  PubMed  Google Scholar 

  22. Cudd A, Nicolau C (1986) Interaction of intravenously injected liposomes with mouse liver mitochondria. A fluorescence and electron microscopy study. Biochim Biophys Acta 860:201–214

    Article  CAS  PubMed  Google Scholar 

  23. D’Ercole AJ, Ye P, Calikoglu AS, Gutierrez-Ospina G (1996) The role of the insulin-like growth factors in the central nervous system. Mol Neurobiol 13:227–255

    Article  PubMed  Google Scholar 

  24. Diemel LT, Jackson SJ, Cuzner ML (2003) Role for TGF-beta1, FGF-2 and PDGF-AA in a myelination of CNS aggregate cultures enriched with macrophages. J Neurosci Res 74:858–867

    Article  CAS  PubMed  Google Scholar 

  25. Duquette P, Girard M (1993) Hormonal factors in susceptibility to multiple sclerosis. Curr Opin Neurol Neurosurg 6:195–201

    CAS  PubMed  Google Scholar 

  26. Emerson MR, Biswas S, LeVine SM (2001) Cuprizone and piperonyl butoxide, proposed inhibitors of T-cell function, attenuate experimental allergic encephalomyelitis in SJL mice. J Neuroimmunol 119:205–213

    Article  CAS  PubMed  Google Scholar 

  27. Emery B, Cate HS, Marriott M et al (2006) Suppressor of cytokine signaling 3 limits protection of leukemia inhibitory factor receptor signaling against central demyelination. Proc Natl Acad Sci USA 103:7859–7864

    Article  CAS  PubMed  Google Scholar 

  28. Flatmark T, Kryvi H, Tangeras A (1980) Induction of megamitochondria by cuprizone (biscyclohexanone oxaldihydrazone). Evidence for an inhibition of the mitochondrial division process. Eur J Cell Biol 23:141–148

    CAS  PubMed  Google Scholar 

  29. Franklin RJ (2002) Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 3:705–714

    Article  CAS  PubMed  Google Scholar 

  30. Friese MA, Montalban X, Willcox N, Bell JI, Martin R, Fugger L (2006) The value of animal models for drug development in multiple sclerosis. Brain 129:1940–1952

    Article  PubMed  Google Scholar 

  31. Garcia-Segura LM, Duenas M, Fernandez-Galaz MC et al (1996) Interaction of the signalling pathways of insulin-like growth factor-I and sex steroids in the neuroendocrine hypothalamus. Horm Res 46:160–164

    Article  CAS  PubMed  Google Scholar 

  32. Geurts JJ, Barkhof F (2008) Grey matter pathology in multiple sclerosis. Lancet Neurol 7:841–851

    Article  PubMed  Google Scholar 

  33. Gold SM, Voskuhl RR (2009) Estrogen treatment in multiple sclerosis. J Neurol Sci

  34. Gonzalez-Perez O, Romero-Rodriguez R, Soriano-Navarro M, Garcia-Verdugo JM, Alvarez-Buylla A (2009) EGF induces the progeny of subventricular zone type B cells to migrate and differentiate into oligodendrocytes. Stem Cells 27(8):2032–2043

    Article  CAS  PubMed  Google Scholar 

  35. 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(3):163–174

    Article  CAS  PubMed  Google Scholar 

  36. Gudi V, Moharregh-Khiabani D, Skripuletz T et al (2009) Regional differences between grey and white matter in cuprizone induced demyelination. Brain Res 1283:127–138

    Article  CAS  PubMed  Google Scholar 

  37. Harsan LA, Steibel J, Zaremba A et al (2008) Recovery from chronic demyelination by thyroid hormone therapy: myelinogenesis induction and assessment by diffusion tensor magnetic resonance imaging. J Neurosci 28:14189–14201

    Article  CAS  PubMed  Google Scholar 

  38. Hoffmann K, Lindner M, Groticke I, Stangel M, Loscher W (2008) Epileptic seizures and hippocampal damage after cuprizone-induced demyelination in C57BL/6 mice. Exp Neurol 210:308–321

    Article  CAS  PubMed  Google Scholar 

  39. Hoppel CL, Tandler B (1973) Biochemical effects of cuprizone on mouse liver and heart mitochondria. Biochem Pharmacol 22:2311–2318

    Article  CAS  PubMed  Google Scholar 

  40. Irvine KA, Blakemore WF (2006) Age increases axon loss associated with primary demyelination in cuprizone-induced demyelination in C57BL/6 mice. J Neuroimmunol 175:69–76

    Article  CAS  PubMed  Google Scholar 

  41. Jiang F, Frederick TJ, Wood TL (2001) IGF-I synergizes with FGF-2 to stimulate oligodendrocyte progenitor entry into the cell cycle. Dev Biol 232:414–423

    Article  CAS  PubMed  Google Scholar 

  42. Jiao J, Chen DF (2008) Induction of neurogenesis in nonconventional neurogenic regions of the adult central nervous system by niche astrocyte-produced signals. Stem Cells 26:1221–1230

    Article  CAS  PubMed  Google Scholar 

  43. Jiao JW, Feldheim DA, Chen DF (2008) Ephrins as negative regulators of adult neurogenesis in diverse regions of the central nervous system. Proc Natl Acad Sci USA 105:8778–8783

    Article  CAS  PubMed  Google Scholar 

  44. Jurevics H, Hostettler J, Muse ED et al (2001) Cerebroside synthesis as a measure of the rate of remyelination following cuprizone-induced demyelination in brain. J Neurochem 77:1067–1076

    Article  CAS  PubMed  Google Scholar 

  45. Kida E, Palminiello S, Golabek AA et al (2006) Carbonic anhydrase II in the developing and adult human brain. J Neuropathol Exp Neurol 65:664–674

    Article  CAS  PubMed  Google Scholar 

  46. Kipp M, Beyer C (2009) Impact of sex steroids on neuroinflammatory processes and experimental multiple sclerosis. Front Neuroendocrinol 30:188–200

    Article  CAS  PubMed  Google Scholar 

  47. Komoly S (2005) Experimental demyelination caused by primary oligodendrocyte dystrophy. Regional distribution of the lesions in the nervous system of mice [corrected]. Ideggyogy Sz 58:40–43

    PubMed  Google Scholar 

  48. Komoly S, Hudson LD, Webster HD, Bondy CA (1992) Insulin-like growth factor I gene expression is induced in astrocytes during experimental demyelination. Proc Natl Acad Sci USA 89:1894–1898

    Article  CAS  PubMed  Google Scholar 

  49. Komoly S, Jeyasingham MD, Pratt OE, Lantos PL (1987) Decrease in oligodendrocyte carbonic anhydrase activity preceding myelin degeneration in cuprizone induced demyelination. J Neurol Sci 79:141–148

    Article  CAS  PubMed  Google Scholar 

  50. Kornek B, Lassmann H (1999) Axonal pathology in multiple sclerosis. A historical note. Brain Pathol 9:651–656

    CAS  PubMed  Google Scholar 

  51. Kotter MR, Li WW, Zhao C, Franklin RJ (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26:328–332

    Article  CAS  PubMed  Google Scholar 

  52. Lassmann H (2007) Experimental models of multiple sclerosis. Rev Neurol (Paris) 163:651–655

    CAS  Google Scholar 

  53. Lassmann H (2008) Models of multiple sclerosis: new insights into pathophysiology and repair. Curr Opin Neurol 21:242–247

    Article  CAS  PubMed  Google Scholar 

  54. Lassmann H, Bartsch U, Montag D, Schachner M (1997) Dying-back oligodendrogliopathy: a late sequel of myelin-associated glycoprotein deficiency. Glia 19:104–110

    Article  CAS  PubMed  Google Scholar 

  55. Lassmann H, Bruck W, Lucchinetti C (2001) Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 7:115–121

    Article  CAS  PubMed  Google Scholar 

  56. Li WW, Penderis J, Zhao C, Schumacher M, Franklin RJ (2006) Females remyelinate more efficiently than males following demyelination in the aged but not young adult CNS. Exp Neurol 202:250–254

    Article  CAS  PubMed  Google Scholar 

  57. Lindner M, Heine S, Haastert K et al (2008) Sequential myelin protein expression during remyelination reveals fast and efficient repair after central nervous system demyelination. Neuropathol Appl Neurobiol 34:105–114

    CAS  PubMed  Google Scholar 

  58. Lindner M, Fokuhl J, Linsmeier F, Trebst C, Stangel M (2009) Chronic toxic demyelination in the central nervous system leads to axonal damage despite remyelination. Neurosci Lett 453:120–125

    Article  CAS  PubMed  Google Scholar 

  59. Linker RA, Kruse N, Israel S et al (2008) Leukemia inhibitory factor deficiency modulates the immune response and limits autoimmune demyelination: a new role for neurotrophic cytokines in neuroinflammation. J Immunol 180:2204–2213

    CAS  PubMed  Google Scholar 

  60. 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

    Article  CAS  PubMed  Google Scholar 

  61. Lucchinetti CF, Bruck W, Rodriguez M, Lassmann H (1996) Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Brain Pathol 6:259–274

    Article  CAS  PubMed  Google Scholar 

  62. Ludwin SK (1978) Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. Lab Invest 39:597–612

    CAS  PubMed  Google Scholar 

  63. Ludwin SK (1980) Chronic demyelination inhibits remyelination in the central nervous system. An analysis of contributing factors. Lab Invest 43:382–387

    CAS  PubMed  Google Scholar 

  64. Ludwin SK, Johnson ES (1981) Evidence for a “dying-back” gliopathy in demyelinating disease. Ann Neurol 9:301–305

    Article  CAS  PubMed  Google Scholar 

  65. Mana P, Fordham SA, Staykova MA et al (2009) Demyelination caused by the copper chelator cuprizone halts T cell mediated autoimmune neuroinflammation. J Neuroimmunol 210:13–21

    Article  CAS  PubMed  Google Scholar 

  66. Marriott MP, Emery B, Cate HS et al (2008) Leukemia inhibitory factor signaling modulates both central nervous system demyelination and myelin repair. Glia 56:686–698

    Article  PubMed  Google Scholar 

  67. Mason JL, Ye P, Suzuki K, D’Ercole AJ, Matsushima GK (2000) Insulin-like growth factor-1 inhibits mature oligodendrocyte apoptosis during primary demyelination. J Neurosci 20:5703–5708

    CAS  PubMed  Google Scholar 

  68. Messori L, Casini A, Gabbiani C, Sorace L, Muniz-Miranda M, Zatta P (2007) Unravelling the chemical nature of copper cuprizone. Dalton Trans Jun 7;(21):2112–2114

    Google Scholar 

  69. Metcalf D (2003) The unsolved enigmas of leukemia inhibitory factor. Stem Cells 21:5–14

    Article  CAS  PubMed  Google Scholar 

  70. Mix E, Meyer-Rienecker H, Zettl UK (2008) Animal models of multiple sclerosis for the development and validation of novel therapies—potential and limitations. J Neurol 255(Suppl 6):7–14

    Article  CAS  PubMed  Google Scholar 

  71. Morell P, Barrett CV, Mason JL et al (1998) Gene expression in brain during cuprizone-induced demyelination and remyelination. Mol Cell Neurosci 12:220–227

    Article  CAS  PubMed  Google Scholar 

  72. Murtie JC, Zhou YX, Le TQ, Vana AC, Armstrong RC (2005) PDGF and FGF2 pathways regulate distinct oligodendrocyte lineage responses in experimental demyelination with spontaneous remyelination. Neurobiol Dis 19:171–182

    Article  CAS  PubMed  Google Scholar 

  73. Norkute A, Hieble A, Braun A et al (2009) Cuprizone treatment induces demyelination and astrocytosis in the mouse hippocampus. J Neurosci Res 87:1343–1355

    Article  CAS  PubMed  Google Scholar 

  74. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N Engl J Med 343:938–952

    Article  CAS  PubMed  Google Scholar 

  75. Oleszak EL, Chang JR, Friedman H, Katsetos CD, Platsoucas CD (2004) Theiler’s virus infection: a model for multiple sclerosis. Clin Microbiol Rev 17:174–207

    Article  CAS  PubMed  Google Scholar 

  76. 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

    Article  CAS  PubMed  Google Scholar 

  77. Patrikios P, Stadelmann C, Kutzelnigg A et al (2006) Remyelination is extensive in a subset of multiple sclerosis patients. Brain 129:3165–3172

    Article  PubMed  Google Scholar 

  78. Penderis J, Shields SA, Franklin RJ (2003) Impaired remyelination and depletion of oligodendrocyte progenitors does not occur following repeated episodes of focal demyelination in the rat central nervous system. Brain 126:1382–1391

    Article  PubMed  Google Scholar 

  79. Schaumburg HH, Wisniewski HM, Spencer PS (1974) Ultrastructural studies of the dying-back process. I. Peripheral nerve terminal and axon degeneration in systemic acrylamide intoxication. J Neuropathol Exp Neurol 33:260–284

    Article  CAS  PubMed  Google Scholar 

  80. Shen S, Liu A, Li J, Wolubah C, Casaccia-Bonnefil P (2008) Epigenetic memory loss in aging oligodendrocytes in the corpus callosum. Neurobiol Aging 29:452–463

    Article  CAS  PubMed  Google Scholar 

  81. Shen S, Sandoval J, Swiss VA, Li J, Dupree J, Franklin RJ, Casaccia-Bonnefil P (2008) Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nat Neurosci 11(9):1024–1034

    Article  CAS  PubMed  Google Scholar 

  82. Sher F, van Dam G, Boddeke E, Copray S (2009) Bioluminescence imaging of Olig2-neural stem cells reveals improved engraftment in a demyelination mouse model. Stem Cells 27:1582–1591

    Article  CAS  PubMed  Google Scholar 

  83. Sicotte NL, Liva SM, Klutch R et al (2002) Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol 52:421–428

    Article  CAS  PubMed  Google Scholar 

  84. Skripuletz T, Bussmann JH, Gudi V et al (2009) Cerebellar cortical demyelination in the murine cuprizone model. Brain Pathol

  85. Snodgress AB, Dorsey CH, Lacey LB (1961) Luxol fast blue staining of degenerating myelinated fibers. Anat Rec 140:83–90

    Article  CAS  PubMed  Google Scholar 

  86. Stangel M, Trebst C (2006) Remyelination strategies: new advancements toward a regenerative treatment in multiple sclerosis. Curr Neurol Neurosci Rep 6:229–235

    Article  PubMed  Google Scholar 

  87. Stidworthy MF, Genoud S, Suter U, Mantei N, Franklin RJ (2003) Quantifying the early stages of remyelination following cuprizone-induced demyelination. Brain Pathol 13:329–339

    Article  PubMed  Google Scholar 

  88. Taniguchi Y, Amazaki M, Furuyama T et al (2009) Sema4D deficiency results in an increase in the number of oligodendrocytes in healthy and injured mouse brains. J Neurosci Res 87(13):2833–2841

    Article  CAS  PubMed  Google Scholar 

  89. Tansey FA, Zhang H, Cammer W (1996) Expression of carbonic anhydrase II mRNA and protein in oligodendrocytes during toxic demyelination in the young adult mouse. Neurochem Res 21:411–416

    Article  CAS  PubMed  Google Scholar 

  90. Taylor LC, Gilmore W, Matsushima GK (2009) SJL mice exposed to cuprizone intoxication reveal strain and gender pattern differences in demyelination. Brain Pathol 19:467–479

    Article  CAS  PubMed  Google Scholar 

  91. Tedeschi H, Mannella CA, Bowman CL (1987) Patch clamping the outer mitochondrial membrane. J Membr Biol 97:21–29

    Article  CAS  PubMed  Google Scholar 

  92. Torkildsen O, Brunborg LA, Myhr KM, Bo L (2008) The cuprizone model for demyelination. Acta Neurol Scand Suppl 188:72–76

    Article  CAS  PubMed  Google Scholar 

  93. Vana AC, Flint NC, Harwood NE, Le TQ, Fruttiger M, Armstrong RC (2007) Platelet-derived growth factor promotes repair of chronically demyelinated white matter. J Neuropathol Exp Neurol 66:975–988

    Article  CAS  PubMed  Google Scholar 

  94. Vanderlocht J, Hellings N, Hendriks JJ et al (2006) Leukemia inhibitory factor is produced by myelin-reactive T cells from multiple sclerosis patients and protects against tumor necrosis factor-alpha-induced oligodendrocyte apoptosis. J Neurosci Res 83:763–774

    Article  CAS  PubMed  Google Scholar 

  95. Vanderlocht J, Hendriks JJ, Venken K, Stinissen P, Hellings N (2006) Effects of IFN- beta, leptin and simvastatin on LIF secretion by T lymphocytes of MS patients and healthy controls. J Neuroimmunol 177:189–200

    Article  CAS  PubMed  Google Scholar 

  96. Venturini G (1973) Enzymic activities and sodium, potassium and copper concentrations in mouse brain and liver after cuprizone treatment in vivo. J Neurochem 21:1147–1151

    Article  CAS  PubMed  Google Scholar 

  97. Wakabayashi T, Asano M, Kurono C (1974) Some aspects of mitochondria having a “septum”. J Electron Microsc (Tokyo) 23:247–254

    CAS  Google Scholar 

  98. Wekerle H (2008) Lessons from multiple sclerosis: models, concepts, observations. Ann Rheum Dis 67(Suppl 3):iii56–iii60

    Article  PubMed  Google Scholar 

  99. Woodruff RH, Fruttiger M, Richardson WD, Franklin RJ (2004) Platelet-derived growth factor regulates oligodendrocyte progenitor numbers in adult CNS and their response following CNS demyelination. Mol Cell Neurosci 25:252–262

    Article  CAS  PubMed  Google Scholar 

  100. Zatta P, Raso M, Zambenedetti P et al (2005) Copper and zinc dismetabolism in the mouse brain upon chronic cuprizone treatment. Cell Mol Life Sci 62:1502–1513

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank U. Zahn, A. Weth and H. Helten for excellent technical assistance and W. Graulich for assistance in figure preparation. We also acknowledge the suggestions and the help of Prof. W.F. Blakemore, MS Society Cambridge Centre for Myelin Repair, UK. This research project was supported by the START-Program (MK) of the Faculty of Medicine, RWTH Aachen University and the Hertie-Foundation (MK).

Author information

Authors and Affiliations

  1. Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany

    Markus Kipp, Tim Clarner, Jon Dang & Cordian Beyer

  2. Department of Neuroscience, University Medical Centre Groningen, A.Deusinglaan 1, 9713 AV, Groningen, The Netherlands

    Sjef Copray

Authors
  1. Markus Kipp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tim Clarner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jon Dang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sjef Copray
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cordian Beyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Markus Kipp.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kipp, M., Clarner, T., Dang, J. et al. The cuprizone animal model: new insights into an old story. Acta Neuropathol 118, 723–736 (2009). https://doi.org/10.1007/s00401-009-0591-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-009-0591-3

Keywords

Search

Navigation