Five Decades of Cuprizone, an Updated Model to Replicate Demyelinating Diseases

Jose    M.    Vega-Riquer; Gerardo       Mendez-Victoriano; Raul    A.    Morales-Luckie; Oscar       Gonzalez-Perez
doi:10.2174/1570159X15666170717120343
Abstract

Introduction: Demyelinating diseases of the central nervous system (CNS) comprise a group of neurological disorders characterized by progressive (and eventually irreversible) loss of oligodendrocytes and myelin sheaths in the white matter tracts. Some of myelin disorders include: Multiple sclerosis, Guillain-Barré syndrome, peripheral nerve polyneuropathy and others. To date, the etiology of these disorders is not well known and no effective treatments are currently available against them. Therefore, further research is needed to gain a better understand and treat these patients. To accomplish this goal, it is necessary to have appropriate animal models that closely resemble the pathophysiology and clinical signs of these diseases. Herein, we describe the model of toxic demyelination induced by cuprizone (CPZ), a copper chelator that reduces the cytochrome and monoamine oxidase activity into the brain, produces mitochondrial stress and triggers the local immune response. These biochemical and cellular responses ultimately result in selective loss of oligodendrocytes and microglia accumulation, which conveys to extensive areas of demyelination and gliosis in corpus callosum, superior cerebellar peduncles and cerebral cortex. Remarkably, some aspects of the histological pattern induced by CPZ are similar to those found in multiple sclerosis. CPZ exposure provokes behavioral changes, impairs motor skills and affects mood as that observed in several demyelinating diseases. Upon CPZ removal, the pathological and histological changes gradually revert. Therefore, some authors have postulated that the CPZ model allows to partially mimic the disease relapses observed in some demyelinating diseases.
Conclusion: for five decades, the model of CPZ-induced demyelination is a good experimental approach to study demyelinating diseases that has maintained its validity, and is a suitable pharmacological model for reproducing some key features of demyelinating diseases, including multiple sclerosis.
Keywords: Cuprizone, myelin, oligodendrocyte, demyelination, remyelination, white matter, neuroinflammation, multiple sclerosis, demyelinating disease, microglia.
« Previous Next »
Graphical Abstract

[1] 
Friese, M.A.; Schattling, B.; Fugger, L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat. Rev. Neurol.,  2014, 10(4), 225-238.
[http://dx.doi.org/10.1038/nrneurol.2014.37] [PMID:  24638138] 
[2] 
Friese, M.A. Widespread synaptic loss in multiple sclerosis. Brain,  2016, 139(Pt 1), 2-4.
[http://dx.doi.org/10.1093/brain/awv349] [PMID:  26747852] 
[3] 
Jürgens, T.; Jafari, M.; Kreutzfeldt, M.; Bahn, E.; Brück, W.; Kerschensteiner, M.; Merkler, D. Reconstruction of single cortical projection neurons reveals primary spine loss in multiple sclerosis. Brain,  2016, 139(Pt 1), 39-46.
[http://dx.doi.org/10.1093/brain/awv353] [PMID:  26667278] 
[4] 
Deber, C.M.; Reynolds, S.J. Central nervous system myelin: structure, function, and pathology. Clin. Biochem.,  1991, 24(2), 113-134.
[http://dx.doi.org/10.1016/0009-9120(91)90421-A] [PMID:  1710177] 
[5] 
Patrikios, P.; Stadelmann, C.; Kutzelnigg, A.; Rauschka, H.; Schmidbauer, M.; Laursen, H.; Sorensen, P.S.; Brück, W.; Lucchinetti, C.; Lassmann, H. Remyelination is extensive in a subset of multiple sclerosis patients. Brain,  2006, 129(Pt 12), 3165-3172.
[http://dx.doi.org/10.1093/brain/awl217] [PMID:  16921173] 
[6] 
Goldschmidt, T.; Antel, J.; König, F.B.; Brück, W.; Kuhlmann, T. Remyelination capacity of the MS brain decreases with disease chronicity. Neurology,  2009, 72(22), 1914-1921.
[http://dx.doi.org/ 10.1212/WNL.0b013e3181a8260a] [PMID:  19487649] 
[7] 
Gudi, V.; Gingele, S.; Skripuletz, T.; Stangel, M. Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned. Front. Cell. Neurosci.,  2014, 8, 73.
[http://dx.doi.org/ 10.3389/fncel.2014.00073] [PMID:  24659953] 
[8] 
Denic, A.; Johnson, A.J.; Bieber, A.J.; Warrington, A.E.; Rodriguez, M.; Pirko, I. The relevance of animal models in multiple sclerosis research. Pathophysiology,  2011, 18(1), 21-29.
[http://dx.doi.org/10.1016/j.pathophys.2010.04.004] [PMID:  20537877] 
[9] 
Cammer, W. The neurotoxicant, cuprizone, retards the differentiation of oligodendrocytes in vitro. J. Neurol. Sci.,  1999, 168(2), 116-120.
[http://dx.doi.org/10.1016/S0022-510X(99)00181-1] [PMID:  10526193] 
[10] 
Kalman, B.; Laitinen, K.; Komoly, S. The involvement of mitochondria in the pathogenesis of multiple sclerosis. J. Neuroimmunol.,  2007, 188(1-2), 1-12.
[http://dx.doi.org/10.1016/j.jneuroim. 2007.03.020] [PMID:  17493689] 
[11] 
Zucconi, G.G.; Cipriani, S.; Scattoni, R.; Balgkouranidou, I.; Hawkins, D.P.; Ragnarsdottir, K.V. Copper deficiency elicits glial and neuronal response typical of neurodegenerative disorders. Neuropathol. Appl. Neurobiol.,  2007, 33(2), 212-225.
[http://dx.doi.org/ 10.1111/j.1365-2990.2006.00793.x] [PMID:  17359362] 
[12] 
van der Star, B.J.; Vogel, D.Y.S.; Kipp, M.; Puentes, F.; Baker, D.; Amor, S. In vitro and in vivo models of multiple sclerosis. CNS Neurol. Disord. Drug Targets,  2012, 11(5), 570-588.
[http://dx.doi.org/10.2174/187152712801661284] [PMID:  22583443] 
[13] 
Clarner, T.; Janssen, K.; Nellessen, L.; Stangel, M.; Skripuletz, T.; Krauspe, B.; Hess, F.M.; Denecke, B.; Beutner, C.; Linnartz-Gerlach, B.; Neumann, H.; Vallières, L.; Amor, S.; Ohl, K.; Tenbrock, K.; Beyer, C.; Kipp, M. CXCL10 triggers early microglial activation in the cuprizone model. J. Immunol.,  2015, 194(7), 3400-3413.
[http://dx.doi.org/10.4049/jimmunol.1401459] [PMID:  25725102] 
[14] 
Blakemore, W.F. Observations on oligodendrocyte degeneration, the resolution of status spongiosus and remyelination in cuprizone intoxication in mice. J. Neurocytol.,  1972, 1(4), 413-426.
[http://dx.doi.org/10.1007/BF01102943] [PMID:  8530973] 
[15] 
Komoly, S.; Hudson, L.D.; Webster, H.D.; Bondy, C.A. Insulin-like growth factor I gene expression is induced in astrocytes during experimental demyelination. Proc. Natl. Acad. Sci. USA,  1992, 89(5), 1894-1898.
[http://dx.doi.org/10.1073/pnas.89.5.1894] [PMID:  1371885] 
[16] 
Pasquini, L.A.; Calatayud, C.A.; Bertone Uña, A.L.; Millet, V.; Pasquini, J.M.; Soto, E.F. The neurotoxic effect of cuprizone on oligodendrocytes depends on the presence of pro-inflammatory cytokines secreted by microglia. Neurochem. Res.,  2007, 32(2), 279-292.
[http://dx.doi.org/10.1007/s11064-006-9165-0] [PMID:  17063394] 
[17] 
Arnett, H.A.; Mason, J.; Marino, M.; Suzuki, K.; Matsushima, G.K.; Ting, J.P.Y. TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat. Neurosci.,  2001, 4(11), 1116-1122.
[http://dx.doi.org/10.1038/nn738] [PMID:  11600888] 
[18] 
Kipp, M.; Clarner, T.; Dang, J.; Copray, S.; Beyer, C. The cuprizone animal model: new insights into an old story. Acta Neuropathol.,  2009, 118(6), 723-736.
[http://dx.doi.org/10.1007/s00401-009-0591-3] [PMID:  19763593] 
[19] 
Nilsson, G. A New colour reaction on copper and certain carbonyl compounds. Acta Chem. Scand.,  1950, 4(1), 205-205.
[http://dx.doi.org/10.3891/acta.chem.scand.04-0205] 
[20] 
Carlton, W.W. Response of mice to the chelating agents sodium diethyldithiocarbamate, alpha-benzoinoxime, and biscyclohexanone oxaldihydrazone. Toxicol. Appl. Pharmacol.,  1966, 8(3), 512-521.
[http://dx.doi.org/10.1016/0041-008X(66)90062-7] [PMID:  6006739] 
[21] 
Benetti, F.; Ventura, M.; Salmini, B.; Ceola, S.; Carbonera, D.; Mammi, S.; Zitolo, A.; D’Angelo, P.; Urso, E.; Maffia, M.; Salvato, B.; Spisni, E. Cuprizone neurotoxicity, copper deficiency and neurodegeneration. Neurotoxicology,  2010, 31(5), 509-517.
[http://dx.doi.org/10.1016/j.neuro.2010.05.008] [PMID:  20685220] 
[22] 
Carlton, W.W. Studies on the induction of hydrocephalus and spongy degeneration by cuprizone feeding and attempts to antidote the toxicity. Life Sci.,  1967, 6(1), 11-19.
[http://dx.doi.org/10. 1016/0024-3205(67)90356-6] [PMID:  6030552] 
[23] 
Ransom Stern, B.; Solioz, M.; Krewski, D.; Aggett, P.; Aw, T-C.; Baker, S.; Crump, K.; Dourson, M.; Haber, L.; Hertzberg, R.; Keen, C.; Meek, B.; Rudenko, L.; Schoeny, R.; Slob, W.; Starr, T. Copper and human health: biochemestry, genetics, and trategies for modeling dose-response relationships. J. Toxicol. Environ. Health,  2007, B(10), 157-222.
[24] 

In Copper in Drinking Water; Washington, DC, 2000. 
[25] 
Scheiber, I.; Dringen, R.; Mercer, J.F.B.  Copper: Effects of deficiency
and overload. Interrelations between essential metal ions
and human diseases; Sigel, A.; Sigel, H.; Sigel, K.O.R., Eds.;
Springer Netherlands: Dordrecht, 2013, 359-387.
[http://dx.doi.org/10.1007/978-94-007-7500-8_11] 
[26] 
Linder, M.C.; Hazegh-Azam, M. Copper biochemistry and molecular biology. Am. J. Clin. Nutr.,  1996, 63(5), 797S-811S.
[PMID:  8615367] 
[27] 
Lindner, M.; Heine, S.; Haastert, K.; Garde, N.; Fokuhl, J.; Linsmeier, F.; Grothe, C.; Baumgärtner, W.; Stangel, M. Sequential myelin protein expression during remyelination reveals fast and efficient repair after central nervous system demyelination. Neuropathol. Appl. Neurobiol.,  2008, 34(1), 105-114.
[PMID:  17961136] 
[28] 
Torkildsen, O.; Brunborg, L.A.; Myhr, K.M.; Bø, L. The cuprizone model for demyelination. Acta Neurol. Scand. Suppl.,  2008, 188, 72-76.
[http://dx.doi.org/10.1111/j.1600-0404.2008.01036.x] [PMID:  18439226] 
[29] 
Hesse, A.; Wagner, M.; Held, J.; Brück, W.; Salinas-Riester, G.; Hao, Z.; Waisman, A.; Kuhlmann, T. In toxic demyelination oligodendroglial cell death occurs early and is FAS independent. Neurobiol. Dis.,  2010, 37(2), 362-369.
[http://dx.doi.org/10.1016/j.nbd. 2009.10.016] [PMID:  19853662] 
[30] 
Liñares, D.; Taconis, M.; Maña, P.; Correcha, M.; Fordham, S.; Staykova, M.; Willenborg, D.O. Neuronal nitric oxide synthase plays a key role in CNS demyelination. J. Neurosci.,  2006, 26(49), 12672-12681.
[http://dx.doi.org/10.1523/JNEUROSCI.0294-06. 2006] [PMID:  17151270] 
[31] 
Arnett, H.A.; Hellendall, R.P.; Matsushima, G.K.; Suzuki, K.; Laubach, V.E.; Sherman, P.; Ting, J.P. The protective role of nitric oxide in a neurotoxicant-induced demyelinating model. J. Immunol.,  2002, 168(1), 427-433.
[http://dx.doi.org/10.4049/jimmunol. 168.1.427] [PMID:  11751989] 
[32] 
Matsushima, G.K.; Morell, P. The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol.,  2001, 11(1), 107-116.
[http://dx.doi.org/10.1111/j.1750-3639.2001.tb00385.x] [PMID:  11145196] 
[33] 
Hiremath, M.M.; Saito, Y.; Knapp, G.W.; Ting, J.P.Y.; Suzuki, K.; Matsushima, G.K. Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice. J. Neuroimmunol.,  1998, 92(1-2), 38-49.
[http://dx.doi.org/10.1016/S0165-5728(98)00168-4] [PMID:  9916878] 
[34] 
Skripuletz, T.; Gudi, V.; Hackstette, D.; Stangel, M. De- and remyelination in the CNS white and grey matter induced by cuprizone: the old, the new, and the unexpected. Histol. Histopathol.,  2011, 26(12), 1585-1597.
[PMID:  21972097] 
[35] 
Goldberg, J.; Daniel, M.; van Heuvel, Y.; Victor, M.; Beyer, C.; Clarner, T.; Kipp, M. Short-term cuprizone feeding induces selective amino acid deprivation with concomitant activation of an integrated stress response in oligodendrocytes. Cell. Mol. Neurobiol.,  2013, 33(8), 1087-1098.
[http://dx.doi.org/10.1007/s10571-013-9975-y] [PMID:  23979168] 
[36] 
Doan, V.; Kleindienst, A.M.; McMahon, E.J.; Long, B.R.; Matsushima, G.K.; Taylor, L.C. Abbreviated exposure to cuprizone is sufficient to induce demyelination and oligodendrocyte loss. J. Neurosci. Res.,  2013, 91(3), 363-373.
[http://dx.doi.org/10.1002/jnr.23174] [PMID:  23280518] 
[37] 
Jurevics, H.; Largent, C.; Hostettler, J.; Sammond, D.W.; Matsushima, G.K.; Kleindienst, A.; Toews, A.D.; Morell, P. Alterations in metabolism and gene expression in brain regions during cuprizone-induced demyelination and remyelination. J. Neurochem.,  2002, 82(1), 126-136.
[http://dx.doi.org/10.1046/j.1471-4159.2002. 00954.x] [PMID:  12091473] 
[38] 
Gudi, V.; Gingele, S.; Skripuletz, T.; Stangel, M. Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned. Front. Cell. Neurosci.,  2014, 8(73), 73.
[PMID:  24659953] 
[39] 
Gudi, V.; Moharregh-Khiabani, D.; Skripuletz, T.; Koutsoudaki, P.N.; Kotsiari, A.; Skuljec, J.; Trebst, C.; Stangel, M. Regional differences between grey and white matter in cuprizone induced demyelination. Brain Res.,  2009, 1283, 127-138.
[http://dx.doi.org/ 10.1016/j.brainres.2009.06.005] [PMID:  19524552] 
[40] 
Goldberg, J.; Clarner, T.; Beyer, C.; Kipp, M. Anatomical Distribution of Cuprizone-Induced Lesions in C57BL6 Mice. J. Mol. Neurosci.,  2015, 57(2), 166-175.
[http://dx.doi.org/10.1007/s12031-015-0595-5] [PMID:  26067430] 
[41] 
Silvestroff, L.; Bartucci, S.; Soto, E.; Gallo, V.; Pasquini, J.; Franco, P. Cuprizone-induced demyelination in CNP:GFP transgenic mice. J. Comp. Neurol.,  2010, 518(12), 2261-2283.
[http://dx.doi.org/10.1002/cne.22330] [PMID:  20437527] 
[42] 
Hübner, N.S.; Mechling, A.E.; Lee, H-L.; Reisert, M.; Bienert, T.; Hennig, J.; von Elverfeldt, D.; Harsan, L-A. The connectomics of brain demyelination: Functional and structural patterns in the cuprizone mouse model. Neuroimage,  2017, 146, 1-18.
[http://dx.doi.org/10.1016/j.neuroimage.2016.11.008] [PMID:  27845252] 
[43] 
Pott, F.; Gingele, S.; Clarner, T.; Dang, J.; Baumgartner, W.; Beyer, C.; Kipp, M. Cuprizone effect on myelination, astrogliosis and microglia attraction in the mouse basal ganglia. Brain Res.,  2009, 1305, 137-149.
[http://dx.doi.org/10.1016/j.brainres.2009.09. 084] [PMID:  19799876] 
[44] 
Yang, H-J.; Wang, H.; Zhang, Y.; Xiao, L.; Clough, R.W.; Browning, R.; Li, X-M.; Xu, H. Region-specific susceptibilities to cuprizone-induced lesions in the mouse forebrain: Implications for the pathophysiology of schizophrenia. Brain Res.,  2009, 1270, 121-130.
[http://dx.doi.org/10.1016/j.brainres.2009.03.011] [PMID:  19306847] 
[45] 
Blakemore, W.F. Demyelination of the superior cerebellar peduncle in the mouse induced by cuprizone. J. Neurol. Sci.,  1973, 20(1), 63-72.
[http://dx.doi.org/10.1016/0022-510X(73)90118-4] [PMID:  4744511] 
[46] 
Carlton, W.W. Response of mice to the chelating agents sodium diethyldithiocarbamate, α-benzoinoxime, and biscyclohexanone oxaldihydrazone. Toxicol. Appl. Pharmacol.,  1966, 8(3), 512-521.
[http://dx.doi.org/10.1016/0041-008X(66)90062-7] [PMID:  6006739] 
[47] 
Groebe, A.; Clarner, T.; Baumgartner, W.; Dang, J.; Beyer, C.; Kipp, M. Cuprizone treatment induces distinct demyelination, astrocytosis, and microglia cell invasion or proliferation in the mouse cerebellum. Cerebellum,  2009, 8(3), 163-174.
[http://dx.doi.org/10. 1007/s12311-009-0099-3] [PMID:  19259754] 
[48] 
Acs, P.; Komoly, S. Selective ultrastructural vulnerability in the cuprizone-induced experimental demyelination. Ideggyogy. Sz.,  2012, 65(7-8), 266-270.
[PMID:  23074847] 
[49] 
Skripuletz, T.; Lindner, M.; Kotsiari, A.; Garde, N.; Fokuhl, J.; Linsmeier, F.; Trebst, C.; Stangel, M. Cortical demyelination is prominent in the murine cuprizone model and is strain-dependent. Am. J. Pathol.,  2008, 172(4), 1053-1061.
[http://dx.doi.org/10. 2353/ajpath.2008.070850] [PMID:  18349131] 
[50] 
Bai, C.B.; Sun, S.; Roholt, A.; Benson, E.; Edberg, D.; Medicetty, S.; Dutta, R.; Kidd, G.; Macklin, W.B.; Trapp, B.  A mouse model
for testing remyelinating therapies. Exp. Neurol.,2016, 283(Pt A),
330-340.
[http://dx.doi.org/10.1016/j.expneurol.2016.06.033] [PMID: 27384502] 
[51] 
Norkute, A.; Hieble, A.; Braun, A.; Johann, S.; Clarner, T.; Baumgartner, W.; Beyer, C.; Kipp, M. Cuprizone treatment induces demyelination and astrocytosis in the mouse hippocampus. J. Neurosci. Res.,  2009, 87(6), 1343-1355.
[http://dx.doi.org/10.1002/jnr.21946] [PMID:  19021291] 
[52] 
Hoffmann, K.; Lindner, M.; Gröticke, I.; Stangel, M.; Löscher, W. Epileptic seizures and hippocampal damage after cuprizone-induced demyelination in C57BL/6 mice. Exp. Neurol.,  2008, 210(2), 308-321.
[http://dx.doi.org/10.1016/j.expneurol.2007.11.005] [PMID:  18096162] 
[53] 
Kipp, M.; Nyamoya, S.; Hochstrasser, T.; Amor, S. Multiple sclerosis animal models: a clinical and histopathological perspective. Brain Pathol.,  2017, 27(2), 123-137.
[http://dx.doi.org/10.1111/bpa.12454] [PMID:  27792289] 
[54] 
Makinodan, M.; Yamauchi, T.; Tatsumi, K.; Okuda, H.; Takeda, T.; Kiuchi, K.; Sadamatsu, M.; Wanaka, A.; Kishimoto, T. Demyelination in the juvenile period, but not in adulthood, leads to long-lasting cognitive impairment and deficient social interaction in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry,  2009, 33(6), 978-985.
[http://dx.doi.org/10.1016/j.pnpbp.2009.05.006] [PMID:  19446597] 
[55] 
Wang, H.; Li, C.; Wang, H.; Mei, F.; Liu, Z.; Shen, H.Y.; Xiao, L. Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit. Neurosci. Bull.,  2013, 29(2), 251-259.
[http://dx.doi.org/10.1007/s12264-013-1323-1] [PMID:  23558591] 
[56] 
Xuan, Y.; Yan, G.; Peng, H.; Wu, R.; Xu, H. Concurrent changes in 1H MRS metabolites and antioxidant enzymes in the brain of C57BL/6 mouse short-termly exposed to cuprizone: possible implications for schizophrenia. Neurochem. Int.,  2014, 69(69), 20-27.
[http://dx.doi.org/10.1016/j.neuint.2014.02.004] [PMID:  24613425] 
[57] 
Armstrong, R.C.; Le, T.Q.; Flint, N.C.; Vana, A.C.; Zhou, Y.X. Endogenous cell repair of chronic demyelination. J. Neuropathol. Exp. Neurol.,  2006, 65(3), 245-256.
[http://dx.doi.org/10.1097/01.jnen.0000205142.08716.7e] [PMID:  16651886] 
[58] 
Lindner, M.; Fokuhl, J.; Linsmeier, F.; Trebst, C.; Stangel, M. Chronic toxic demyelination in the central nervous system leads to axonal damage despite remyelination. Neurosci. Lett.,  2009, 453(2), 120-125.
[http://dx.doi.org/10.1016/j.neulet.2009.02.004] [PMID:  19356606] 
[59] 
Franco-Pons, N.; Torrente, M.; Colomina, M.T.; Vilella, E. Behavioral deficits in the cuprizone-induced murine model of demyelination/remyelination. Toxicol. Lett.,  2007, 169(3), 205-213.
[http://dx.doi.org/10.1016/j.toxlet.2007.01.010] [PMID:  17317045] 
[60] 
Doucette, J.R.; Jiao, R.; Nazarali, A.J. Age-related and cuprizone-induced changes in myelin and transcription factor gene expression and in oligodendrocyte cell densities in the rostral corpus callosum of mice. Cell. Mol. Neurobiol.,  2010, 30(4), 607-629.
[http://dx.doi.org/10.1007/s10571-009-9486-z] [PMID:  20063055] 
[61] 
Ludwin, S.K. Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. Lab. Invest.,  1978, 39(6), 597-612.
[PMID:  739762] 
[62] 
Takahashi, N.; Sakurai, T.; Davis, K.L.; Buxbaum, J.D.L. Linking oligodendrocyte and myelin dysfunction to neurocircuitry abnormalities in schizophrenia. Prog. Neurobiol.,  2011, 93(1), 13-24.
[http://dx.doi.org/10.1016/j.pneurobio.2010.09.004] [PMID:  20950668] 
[63] 
Xu, H.; Li, X.M. White matter abnormalities and animal models examining a putative role of altered white matter in schizophrenia. Schizophr. Res. Treatment,  2011, 2011, 826976.
[http://dx.doi.org/10.1155/2011/826976] [PMID:  22937274] 
[64] 
Zhang, H.; Zhang, Y.; Xu, H.; Wang, L.; Zhao, J.; Wang, J.; Zhang, Z.; Tan, Q.; Kong, J.; Huang, Q.; Li, X.M. Locomotor activity and anxiety status, but not spatial working memory, are affected in mice after brief exposure to cuprizone. Neurosci. Bull.,  2013, 29(5), 633-641.
[http://dx.doi.org/10.1007/s12264-013-1369-0] [PMID:  23990221] 
[65] 
Tezuka, T.; Tamura, M.; Kondo, M.A.; Sakaue, M.; Okada, K.; Takemoto, K.; Fukunari, A.; Miwa, K.; Ohzeki, H.; Kano, S.; Yasumatsu, H.; Sawa, A.; Kajii, Y. Cuprizone short-term exposure: astrocytic IL-6 activation and behavioral changes relevant to psychosis. Neurobiol. Dis.,  2013, 59, 63-68.
[http://dx.doi.org/10. 1016/j.nbd.2013.07.003] [PMID:  23867234] 
[66] 
Xu, H.; Yang, H.J.; Zhang, Y.; Clough, R.; Browning, R.; Li, X.M. Behavioral and neurobiological changes in C57BL/6 mice exposed to cuprizone. Behav. Neurosci.,  2009, 123(2), 418-429.
[http://dx.doi.org/10.1037/a0014477] [PMID:  19331464] 
[67] 
Ludwin, S.K. Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. Lab. Invest.,  1978, 39(6), 597-612.
[PMID:  739762] 
[68] 
Taylor, L.C.; Gilmore, W.; Ting, J.P.; Matsushima, G.K. Cuprizone induces similar demyelination in male and female C57BL/6 mice and results in disruption of the estrous cycle. J. Neurosci. Res.,  2010, 88(2), 391-402.
[http://dx.doi.org/10.1002/jnr.22215] [PMID:  19746424] 
[69] 
Taylor, L.C.; Gilmore, W.; Matsushima, G.K. SJL mice exposed to cuprizone intoxication reveal strain and gender pattern differences in demyelination. Brain Pathol.,  2009, 19(3), 467-479.
[http://dx.doi.org/10.1111/j.1750-3639.2008.00230.x] [PMID:  19016742] 
[70] 
Narayanan, S. P.; Flores, A. I.; Wang, F.; Macklin, W. B.  signals
through the mammalian target of rapamycin pathway to regulate
CNS myelination. 2009, 29(21), 6860-70.
[71] 
Sachs, H.H.; Bercury, K.K.; Popescu, D.C.; Narayanan, S.P.; Macklin, W.B. A new model of cuprizone-mediated demyelination/remyelination. ASN Neuro,  2014, 6(5), 1759091414551955.
[http://dx.doi.org/10.1177/1759091414551955] [PMID:  25290063] 
[72] 
Polman, C.H.; Reingold, S.C.; Banwell, B.; Clanet, M.; Cohen, J.A.; Filippi, M.; Fujihara, K.; Havrdova, E.; Hutchinson, M.; Kappos, L.; Lublin, F.D.; Montalban, X.; O’Connor, P.; Sandberg-Wollheim, M.; Thompson, A.J.; Waubant, E.; Weinshenker, B.; Wolinsky, J.S. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol.,  2011, 69(2), 292-302.
[http://dx.doi.org/10.1002/ana.22366] [PMID:  21387374] 
[73] 
Robinson, A.P.; Harp, C.T.; Noronha, A.; Miller, S.D. The experimental autoimmune encephalomyelitis (EAE) model of MS: utility for understanding disease pathophysiology and treatment. Handb. Clin. Neurol.,  2014, 122, 173-189.
[http://dx.doi.org/10.1016/B978-0-444-52001-2.00008-X] [PMID:  24507518] 
[74] 
Merkler, D.; Schmelting, B.; Czéh, B.; Fuchs, E.; Stadelmann, C.; Brück, W. Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in the common marmoset reflects the immunopathology of pattern II multiple sclerosis lesions. Mult. Scler.,  2006, 12(4), 369-374.
[http://dx.doi.org/10. 1191/1352458506ms1290oa] [PMID:  16900750] 
[75] 
Martinez, N.E.; Sato, F.; Omura, S.; Minagar, A.; Alexander, J.S.; Tsunoda, I. Immunopathological Patterns from EAE and Theiler’s Virus Infection: Is Multiple Sclerosis a Homogenous 1-stage or Heterogenous 2-stage Disease? Pathophysiology,  2013, 20(1), 71-84.
[76] 
Oleszak, E.L.; Chang, J.R.; Friedman, H.; Katsetos, C.D.; Platsoucas, C.D. Theiler’s virus infection: a model for multiple sclerosis. Clin. Microbiol. Rev.,  2004, 17(1), 174-207.
[http://dx.doi.org/10. 1128/CMR.17.1.174-207.2004] [PMID:  14726460] 
[77] 
de Paula Faria, D.; de Vries, E.F.; Sijbesma, J.W.; Buchpiguel, C.A.; Dierckx, R.A.; Copray, S.C. PET imaging of glucose metabolism, neuroinflammation and demyelination in the lysolecithin rat model for multiple sclerosis. Mult. Scler.,  2014, 20(11), 1443-1452.
[http://dx.doi.org/10.1177/1352458514526941] [PMID:  24622349] 
[78] 
Rawji, K.S.; Yong, V.W. The benefits and detriments of macrophages/microglia in models of multiple sclerosis. Clin. Dev. Immunol.,  2013, 2013, 948976.
[http://dx.doi.org/10.1155/2013/948976] [PMID:  23840244] 
[79] 
Veto, S.; Acs, P.; Bauer, J.; Lassmann, H.; Berente, Z.; Setalo, G., Jr; Borgulya, G.; Sumegi, B.; Komoly, S.; Gallyas, F., Jr; Illes, Z. Inhibiting poly(ADP-ribose) polymerase: a potential therapy against oligodendrocyte death. Brain,  2010, 133(Pt 3), 822-834.
[http://dx.doi.org/10.1093/brain/awp337] [PMID:  20157013] 
[80] 
Metz, I.; Weigand, S.D.; Popescu, B.F.G.; Frischer, J.M.; Parisi, J.E.; Guo, Y.; Lassmann, H.; Brück, W.; Lucchinetti, C.F. Pathologic heterogeneity persists in early active multiple sclerosis lesions. Ann. Neurol.,  2014, 75(5), 728-738.
[http://dx.doi.org/10. 1002/ana.24163] [PMID:  24771535] 
[81] 
Morell, P.; Barrett, C.V.; Mason, J.L.; Toews, A.D.; Hostettler, J.D.; Knapp, G.W.; Matsushima, G.K. Gene expression in brain during cuprizone-induced demyelination and remyelination. Mol. Cell. Neurosci.,  1998, 12(4-5), 220-227.
[http://dx.doi.org/10.1006/mcne.1998.0715] [PMID:  9828087] 
[82] 
Ransohoff, R.M. Animal models of multiple sclerosis: the good, the bad and the bottom line. Nat. Neurosci.,  2012, 15(8), 1074-1077.
[http://dx.doi.org/10.1038/nn.3168] [PMID:  22837037] 
[83] 
Praet, J.; Guglielmetti, C.; Berneman, Z.; Van der Linden, A.; Ponsaerts, P. Cellular and molecular neuropathology of the cuprizone mouse model: clinical relevance for multiple sclerosis. Neurosci. Biobehav. Rev.,  2014, 47, 485-505.
[http://dx.doi.org/10.1016/j. neubiorev.2014.10.004] [PMID:  25445182] 
[84] 
Carlton, W.W. Studies on the induction of hydrocephalus and spongy degeneration by cuprizone feeding and attempts to antidote the toxicity. Life Sci.,  1967, 6(1), 11-19.
[http://dx.doi.org/10. 1016/0024-3205(67)90356-6] [PMID:  6030552] 
[85] 
Bénardais, K.; Kotsiari, A.; Skuljec, J.; Koutsoudaki, P.N.; Gudi, V.; Singh, V.; Vulinović, F.; Skripuletz, T.; Stangel, M. Cuprizone [bis(cyclohexylidenehydrazide)] is selectively toxic for mature oligodendrocytes. Neurotox. Res.,  2013, 24(2), 244-250.
[http://dx.doi.org/10.1007/s12640-013-9380-9] [PMID:  23392957] 
[86] 
Hiremath, M.M.; Saito, Y.; Knapp, G.W.; Ting, J.P.; Suzuki, K.; Matsushima, G.K. Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice. J. Neuroimmunol.,  1998, 92(1-2), 38-49.
[http://dx.doi.org/10.1016/S0165-5728(98)00168-4] [PMID:  9916878] 
[87] 
Kesterson, J.W.; Carlton, W.W. Monoamine oxidase inhibition and the activity of other oxidative enzymes in the brains of mice fed cuprizone. Toxicol. Appl. Pharmacol.,  1971, 20(3), 386-395.
[http://dx.doi.org/10.1016/0041-008X(71)90281-X] [PMID:  4399886] 
[88] 
Venturini, G. Enzymic activities and sodium, potassium and copper concentrations in mouse brain and liver after cuprizone treatment in vivo. J. Neurochem.,  1973, 21(5), 1147-1151.
[http://dx.doi.org/ 10.1111/j.1471-4159.1973.tb07569.x] [PMID:  4357499] 
[89] 
Suzuki, K. Giant hepatic mitochondria: production in mice fed with cuprizone. Science,  1969, 163(3862), 81-82.
[http://dx.doi.org/ 10.1126/science.163.3862.81] [PMID:  5763494] 
[90] 
Wakabayashi, T. Megamitochondria formation - physiology and pathology. J. Cell. Mol. Med.,  2002, 6(4), 497-538.
[http://dx.doi.org/10.1111/j.1582-4934.2002.tb00452.x] [PMID:  12611638] 
[91] 
Veto, S.; Acs, P.; Bauer, J.; Lassmann, H.; Berente, Z.; Setalo, G., Jr; Borgulya, G.; Sumegi, B.; Komoly, S.; Gallyas, F., Jr; Illes, Z. Inhibiting poly(ADP-ribose) polymerase: a potential therapy against oligodendrocyte death. Brain,  2010, 133(Pt 3), 822-834.
[http://dx.doi.org/10.1093/brain/awp337] [PMID:  20157013] 
[92] 
Baumann, N.; Pham-Dinh, D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol. Rev.,  2001, 81(2), 871-927.
[http://dx.doi.org/10.1152/physrev.2001.81. 2.871] [PMID:  11274346] 
[93] 
Palumbo, S.; Toscano, C.D.; Parente, L.; Weigert, R.; Bosetti, F. Time-dependent changes in the brain arachidonic acid cascade during cuprizone-induced demyelination and remyelination. Prostaglandins Leukot. Essent. Fatty Acids,  2011, 85(1), 29-35.
[http://dx.doi.org/10.1016/j.plefa.2011.04.001] [PMID:  21530210] 
[94] 
Carey, E.M.; Freeman, N.M. Biochemical changes in Cuprizone-induced spongiform encephalopathy. I. Changes in the activities of 2′,3′-cyclic nucleotide 3′-phosphohydrolase, oligodendroglial ceramide galactosyl transferase, and the hydrolysis of the alkenyl group of alkenyl, acyl-glycerophospholipids by plasmalogenase in different regions of the brain. Neurochem. Res.,  1983, 8(8), 1029-1044.
[http://dx.doi.org/10.1007/BF00965198] [PMID:  6312351] 
[95] 
Neu, I.; Woelk, H. Investigations of the lipid metabolism of the white matter in multiple sclerosis: changes in glycero-phosphatides and lipid-splitting enzymes. Neurochem. Res.,  1982, 7(6), 727-735.
[http://dx.doi.org/10.1007/BF00965525] [PMID:  7121719] 
[96] 
Balboa, M.A.; Varela-Nieto, I.; Killermann Lucas, K.; Dennis, E.A. Expression and function of phospholipase A(2) in brain. FEBS Lett.,  2002, 531(1), 12-17.
[http://dx.doi.org/10.1016/S0014-5793 (02)03481-6] [PMID:  12401195] 
[97] 
Hemm, R.D.; Carlton, W.W.; Welser, J.R. Ultrastructural changes of cuprizone encephalopathy in mice. Toxicol. Appl. Pharmacol.,  1971, 18(4), 869-882.
[http://dx.doi.org/10.1016/0041-008X(71) 90235-3] [PMID:  5570239] 
[98] 
Porter, A.G.; Jänicke, R.U. Emerging roles of caspase-3 in apoptosis. Cell Death Differ.,  1999, 6(2), 99-104.
[http://dx.doi.org/10. 1038/sj.cdd.4400476] [PMID:  10200555] 
[99] 
Tezuka, T.; Tamura, M.; Kondo, M.A.; Sakaue, M.; Okada, K.; Takemoto, K.; Fukunari, A.; Miwa, K.; Ohzeki, H.; Kano, S.; Yasumatsu, H.; Sawa, A.; Kajii, Y. Cuprizone short-term exposure: astrocytic IL-6 activation and behavioral changes relevant to psychosis. Neurobiol. Dis.,  2013, 59, 63-68.
[http://dx.doi.org/10. 1016/j.nbd.2013.07.003] [PMID:  23867234] 
[100] 
Gao, X.; Gillig, T.A.; Ye, P.; D’Ercole, A.J.; Matsushima, G.K.; Popko, B. Interferon-gamma protects against cuprizone-induced demyelination. Mol. Cell. Neurosci.,  2000, 16(4), 338-349.
[http://dx.doi.org/10.1006/mcne.2000.0883] [PMID:  11085872] 
[101] 
Krakowski, M.; Owens, T. Interferon-gamma confers resistance to experimental allergic encephalomyelitis. Eur. J. Immunol.,  1996, 26(7), 1641-1646.
[http://dx.doi.org/10.1002/eji.1830260735] [PMID:  8766573] 
[102] 
Willenborg, D.O.; Fordham, S.; Bernard, C.C.; Cowden, W.B.; Ramshaw, I.A. IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J. Immunol.,  1996, 157(8), 3223-3227.
[PMID:  8871615] 
[103] 
Trebst, C.; Heine, S.; Lienenklaus, S.; Lindner, M.; Baumgärtner, W.; Weiss, S.; Stangel, M. Lack of interferon-beta leads to accelerated remyelination in a toxic model of central nervous system demyelination. Acta Neuropathol.,  2007, 114(6), 587-596.
[http://dx.doi.org/10.1007/s00401-007-0300-z] [PMID:  17940777] 
[104] 
Zendedel, A.; Beyer, C.; Kipp, M. Cuprizone-induced demyelination as a tool to study remyelination and axonal protection. J. Mol. Neurosci.,  2013, 51(2), 567-572.
[http://dx.doi.org/10.1007/s12031-013-0026-4] [PMID:  23666824] 
[105] 
Linder, M.C.; Hazegh-Azam, M. Copper biochemistry and molecular biology. Am. J. Clin. Nutr.,  1996, 63(5), 797S-811S.
[PMID:  8615367] 
[106] 
Jurevics, H.; Largent, C.; Hostettler, J.; Sammond, D.W.K.; Matsushima, G.K.; Kleindienst, A.; Toews, A.D.; Morell, P. Alterations in metabolism and gene expression in brain regions during cuprizone-induced demyelination and remyelination. J. Neurochem.,  2002, 82(1), 126-136.
[http://dx.doi.org/10.1046/j.1471-4159.2002. 00954.x] [PMID:  12091473] 
[107] 
Blakemore, W.F. Observations on oligodendrocyte degeneration, the resolution of status spongiosus and remyelination in cuprizone intoxication in mice. J. Neurocytol.,  1972, 1(4), 413-426.
[http://dx.doi.org/10.1007/BF01102943] [PMID:  8530973] 
[108] 
Blakemore, W.F. Demyelination of the superior cerebellar peduncle in the mouse induced by cuprizone. J. Neurol. Sci.,  1973, 20(1), 63-72.
[http://dx.doi.org/10.1016/0022-510X(73)90118-4] [PMID:  4744511] 
[109] 
Bai, C. B.; Sun, S.; Roholt, A.; Benson, E.; Edberg, D.; Medicetty, S.; Dutta, R.; Kidd, G.; Macklin, W. B.; Trapp, B. A mouse model for testing remyelinating therapies Exp Neurol,, 2016. 283(Pt A), 330-40.
[110] 
Yang, H.J.; Wang, H.; Zhang, Y.; Xiao, L.; Clough, R.W.; Browning, R.; Li, X.M.; Xu, H. Region-specific susceptibilities to cuprizone-induced lesions in the mouse forebrain: Implications for the pathophysiology of schizophrenia. Brain Res.,  2009, 1270, 121-130.
[http://dx.doi.org/10.1016/j.brainres.2009.03.011] [PMID:  19306847] 
[111] 
Hübner, N.S.; Mechling, A.E.; Lee, H.L.; Reisert, M.; Bienert, T.; Hennig, J.; von Elverfeldt, D.; Harsan, L.A. The connectomics of brain demyelination: Functional and structural patterns in the cuprizone mouse model. Neuroimage,  2017, 146, 1-18.
[http://dx.doi.org/10.1016/j.neuroimage.2016.11.008] [PMID:  27845252] 
[112] 
Hoffmann, K.; Lindner, M.; Gröticke, I.; Stangel, M.; Löscher, W. Epileptic seizures and hippocampal damage after cuprizone-induced demyelination in C57BL/6 mice. Exp. Neurol.,  2008, 210(2), 308-321.
[http://dx.doi.org/10.1016/j.expneurol.2007.11. 005] [PMID:  18096162] 
[113] 
Suzuki, K.; Kikkawa, Y. Status spongiosus of CNS and hepatic changes induced by cuprizone (biscyclohexanone oxalyldihydrazone). Am. J. Pathol.,  1969, 54(2), 307-325.
[PMID:  5765567] 
[114] 
Elsworth, S.; Howell, J.M. Variation in the response of mice to cuprizone. Res. Vet. Sci.,  1973, 14(3), 385-387.
[PMID:  4805158] 
[115] 
Bakker, D.A.; Ludwin, S.K. Blood-brain barrier permeability during Cuprizone-induced demyelination. Implications for the pathogenesis of immune-mediated demyelinating diseases. J. Neurol. Sci.,  1987, 78(2), 125-137.
[http://dx.doi.org/10.1016/0022-510X (87)90055-4] [PMID:  3553434] 
[116] 
Chen, Z.; Chen, J.T.; Johnson, M.; Gossman, Z.C.; Hendrickson, M.; Sakaie, K.; Martinez-Rubio, C.; Gale, J.T.; Trapp, B.D. Cuprizone does not induce CNS demyelination in nonhuman primates. Ann. Clin. Transl. Neurol.,  2015, 2(2), 208-213.
[http://dx.doi.org/ 10.1002/acn3.159] [PMID:  25750925] 
[117] 
Silvestroff, L.; Bartucci, S.; Pasquini, J.; Franco, P. Cuprizone-induced demyelination in the rat cerebral cortex and thyroid hormone effects on cortical remyelination. Exp. Neurol.,  2012, 235(1), 357-367.
[http://dx.doi.org/10.1016/j.expneurol.2012.02.018] [PMID:  22421533] 
[118] 
Love, S. Cuprizone neurotoxicity in the rat: morphologic observations. J. Neurol. Sci.,  1988, 84(2-3), 223-237.
[http://dx.doi.org/10. 1016/0022-510X(88)90127-X] [PMID:  2837540] 
[119] 
Carlton, W.W. Spongiform encephalopathy induced in rats and guinea pigs by cuprizone. Exp. Mol. Pathol.,  1969, 10(3), 274-287.
[http://dx.doi.org/10.1016/0014-4800(69)90057-4] [PMID:  5788627] 
[120] 
Valeiras, B.; Rosato Siri, M.V.; Codagnone, M.; Reinés, A.; Pasquini, J.M. Gender influence on schizophrenia-relevant abnormalities in a cuprizone demyelination model. Glia,  2014, 62(10), 1629-1644.
[http://dx.doi.org/10.1002/glia.22704] [PMID:  24890315] 
[121] 
Hall, S.M. The effect of injections of lysophosphatidyl choline into white matter of the adult mouse spinal cord. J. Cell Sci.,  1972, 10(2), 535-546.
[PMID:  5018033] 
[122] 
Jeffery, N.D.; Blakemore, W.F. Remyelination of mouse spinal cord axons demyelinated by local injection of lysolecithin. J. Neurocytol.,  1995, 24(10), 775-781.
[http://dx.doi.org/10.1007/BF01191213] [PMID:  8586997] 
[123] 
Cerina, M.; Narayanan, V.; Göbel, K.; Bittner, S.; Ruck, T.; Meuth, P.; Herrmann, A.M.; Stangel, M.; Gudi, V.; Skripuletz, T.; Daldrup, T.; Wiendl, H.; Seidenbecher, T.; Ehling, P.; Kleinschnitz, C.; Pape, H-C.; Budde, T.; Meuth, S.G. The quality of cortical network function recovery depends on localization and degree of axonal demyelination. Brain Behav. Immun.,  2017, 59, 103-117.
[http://dx.doi.org/10.1016/j.bbi.2016.08.014] [PMID:  27569659] 
[124] 
van der Star, J. In vitro and in vivo models of multiple sclerosis. CNS Neurol. Disord. Drug Targets,  2012, 11(5), 570-588.
[125] 
Shindler, K.S.; Ventura, E.; Dutt, M.; Rostami, A. Inflammatory demyelination induces axonal injury and retinal ganglion cell apoptosis in experimental optic neuritis. Exp. Eye Res.,  2008, 87(3), 208-213.
[http://dx.doi.org/10.1016/j.exer.2008.05.017] [PMID:  18653182] 
[126] 
Ulrich, R.; Baumgärtner, W.; Gerhauser, I.; Seeliger, F.; Haist, V.; Deschl, U.; Alldinger, S. MMP-12, MMP-3, and TIMP-1 are markedly upregulated in chronic demyelinating theiler murine encephalomyelitis. J. Neuropathol. Exp. Neurol.,  2006, 65(8), 783-793.
[http://dx.doi.org/10.1097/01.jnen.0000229990.32795.0d] [PMID:  16896312] 
[127] 
Gudi, V.; Gai, L.; Herder, V.; Tejedor, L.S.; Kipp, M.; Amor, S.; Sühs, K.W.; Hansmann, F.; Beineke, A.; Baumgärtner, W.; Stangel, M.; Skripuletz, T. Synaptophysin is a reliable marker for axonal damage. J. Neuropathol. Exp. Neurol., 2017. Epub ahead of print
[http://dx.doi.org/10.1093/jnen/nlw114] [PMID:  28177496] 
Rights & Permissions Print Cite
Article Metrics
44
9
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1570159X15666170717120343	Print ISSN 1570-159X
Publisher Name Bentham Science Publisher	Online ISSN 1875-6190
Current Neuropharmacology

Five Decades of Cuprizone, an Updated Model to Replicate Demyelinating Diseases

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Related Articles

Abstract
