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Regional Heterogeneity of Cuprizone-Induced Demyelination: Topographical Aspects of the Midline of the Corpus Callosum

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Abstract

The cuprizone model is a suitable animal model of de- and remyelination secondary to toxin-induced oligodendrogliopathy. From a pharmaceutical point of view, the cuprizone model is a valuable tool to study the potency of compounds which interfere with toxin-induced oligodendrocyte cell death or boost/inhibit remyelinating pathways and processes. The aim of this study was to analyze the vulnerability of neighboring white mater tracts (i.e., the fornix and cingulum) next to the midline of the corpus callosum which is the region of interest of most studies using this model. Male mice were fed cuprizone for various time periods. Different white matter areas were analyzed for myelin (anti-PLP), microglia (anti-IBA1), and astrocyte (anti-GFAP) responses by means of immunohistochemistry. Furthermore, Luxol fast blue–periodic acid Schiff stains were performed to validate loss of myelin-reactive fibers in the different regions. Cuprizone induced profound demyelination of the midline of the corpus callosum and medial parts of the cingulum that was paralleled by a significant astrocyte and microglia response. In contrast, lateral parts of the corpus callosum and the cingulum, as well as the fornix region which is just beneath the midline of the corpus callosum appeared to be resistant to cuprizone exposure. Furthermore, resistant areas displayed reduced astrogliosis and microgliosis. This study clearly demonstrates that neighboring white matter tracts display distinct vulnerability to toxin-induced demyelination. This important finding has direct relevance for evaluation strategies in this frequently used animal model for multiple sclerosis.

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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

    Article  PubMed  Google Scholar 

  • Baertling F, Kokozidou M, Pufe T, Clarner T, Windoffer R, Wruck CJ, Brandenburg LO, Beyer C, Kipp M (2010) ADAM12 is expressed by astrocytes during experimental demyelination. Brain Res 1326:1–14

    Article  PubMed  CAS  Google Scholar 

  • Brück W, Pförtner R, Pham T, Zhang J, Hayardeny L, Piryatinsky V, Hanisch UK, Regen T, van Rossum D, Brakelmann L, Hagemeier K, Kuhlmann T, Stadelmann C, John GR, Kramann N, Wegner C (2012) Reduced astrocytic NF-κB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathol 124(3):411–424

    Google Scholar 

  • Buschmann JP, Berger K, Awad H, Clarner T, Beyer C, Kipp M (2012) Inflammatory response and chemokine expression in the white matter corpus callosum and gray matter cortex region during cuprizone-induced demyelination. J Mol Neurosci 48(1):66–76

    Google Scholar 

  • Carlton WW (1967) Studies on the induction of hydrocephalus and spongy degeneration by cuprizone feeding and attempts to antidote the toxicity. Life Sci 6(1):11–19

    Google Scholar 

  • 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(10):1468–1480. doi:10.1002/glia.22367

    Google Scholar 

  • Clarner T, Parabucki A, Beyer C, Kipp M (2011) Corticosteroids impair remyelination in the corpus callosum of cuprizone-treated mice. J Neuroendocrinol 23:601–611

    Article  PubMed  CAS  Google Scholar 

  • Garay L, Gonzalez Deniselle MC, Gierman L, Meyer M, Lima A, Roig P, De Nicola AF (2008) Steroid protection in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neuroimmunomodulation 15:76–83

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Herder V, Hansmann F, Stangel M, Skripuletz T, Baumgartner W, Beineke A (2011) Lack of cuprizone-induced demyelination in the murine spinal cord despite oligodendroglial alterations substantiates the concept of site-specific susceptibilities of the central nervous system. Neuropathol Appl Neurobiol 37:676–684

    Article  PubMed  CAS  Google Scholar 

  • Kang Z, Liu L, Spangler R, Spear C, Wang C, Gulen MF, Veenstra M, Ouyang W, Ransohoff RM, Li X (2012) IL-17-induced Act1-mediated signaling is critical for cuprizone-induced demyelination. J Neurosci 32:8284–8292

    Article  PubMed  CAS  Google Scholar 

  • Kipp M, Norkute A, Johann S, Lorenz L, Braun A, Hieble A, Gingele S, Pott F, Richter J, Beyer C (2008) Brain-region-specific astroglial responses in vitro after LPS exposure. J Mol Neurosci 35:235–243

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Kipp M, Norkus A, Krauspe B, Clarner T, Berger K, van der Valk P, Amor S, Beyer C (2011) The hippocampal fimbria of cuprizone-treated animals as a structure for studying neuroprotection in multiple sclerosis. Inflamm Res 60:723–726

    Article  PubMed  CAS  Google Scholar 

  • Kipp M, van der Valk P, Amor S (2012) Pathology of multiple sclerosis. CNS Neurol Disord Drug Targets 11:506–517

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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  PubMed  CAS  Google Scholar 

  • 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  PubMed  CAS  Google Scholar 

  • Manrique-Hoyos N, Jurgens T, Gronborg M, Kreutzfeldt M, Schedensack M, Kuhlmann T, Schrick C, Bruck W, Urlaub H, Simons M, Merkler D (2012) Late motor decline after accomplished remyelination: impact for progressive multiple sclerosis. Ann Neurol 71:227–244

    Article  PubMed  Google Scholar 

  • Norkute A, Hieble A, Braun A, Johann S, Clarner T, Baumgartner W, Beyer C, Kipp M (2009) Cuprizone treatment induces demyelination and astrocytosis in the mouse hippocampus. J Neurosci Res 87:1343–1355

    Article  PubMed  CAS  Google Scholar 

  • Palumbo S, Toscano CD, Parente L, Weigert R, Bosetti F (2012) The cyclooxygenase-2 pathway via the PGE(2) EP2 receptor contributes to oligodendrocytes apoptosis in cuprizone-induced demyelination. J Neurochem 121:418–427

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • van der Star BJ, Vogel DV, Kipp M, Puentes F, Baker D, Amor S (2012a) In vitro and in vivo models of multiple sclerosis. CNS Neurol Disord Drug Targets

  • van der Star BJ, Vogel DY, Kipp M, Puentes F, Baker D, Amor S (2012b) In vitro and in vivo models of multiple sclerosis. CNS Neurol Disord Drug Targets 11:570–588

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Voss EV, Skuljec J, Gudi V, Skripuletz T, Pul R, Trebst C, Stangel M (2012) Characterisation of microglia during de- and remyelination: can they create a repair promoting environment? Neurobiol Dis 45:519–528

    Article  PubMed  CAS  Google Scholar 

  • Wood ET, Ronen I, Techawiboonwong A, Jones CK, Barker PB, Calabresi P, Harrison D, Reich DS (2012) Investigating axonal damage in multiple sclerosis by diffusion tensor spectroscopy. J Neurosci 32:6665–6669

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank H. Helten and S. Vidal de la Torre for technical assistance. This study was supported by a START grant of the Medical Faculty, RWTH Aachen (TC).

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Authors and Affiliations

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

    T. Schmidt, H. Awad, A. Slowik, C. Beyer, M. Kipp & T. Clarner

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  1. T. Schmidt
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  2. H. Awad
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  3. A. Slowik
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  4. C. Beyer
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  5. M. Kipp
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  6. T. Clarner
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Corresponding author

Correspondence to M. Kipp.

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T. Schmidt and H. Awad contributed equally to this work.

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Schmidt, T., Awad, H., Slowik, A. et al. Regional Heterogeneity of Cuprizone-Induced Demyelination: Topographical Aspects of the Midline of the Corpus Callosum. J Mol Neurosci 49, 80–88 (2013). https://doi.org/10.1007/s12031-012-9896-0

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  • DOI: https://doi.org/10.1007/s12031-012-9896-0

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