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Therapeutic Efficacy of Erythropoietin in Experimental Autoimmune Encephalomyelitis in Mice, a Model of Multiple Sclerosis

  • Ilaria Cervellini
  • Pietro Ghezzi
  • Manuela Mengozzi
Part of the Methods in Molecular Biology book series (MIMB, volume 982)

Abstract

Erythropoietin (EPO) has neuroprotective effects in many models of damage and disease of the nervous system where neuroinflammation plays a substantial role, including experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Since the first pioneering studies, in which EPO was shown to protect rats with acute EAE mainly by inhibiting inflammation, many other studies have pointed out other mechanisms of protection, including oligodendrogenesis and inhibition of axonal damage.

Here we review the preclinical studies in which EPO has shown therapeutic efficacy in several models of EAE in mice and rats. Moreover, we report in detail the protocol to administer EPO to mice with myelin oligodendrocyte glycoprotein (MOG)-induced chronic progressive EAE, and a representative result. In this model, EPO inihibits the clinical score of the disease when administered according to a preventive but also to a therapeutic schedule, and therefore at disease onset, suggesting that it might not only inhibit inflammation but also actively stimulate repair.

Key words

Neuroinflammation Demyelination Neuroprotection Animal model Myelin ­oligodendrocyte glycoprotein 

Notes

Acknowledgments

This work was realized as part of the TC2N “Trans Channel Neuroscience Network” Interreg IV A 2 Mers Seas Zeeëns program, “Investing in your future” crossborder cooperation programme 2007–2013 part financed by the European Union (European Regional Development Fund).

References

  1. 1.
    Trapp BD, Nave KA (2008) Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 31:247–269PubMedCrossRefGoogle Scholar
  2. 2.
    Makar TK, Bever CT, Singh IS et al (2009) Brain-derived neurotrophic factor gene delivery in an animal model of multiple sclerosis using bone marrow stem cells as a vehicle. J Neuroimmunol 210:40–51PubMedCrossRefGoogle Scholar
  3. 3.
    Brines ML, Ghezzi P, Keenan S et al (2000) Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97:10526–10531PubMedCrossRefGoogle Scholar
  4. 4.
    Bartels C, Spate K, Krampe H, Ehrenreich H (2008) Recombinant human erythropoietin: novel strategies for neuroprotective/neuro-regenerative treatment of multiple sclerosis. Ther Adv Neurol Disord 1:193–206PubMedCrossRefGoogle Scholar
  5. 5.
    Sargin D, Friedrichs H, El-Kordi A et al (2010) Erythropoietin as neuroprotective and neuroregenerative treatment strategy: comprehensive overview of 12 years of preclinical and clinical research. Best Pract Res Clin Anaesthesiol 24:573–594PubMedCrossRefGoogle Scholar
  6. 6.
    Ehrenreich H, Fischer B, Norra C et al (2007) Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain 130:2577–2588PubMedCrossRefGoogle Scholar
  7. 7.
    Agnello D, Bigini P, Villa P et al (2002) Erythropoietin exerts an anti-inflammatory effect on the CNS in a model of experimental autoimmune encephalomyelitis. Brain Res 952:128–134PubMedCrossRefGoogle Scholar
  8. 8.
    Sattler MB, Merkler D, Maier K et al (2004) Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis. Cell Death Differ 11(Suppl 2):S181–S192PubMedCrossRefGoogle Scholar
  9. 9.
    Diem R, Sattler MB, Merkler D et al (2005) Combined therapy with methylprednisolone and erythropoietin in a model of multiple sclerosis. Brain 128:375–385PubMedCrossRefGoogle Scholar
  10. 10.
    Li W, Maeda Y, Yuan RR et al (2004) Beneficial effect of erythropoietin on experimental ­allergic encephalomyelitis. Ann Neurol 56:767–777PubMedCrossRefGoogle Scholar
  11. 11.
    Gold R, Linington C, Lassmann H (2006) Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129:1953–1971PubMedCrossRefGoogle Scholar
  12. 12.
    Steinman L, Zamvil SS (2006) How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis. Ann Neurol 60:12–21PubMedCrossRefGoogle Scholar
  13. 13.
    Furlan R, Cuomo C, Martino G (2009) Animal models of multiple sclerosis. Methods Mol Biol 549:157–173PubMedCrossRefGoogle Scholar
  14. 14.
    Aharoni R, Vainshtein A, Stock A et al (2011) Distinct pathological patterns in relapsing-remitting and chronic models of experimental autoimmune enchephalomyelitis and the neuroprotective effect of glatiramer acetate. J Autoimmun 37:228–241PubMedCrossRefGoogle Scholar
  15. 15.
    Herrero-Herranz E, Pardo LA, Gold R et al (2008) Pattern of axonal injury in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis: implications for multiple sclerosis. Neurobiol Dis 30:162–173PubMedCrossRefGoogle Scholar
  16. 16.
    Zhang J, Li Y, Cui Y et al (2005) Erythropoietin treatment improves neurological functional recovery in EAE mice. Brain Res 1034:34–39PubMedCrossRefGoogle Scholar
  17. 17.
    Mengozzi M, Cervellini I, Bigini P et al (2008) Endogenous erythropoietin as part of the cytokine network in the pathogenesis of experimental autoimmune encephalomyelitis. Mol Med 14:682–688PubMedCrossRefGoogle Scholar
  18. 18.
    Kang SY, Kang JH, Choi JC et al (2009) Expression of erythropoietin in the spinal cord of lewis rats with experimental autoimmune encephalomyelitis. J Clin Neurol 5:39–45PubMedCrossRefGoogle Scholar
  19. 19.
    Bennett CL, Silver SM, Djulbegovic B et al (2008) Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299:914–924PubMedCrossRefGoogle Scholar
  20. 20.
    Leist M, Ghezzi P, Grasso G et al (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305:239–242PubMedCrossRefGoogle Scholar
  21. 21.
    Savino C, Pedotti R, Baggi F et al (2006) Delayed administration of erythropoietin and its non-erythropoietic derivatives ameliorates chronic murine autoimmune encephalomyelitis. J Neuroimmunol 172:27–37PubMedCrossRefGoogle Scholar
  22. 22.
    Yuan R, Maeda Y, Li W et al (2008) Erythropoietin: a potent inducer of peripheral immuno/inflammatory modulation in autoimmune EAE. PLoS One 3:e1924PubMedCrossRefGoogle Scholar
  23. 23.
    Chen SJ, Wang YL, Lo WT et al (2010) Erythropoietin enhances endogenous haem oxygenase-1 and represses immune responses to ameliorate experimental autoimmune encephalomyelitis. Clin Exp Immunol 162:210–223PubMedCrossRefGoogle Scholar
  24. 24.
    Thorne M, Moore CS, Robertson GS (2009) Lack of TIMP-1 increases severity of experimental autoimmune encephalomyelitis: effects of darbepoetin alfa on TIMP-1 null and wild-type mice. J Neuroimmunol 211:92–100PubMedCrossRefGoogle Scholar
  25. 25.
    Miller SD, Karpus WJ (2007) Experimental autoimmune encephalomyelitis in the mouse. Curr Protoc Immunol  Chapter 15, Unit 15 11.
  26. 26.
    Erbayraktar S, Yilmaz O, Gokmen N et al (2003) Erythropoietin is a multifunctional ­tissue-protective cytokine. Curr Hematol Rep 2:465–470PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Ilaria Cervellini
    • 1
  • Pietro Ghezzi
    • 1
  • Manuela Mengozzi
    • 1
  1. 1.Brighton & Sussex Medical SchoolBrightonUK

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