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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Trapp BD, Nave KA (2008) Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 31:247–269
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 210:40–51
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 97:10526–10531
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 1:193–206
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 24:573–594
Ehrenreich H, Fischer B, Norra C et al (2007) Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain 130:2577–2588
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 952:128–134
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–S192
Diem R, Sattler MB, Merkler D et al (2005) Combined therapy with methylprednisolone and erythropoietin in a model of multiple sclerosis. Brain 128:375–385
Li W, Maeda Y, Yuan RR et al (2004) Beneficial effect of erythropoietin on experimental allergic encephalomyelitis. Ann Neurol 56:767–777
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 129:1953–1971
Steinman L, Zamvil SS (2006) How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis. Ann Neurol 60:12–21
Furlan R, Cuomo C, Martino G (2009) Animal models of multiple sclerosis. Methods Mol Biol 549:157–173
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 37:228–241
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 30:162–173
Zhang J, Li Y, Cui Y et al (2005) Erythropoietin treatment improves neurological functional recovery in EAE mice. Brain Res 1034:34–39
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 14:682–688
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 5:39–45
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 299:914–924
Leist M, Ghezzi P, Grasso G et al (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305:239–242
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 172:27–37
Yuan R, Maeda Y, Li W et al (2008) Erythropoietin: a potent inducer of peripheral immuno/inflammatory modulation in autoimmune EAE. PLoS One 3:e1924
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 162:210–223
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 211:92–100
Miller SD, Karpus WJ (2007) Experimental autoimmune encephalomyelitis in the mouse. Curr Protoc Immunol Chapter 15, Unit 15 11.
Erbayraktar S, Yilmaz O, Gokmen N et al (2003) Erythropoietin is a multifunctional tissue-protective cytokine. Curr Hematol Rep 2:465–470
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).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Cervellini, I., Ghezzi, P., Mengozzi, M. (2013). Therapeutic Efficacy of Erythropoietin in Experimental Autoimmune Encephalomyelitis in Mice, a Model of Multiple Sclerosis. In: Ghezzi, P., Cerami, A. (eds) Tissue-Protective Cytokines. Methods in Molecular Biology, vol 982. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-308-4_10
Download citation
DOI: https://doi.org/10.1007/978-1-62703-308-4_10
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-62703-307-7
Online ISBN: 978-1-62703-308-4
eBook Packages: Springer Protocols