Skip to main content

Advertisement

SpringerLink
Log in

Efficacy of combination therapy with erythropoietin and methylprednisolone in clinical recovery of severe relapse in multiple sclerosis

  • Original Article
  • Published:
Acta Neurologica Belgica Aims and scope Submit manuscript

Abstract

Multiple sclerosis (MS) is a multifaceted disease in which genetic and environmental factors are involved. Although neurodegeneration aspect of MS has major influence in patients’ disability, none of the available treatments have been shown to obviously reduce neurodegeneration. Recently, the role of Erythropoietin (EPO) as a neuroprotective and anti-inflammatory agent has been attracted tremendous interest. In the present randomized double-blind pilot study, we combined EPO with methylprednisolone (MPred) in severe motor relapsing–remitting MS (RR-MS) patients to target both inflammatory and neurodegenerative aspects of disease. Twenty patients with RR-MS in relapse phase were randomized into two groups. The case group (10 patients) received intravenous MPred (1,000 mg/24 h) and intravenous EPO (20,000 U/24 h) for five consecutive days, and the control group (10 patients) received just MPred at the same dose as the case group, and a placebo. Both groups were followed for 3 months by ambulatory index (AI), Expanded Disability Status Scale (EDSS) and by magnetic resonance imaging (MRI) parameters. Improvement in maximal distance walking, reflected by reduction in AI and EDSS, was observed in EPO group after second month and continued after 3 months. Furthermore, MRI data analysis showed significant reduction in the number of T2WI lesions in EPO group without any significant change in contrast enhancing and black hole lesions. There was no major side effect in EPO group. The results of this first therapeutic pilot trial in RR-MS patients are promising, but need to be validated in larger trials.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. New Eng J Med 338(5):278–285 (Epub 1998/01/29)

    Article  CAS  PubMed  Google Scholar 

  2. Losseff NA, Wang L, Lai HM, Yoo DS, Gawne-Cain ML, McDonald WI et al (1996) Progressive cerebral atrophy in multiple sclerosis. A serial MRI study. Brain J Neurol 119(Pt 6):2009–2019 (Epub 1996/12/01)

    Article  Google Scholar 

  3. Peterson JW, Bo L, Mork S, Chang A, Trapp BD (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50(3):389–400 (Epub 2001/09/18)

    Article  CAS  PubMed  Google Scholar 

  4. Smith T, Groom A, Zhu B, Turski L (2000) Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat Med 6(1):62–66 (Epub 1999/12/29)

    Article  CAS  PubMed  Google Scholar 

  5. Meyer R, Weissert R, Diem R, Storch MK, de Graaf KL, Kramer B et al (2001) Acute neuronal apoptosis in a rat model of multiple sclerosis. J Neurosci Off J Soc Neurosci 21(16):6214–6220 (Epub 2001/08/07)

    CAS  Google Scholar 

  6. Brusaferri F, Candelise L (2000) Steroids for multiple sclerosis and optic neuritis: a meta-analysis of randomized controlled clinical trials. J Neurol 247(6):435–442 (Epub 2000/08/10)

    Article  CAS  PubMed  Google Scholar 

  7. Diem R, Hobom M, Maier K, Weissert R, Storch MK, Meyer R et al (2003) Methylprednisolone increases neuronal apoptosis during autoimmune CNS inflammation by inhibition of an endogenous neuroprotective pathway. J Neurosci Off J Soc Neurosci 23(18):6993–7000 PEpub 2003/08/09)

    CAS  Google Scholar 

  8. Noseworthy JH, Gold R, Hartung HP (1999) Treatment of multiple sclerosis: recent trials and future perspectives. Curr Opin Neurol 12(3):279–293 (Epub 1999/09/28)

    Article  CAS  PubMed  Google Scholar 

  9. Parry A, Corkill R, Blamire AM, Palace J, Narayanan S, Arnold D et al (2003) Beta-interferon treatment does not always slow the progression of axonal injury in multiple sclerosis. J Neurol 250(2):171–178 (Epub 2003/02/08)

    Article  CAS  PubMed  Google Scholar 

  10. Ehrenreich H, Fischer B, Norra C, Schellenberger F, Stender N, Stiefel M et al (2007) Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain J Neurol 130(Pt 10):2577–2588 (Epub 2007/08/31)

    Article  Google Scholar 

  11. Ehrenreich H, Aust C, Krampe H, Jahn H, Jacob S, Herrmann M et al (2004) Erythropoietin: novel approaches to neuroprotection in human brain disease. Metab Brain Dis 19(3–4):195–206 (Epub 2004/11/24)

    Article  CAS  PubMed  Google Scholar 

  12. Juul S (2004) Recombinant erythropoietin as a neuroprotective treatment: in vitro and in vivo models. Clin Perinatol 31(1):129–142 (Epub 2004/06/09)

    Article  CAS  PubMed  Google Scholar 

  13. Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C et al (2000) Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 97(19):10526–10531 (Epub 2000/09/14)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Jelkmann W (1992) Erythropoietin: structure, control of production, and function. Physiol Rev 72(2):449–489 (Epub 1992/04/01)

    CAS  PubMed  Google Scholar 

  15. Hasselblatt M, Ehrenreich H, Siren AL (2006) The brain erythropoietin system and its potential for therapeutic exploitation in brain disease. J Neurosurg Anesthesiol 18(2):132–138 (Epub 2006/04/22)

    Article  PubMed  Google Scholar 

  16. Konishi Y, Chui DH, Hirose H, Kunishita T, Tabira T (1993) Trophic effect of erythropoietin and other hematopoietic factors on central cholinergic neurons in vitro and in vivo. Brain Res 609(1–2):29–35 (Epub 1993/04/23)

    Article  CAS  PubMed  Google Scholar 

  17. Campana WM, Myers RR (2001) Erythropoietin and erythropoietin receptors in the peripheral nervous system: changes after nerve injury. FASEB J Off Publ Federation Am Soc Exp Biol 15(10):1804–1806 (Epub 2001/08/02)

    CAS  Google Scholar 

  18. Shingo T, Sorokan ST, Shimazaki T, Weiss S (2001) Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci Off J Soc Neurosci 21(24):9733–9743 (Epub 2001/12/12)

    CAS  Google Scholar 

  19. Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P et al (2001) Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci USA 98(7):4044–4049 (Epub 2001/03/22)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Celik M, Gokmen N, Erbayraktar S, Akhisaroglu M, Konakc S, Ulukus C et al (2002) Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. Proc Natl Acad Sci USA 99(4):2258–2263 (Epub 2002/02/21)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Keswani SC, Buldanlioglu U, Fischer A, Reed N, Polley M, Liang H et al (2004) A novel endogenous erythropoietin mediated pathway prevents axonal degeneration. Ann Neurol 56(6):815–826 (Epub 2004/10/08)

    Article  CAS  PubMed  Google Scholar 

  22. Li W, Maeda Y, Yuan RR, Elkabes S, Cook S, Dowling P (2004) Beneficial effect of erythropoietin on experimental allergic encephalomyelitis. Ann Neurol 56(6):767–777 (Epub 2004/11/25)

    Article  CAS  PubMed  Google Scholar 

  23. Savino C, Pedotti R, Baggi F, Ubiali F, Gallo B, Nava S et al (2006) Delayed administration of erythropoietin and its non-erythropoietic derivatives ameliorates chronic murine autoimmune encephalomyelitis. J Neuroimmunol 172(1–2):27–37 (Epub 2005/12/13)

    Article  CAS  PubMed  Google Scholar 

  24. Agnello D, Bigini P, Villa P, Mennini T, Cerami A, Brines ML et al (2002) Erythropoietin exerts an anti-inflammatory effect on the CNS in a model of experimental autoimmune encephalomyelitis. Brain Res 952(1):128–134 (Epub 2002/10/05)

    Article  CAS  PubMed  Google Scholar 

  25. Avasarala JR, Konduru SS (2005) Recombinant erythropoietin down-regulates IL-6 and CXCR4 genes in TNF-alpha-treated primary cultures of human microvascular endothelial cells: implications for multiple sclerosis. J Mol Neurosci MN 25(2):183–189 (Epub 2005/03/24)

    Article  CAS  Google Scholar 

  26. Genc K, Genc S, Baskin H, Semin I (2006) Erythropoietin decreases cytotoxicity and nitric oxide formation induced by inflammatory stimuli in rat oligodendrocytes. Physiol Res Acad Scientiarum Bohemoslovaca 55(1):33–38 (Epub 2005/04/29)

    CAS  Google Scholar 

  27. Zhang J, Li Y, Cui Y, Chen J, Lu M, Elias SB et al (2005) Erythropoietin treatment improves neurological functional recovery in EAE mice. Brain Res 1034(1–2):34–39 (Epub 2005/02/17)

    Article  CAS  PubMed  Google Scholar 

  28. Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33(11):1444–1452 (Epub 1983/11/01)

    Article  CAS  PubMed  Google Scholar 

  29. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M et al (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69(2):292–302 (Epub 2011/03/10)

    Article  PubMed Central  PubMed  Google Scholar 

  30. Sattler MB, Merkler D, Maier K, Stadelmann C, Ehrenreich H, Bahr M 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 (Epub 2004/10/02)

    Article  PubMed  Google Scholar 

  31. Sinnecker T, Mittelstaedt P, Dorr J, Pfueller CF, Harms L, Niendorf T et al (2012) Multiple sclerosis lesions and irreversible brain tissue damage: a comparative ultrahigh-field strength magnetic resonance imaging study. Arch Neurol 69(6):739–745 (Epub 2012/02/22)

    Article  PubMed  Google Scholar 

  32. Diem R, Sattler MB, Merkler D, Demmer I, Maier K, Stadelmann C et al (2005) Combined therapy with methylprednisolone and erythropoietin in a model of multiple sclerosis. Brain J Neurol 128(Pt 2):375–385 (Epub 2004/12/17)

    Google Scholar 

  33. Campbell Z, Sahm D, Donohue K, Jamison J, Davis M, Pellicano C et al (2012) Characterizing contrast-enhancing and re-enhancing lesions in multiple sclerosis. Neurology 78(19):1493–1499 (Epub 2012/04/28)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Gorio A, Madaschi L, Di Stefano B, Carelli S, Di Giulio AM, De Biasi S et al (2005) Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury. Proc Natl Acad Sci USA 102(45):16379–16384 (Epub 2005/11/02)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Naismith RT, Xu J, Tutlam NT, Scully PT, Trinkaus K, Snyder AZ et al (2010) Increased diffusivity in acute multiple sclerosis lesions predicts risk of black hole. Neurology 74(21):1694–1701 (Epub 2010/05/26)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Sloka JS, Stefanelli M (2005) The mechanism of action of methylprednisolone in the treatment of multiple sclerosis. Mult Scler 11(4):425–432 (Epub 2005/07/27)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank research development office of Sina hospital for their assistance in the preparation of the manuscript and Cinnagen Company for the unrestricted research grant to perform this study.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Sina MS Research Center, Neuroscience Institute, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Fatemeh Najmi Varzaneh, Farnaz Najmi Varzaneh, Amir Reza Azimi & Mohammad Ali Sahraian

  2. Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

    Farnaz Najmi Varzaneh & Nima Rezaei

  3. Molecular Immunology Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Nima Rezaei

  4. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Nima Rezaei

Authors
  1. Fatemeh Najmi Varzaneh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Farnaz Najmi Varzaneh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amir Reza Azimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nima Rezaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammad Ali Sahraian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammad Ali Sahraian.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Najmi Varzaneh, F., Najmi Varzaneh, F., Azimi, A.R. et al. Efficacy of combination therapy with erythropoietin and methylprednisolone in clinical recovery of severe relapse in multiple sclerosis. Acta Neurol Belg 114, 273–278 (2014). https://doi.org/10.1007/s13760-014-0286-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13760-014-0286-y

Keywords

Search

Navigation