Archives of Orthopaedic and Trauma Surgery

, Volume 129, Issue 2, pp 189–194 | Cite as

The efficacy of erythropoietin on acute spinal cord injury. An experimental study on a rat model

  • Vasileios A. Kontogeorgakos
  • Spyridon Voulgaris
  • Anastasios V. Korompilias
  • Marios Vekris
  • Konstantinos S. Polyzoidis
  • Konstantinos Bourantas
  • Alexandros E. Beris
Orthopaedic Surgery



The accumulated knowledge of erythropoietin (EPO) interaction in neural injury has led to potentially novel therapeutic strategies. Previous experimental studies of recombinant human EPO (rhEPO) administration have shown favorable results after central and peripheral neural injury. In the present study we used the aneurysmal clip model to evaluate the efficacy of two different regimes of rhEPO administration on the functional outcome after severe acute spinal cord injury (ASCI).

Materials and methods

Thirty rats were operated on with posterior laminectomy at thoracic 10th vertebra. Spinal cord trauma produced by extradural placement of the aneurysm clip, for 1 min. Animals were divided into three groups; the first group received a low total EPO dose (EPO-L), (2 doses of 1,000 IU each s.c.). The second group was administered the high total EPO dose (EPO-H), (14 doses of 1,000 IU each s.c.), and the third was the Control group, which received normal saline in the same time fashion with EPO-H group. Follow-up was for 6 weeks. Estimation of the functional progress of each rat was calculated using the locomotor rating scale of Basso et al, with a range from 0 to 21.


After surgery the animals suffered paraplegia with urinary disturbances. Rats that received EPO demonstrated statistically significant functional improvement compared to the Control group, throughout study interval. On the last follow-up at 6 weeks the EPO-L rats achieved a mean score 17.3 ± 1.15, the EPO-H 14.7 ± 1.82, and the control group 8.2 ± 0.78. Comparison between the two EPO groups reveals superior final outcome of the group treated with lower total dose.


Our study supports current knowledge, that EPO administration has a positive effect on functional recovery after experimental ASCI. These data reflect the positive impact of EPO on the pathophysiologic cascade of secondary neural damage. However, we observed a dose-related effect on functional recovery. Interestingly, large doses do not seem to favor the neurological recovery as lower doses do.


Erythropoietin EPO Acute spinal cord injury Neuroprotection 


  1. 1.
    Allen AR (1911) Surgery for experimental lesions of spinal cord equivalent to crush injury of fracture dislocation of spinal column. A preliminary report. JAMA 57:878–880Google Scholar
  2. 2.
    Arishima Y, Takao S, Ichiro Y, Kazunori Y, Setsuro K (2006) Preventive effect of erythropoietin on spinal cord cell apoptosis following acute traumatic injury in rats. Spine 31:2432–2438PubMedCrossRefGoogle Scholar
  3. 3.
    Baptiste D, Fehlings M (2006) Pharmacological approaches to repair the injured spinal cord. J Neurotrauma 23:318–334PubMedCrossRefGoogle Scholar
  4. 4.
    Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12:1–21PubMedCrossRefGoogle Scholar
  5. 5.
    Bianchi R, Buyukakilli B, Brines M et al (2004) Erythropoietin both protect from and reverses experimental diabetic neuropathy. Proc Natl Acad Sci 101:823–828PubMedCrossRefGoogle Scholar
  6. 6.
    Bracken MB, Shepard MJ, Collins WF et al (1990) A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury. N Engl J Med 322(20):1405–1411PubMedCrossRefGoogle Scholar
  7. 7.
    Bracken MB, Shepard MJ, Holford TR et al (1997) Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the third national acute spinal cord injury randomized controlled trial. National Acute Spinal Cord Injury Study. JAMA 277:1597–1604PubMedCrossRefGoogle Scholar
  8. 8.
    Brines M, Cerami A (2006) Discovering erythropoietin’s extra-hematopoietic functions: biology and clinical promise. Kidney Int 70:246–250PubMedCrossRefGoogle Scholar
  9. 9.
    Brines ML, Ghezzi P, Keenam S et al (2000) Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc Natl Acad Sci 97:10526–10531PubMedCrossRefGoogle Scholar
  10. 10.
    Calvillo L, Latini R, Kajstura J et al (2003) Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci 100:4802–4806PubMedCrossRefGoogle Scholar
  11. 11.
    Celik M, Gökmen N, Erbayraktar S et al (2002) Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. Proc Natl Acad Sci 99:2258–2263PubMedCrossRefGoogle Scholar
  12. 12.
    Cetin A, Nas K, Buyukbayram H, Ceviz A, Olmez G (2006) The effects of systemically administered methylprednisolone and recombinant human erythropoietin after acute spinal cord compressive injury in rats. Eur Spine J 15:1539–1544PubMedCrossRefGoogle Scholar
  13. 13.
    Digicaylioglu M, Lipton SA (2001) Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kB signalling cascades. Nature 412:641–647PubMedCrossRefGoogle Scholar
  14. 14.
    Dusart I, Schwab ME (1994) Secondary cell death and the inflammatory reaction after dorsal hemisection of the rat spinal cord. Eur J Neurosci 6:712–724PubMedCrossRefGoogle Scholar
  15. 15.
    Eid T, Brines M (2002) Recombinant human erythropoietin for neuroprotection: what is the evidence? Clin Breast Cancer 3(Suppl 3):109–115CrossRefGoogle Scholar
  16. 16.
    Gassmann M, Heinicke K, Soliz J et al (2003) Non-erythroid functions of erythropoietin. Adv Exp Med Biol 543:323–330PubMedGoogle Scholar
  17. 17.
    Geisler FH, Coleman WP, Grieco G et al (2001) The Sygen multi-center acute spinal cord injury study. Spine 26(Suppl 24):87–98CrossRefGoogle Scholar
  18. 18.
    Gorio A, Gokmen N, Erbayraktar S et al (2002) Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci 99:9450–9455PubMedCrossRefGoogle Scholar
  19. 19.
    Gorio A, Madaschi L, Di Stefano B et al (2005) Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury. Proc Natl Acad Sci 102:16379–16384PubMedCrossRefGoogle Scholar
  20. 20.
    Grasso G, Sfacteria A, Erbayraktar S et al (2006) Amelioration of spinal cord compressive injury by pharmacological preconditioning with erythropoietin and a nonerythropoietic erythropoietin derivative. J Neurosurg Spine 4:310–318PubMedCrossRefGoogle Scholar
  21. 21.
    Grasso G, Sfacteria A, Passalacqua M et al (2005) Erythropoietin and erythropoietin receptor expression after experimental spinal cord injury encourages therapy by exogenous erythropoietin. Neurosurgery 56:821–827PubMedCrossRefGoogle Scholar
  22. 22.
    Harada N, Taoka Y, Okajima K (2006) Role of prostacyclin in the development of compression trauma-induced spinal cord injury in rats. J Neurotrauma 23:1739–1749PubMedCrossRefGoogle Scholar
  23. 23.
    Jacobson LO, Goldwasser E, Fried W, Plzak L (1957) Role of the kidney in erythropoiesis. Nature 179:633PubMedCrossRefGoogle Scholar
  24. 24.
    Jelkmann W (1994) Biology of erythropoietin. Clin Invest 72(Suppl 6):3–10Google Scholar
  25. 25.
    Kaptanoglu E, Solaroglu I, Okutan O, Surucu HS, Akbiyik F, Beskonakli E (2004) Erythropoietin exerts neuroprotection after acute spinal cord injury in rats: effect on lipid peroxidation and early ultrastructural findings. Neurosurg Rev 27:113–120PubMedCrossRefGoogle Scholar
  26. 26.
    Kaufman JS, Reda DJ, Fye CL et al (1998) Subcutaneous compared with intravenous epoeitin in patients receiving hemodialysis. Department of Veterans Affairs Cooperative Study Group on erythropoietin in hemodialysis patients. N Engl J Med 339:578–583PubMedCrossRefGoogle Scholar
  27. 27.
    Khan M, Griebel R, Rozdilsky B, Politis M (1985) Hemorrhagic changes in experimental spinal cord injury models. Can J Neurol Sci 12:259–262PubMedGoogle Scholar
  28. 28.
    Leist M, Ghezzi P, Grasso G (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305:239–242PubMedCrossRefGoogle Scholar
  29. 29.
    Lipton S (2004) Erythropoietin for neurologic protection and diabetic neuropathy. N Engl J Med 350(24):2516–2517PubMedCrossRefGoogle Scholar
  30. 30.
    Lykissas MG, SAkellariou E, Vekris MD et al (2007) Axonal regeneration stimulated by erythropoietin: an experimental study in rats. J Neurosci Methods 164:107–115PubMedCrossRefGoogle Scholar
  31. 31.
    Masuda S, Nagao M, Sasaki R (1999) Erythropoietic, neurotrophic, and angiogenic functions of erythropoietin and regulation of erythropoietin production. Int J Hematol 70:1–6PubMedGoogle Scholar
  32. 32.
    Masuda S, Okano M, Yamagishi K, Nagao M, Ueda M, Sasaki R (1994) A novel site of erythropoietin production. Oxygen-dependent production in cultured rat astrocytes. J Biol Chem 269:19488–19493PubMedGoogle Scholar
  33. 33.
    Minoda Y, Sakawa A, Fukuoka S, Tada K, Takaoka K (2004) Blood management for patients with hemoglobin level lower than 130 g/l in total knee arthroplasty. Arch Orthop Trauma Surg 124(5):317–319PubMedCrossRefGoogle Scholar
  34. 34.
    Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R (1997) Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 76:105–116PubMedCrossRefGoogle Scholar
  35. 35.
    Rivlin AS, Tator CH (1978) Effect of duration of acute spinal cord compression in a new acute cord injury in the rat. Surg Neurol 10:38–43PubMedGoogle Scholar
  36. 36.
    Sasaki R, Masuda S, Nagao M (2000) Erythropoietin: multiple physiological functions and regulation of biosynthesis. Biosci Biotechnol Biochem 64:1775–1793PubMedCrossRefGoogle Scholar
  37. 37.
    Sayer FT, Kronvall E, Nilsson OG (2006) Methylprednisolone treatment in acute spinal cord injury: the myth challenged through a structured analysis of published literature. Spine J 6:335–343PubMedCrossRefGoogle Scholar
  38. 38.
    Schwartz G, Fehlings MG (2001) Evaluation of the neuroprotective effects of sodium channel blockers after spinal cord injury: improved behavioral and neuroanatomical recovery with riluzole. J Neurosurg Spine 94:245–256CrossRefGoogle Scholar
  39. 39.
    Sekhon LH, Fehlings MG (2001) Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine 26(Suppl 24):2–12CrossRefGoogle Scholar
  40. 40.
    Sekiguchi Y, Kikuchi S, Myers RR., Campana WM (2003) Erythropoietin inhibits spinal neuronal apoptosis and pain following nerve root crush. Spine 28:2577–2584PubMedCrossRefGoogle Scholar
  41. 41.
    Shi R, Borgens RB (2000) Anatomical repair of nerve membranes in crushed mammalian spinal cord with polyethylene glycol. J Neurocytol 29:633–643PubMedCrossRefGoogle Scholar
  42. 42.
    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 21:9733–9743PubMedGoogle Scholar
  43. 43.
    Siren AL, Knerlich F, Poser W, Gleiter CH, Bruck W, Ehrenreich H (2001) Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol (Berl) 101:271–276Google Scholar
  44. 44.
    Stohlawetz PJ, Dzirlo L, Hergovich N (2000) Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood 95:2983–2989PubMedGoogle Scholar
  45. 45.
    Tator CH (1995) Update on the pathophysiology and pathology of acute spinal cord injury. Brain Pathol 5:407–413PubMedCrossRefGoogle Scholar
  46. 46.
    Wells JE, Hurlbert RJ, Fehlings MG et al (2003) Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice. Brain 126:1628–1637PubMedCrossRefGoogle Scholar
  47. 47.
    Wolf RF, Peng J, Friese P, Gilmore LS, Burstein SA, Dale GL (1997) Erythropoietin administration increases production and reactivity of platelets in dogs. Thromb Haemost 78:1505–1509PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Vasileios A. Kontogeorgakos
    • 1
  • Spyridon Voulgaris
    • 2
  • Anastasios V. Korompilias
    • 1
  • Marios Vekris
    • 1
  • Konstantinos S. Polyzoidis
    • 3
  • Konstantinos Bourantas
    • 4
  • Alexandros E. Beris
    • 1
  1. 1.Department of Orthopaedic SurgerySchool of Medicine, University of IoanninaIoanninaGreece
  2. 2.Department of NeurosurgerySchool of Medicine, University of IoanninaIoanninaGreece
  3. 3.Department of NeurosurgeryAristotle University of Thessalonica, School of Medicine, AXEPA HospitalThessalonicaGreece
  4. 4.Department of HaematologySchool of Medicine, University of IoanninaIoanninaGreece

Personalised recommendations