[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

Erythropoietin Therapy for Acute Stroke Is Both Safe and Beneficial

  • Clinical Trial
  • Published:
Molecular Medicine Aims and scope Submit manuscript

Abstract

Background

Erythropoietin (EPO) and its receptor play a major role in embryonic brain, are weakly expressed in normal postnatal/adult brain and up-regulated upon metabolic stress. EPO protects neurons from hypoxic/ischemic injury. The objective of this trial is to study the safety and efficacy of recombinant human EPO (rhEPO) for treatment of ischemic stroke in man.

Materials and Methods

The trial consisted of a safety part and an efficacy part. In the safety study, 13 patients received rhEPO intravenously (3.3 × 104 IU/50 ml/30 min) once daily for the first 3 days after stroke. In the double-blind randomized proof-of-concept trial, 40 patients received either rhEPO or saline. Inclusion criteria were age <80 years, ischemic stroke within the middle cerebral artery territory confirmed by diffusion-weighted MRI, symptom onset <8 hr before drug administration, and deficits on stroke scales. The study endpoints were functional outcome at day 30 (Barthel Index, modified Rankin scale), NIH and Scandinavian stroke scales, evolution of infarct size (sequential MRI evaluation using diffusion-weighted [DWI] and fluid-attenuated inversion recovery sequences [FLAIR]) and the damage marker S100ß.

Results

No safety concerns were identified. Cerebrospinal fluid EPO increased to 60–100 times that of nontreated patients, proving that intravenously administered rhEPO reaches the brain. In the efficacy trial, patients received rhEPO within 5 hr of onset of symptoms (median, range 2:40–7:55). Admission neurologic scores and serum S100β concentrations were strong predictors ofoutcome. Analysis of covariance controlled for these two variables indicated that rhEPO treatment was associated with an improvement in follow-up and outcome scales. A strong trend for reduction in infarct size in rhEPO patients as compared to controls was observed by MRI.

Conclusion

Intravenous high-dose rhEPO is well tolerated in acute ischemic stroke and associated with an improvement in clinical outcome at 1 month. A larger scale clinical trial is warranted.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. (1995) Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 333: 1581–1587.

    Article  Google Scholar 

  2. Zhu Y, D’Andrea AD. (1994) The molecular physiology of erythropoietin and the erythropoietin receptor. Curr. Opin. Hematol. 1: 113–118.

    PubMed  CAS  Google Scholar 

  3. Jelkmann W. (1994) Biology of erythropoietin. Clin. Invest. 72: S3–S10.

    CAS  Google Scholar 

  4. Brines ML, Ghezzi P, Keenan S, et al. (2000) From the cover: erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc. Natl. Acad. Sci. U.S.A. 97: 10526–10531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Juul SE, Anderson DK, Li Y, Christensen RD. (1998) Erythropoietin and erythropoietin receptor in the developing human central nervous system. Pediatr. Res. 43: 40–49.

    Article  CAS  PubMed  Google Scholar 

  6. Marti HH, Wenger RH, Rivas LA, et al. (1996) Erythropoietin gene expression in human, monkey and murine brain. Eur. J. Neurosci. 8: 666–676.

    Article  CAS  PubMed  Google Scholar 

  7. 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: 105–116.

    Article  CAS  PubMed  Google Scholar 

  8. Lewczuk P, Hasselblatt M, Kamrowski-Kruck H, et al. (2000) Survival of hippocampal neurons in culture upon hypoxia: effect of erythropoietin. Neuroreport 11: 3485–3488.

    Article  CAS  PubMed  Google Scholar 

  9. Bernaudin M, Bellail A, Marti HH, et al. (2000) Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain. Glia 30: 271–278.

    Article  CAS  PubMed  Google Scholar 

  10. 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: 19488–19493.

    PubMed  CAS  Google Scholar 

  11. Sirén 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: 271–276.

    Google Scholar 

  12. Bernaudin M, Marti HH, Roussel S, et al. (1999) A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 19: 643–651.

    Article  CAS  PubMed  Google Scholar 

  13. Sadamoto Y, Igase K, Sakanaka M, et al. (1998) Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem. Biophys. Res. Commun. 253: 26–32.

    Article  CAS  PubMed  Google Scholar 

  14. Sakanaka M, Wen TC, Matsuda S, et al. (1998) In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc. Natl. Acad. Sci. U.S.A. 95: 4635–4640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sirén AL, Fratelli M, Brines M, et al. (2001) Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc. Natl. Acad. Sci. U.S.A. 98: 4044–4049.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Nagai A, Nakagawa E, Choi HB, Hatori K, Kobayashi S, Kim SU. (2001) Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture. J. Neuropathol. Exp. Neurol. 60: 386–392.

    Article  CAS  PubMed  Google Scholar 

  17. Sela S, Shurtz-Swirski R, Sharon R, et al. (2001) The polymorphonuclear leukocyte—a new target for erythropoietin. Nephron 88: 205–210.

    Article  CAS  PubMed  Google Scholar 

  18. Herrmann M, Vos P, Wunderlich MT, de Bruijn CH, Lamers KJ. (2000) Release of glial tissue-specific proteins after acute stroke: a comparative analysis of serum concentrations of protein S-100B and glial fibrillary acidic protein. Stroke 31: 2670–2677.

    Article  CAS  PubMed  Google Scholar 

  19. Wunderlich MT, Ebert AD, Kratz T, Goertler M, Jost S, Herrmann M. (1999) Early neurobehavioral outcome after stroke is related to release of neurobiochemical markers of brain damage. Stroke 30: 1190–1195.

    Article  CAS  PubMed  Google Scholar 

  20. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. (1987) Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N. Engl. J. Med. 316: 73–78.

    Article  CAS  PubMed  Google Scholar 

  21. Adams HP Jr, Davis PH, Leira EC, et al. (1999) Baseline NIH Stroke Scale score strongly predicts outcome after stroke: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology 53: 126–131.

    Article  CAS  PubMed  Google Scholar 

  22. Buttner T, Weyers S, Postert T, Sprengelmeyer R, Kuhn W. (1997) S-100 protein: serum marker of focal brain damage after ischemic territorial MCA infarction. Stroke 28: 1961–1965.

    Article  CAS  PubMed  Google Scholar 

  23. Beaulieu C, de Crespigny A, Tong DC, Moseley ME, Albers GW, Marks MP. (1999) Longitudinal magnetic resonance imaging study of perfusion and diffusion in stroke: evolution of lesion volume and correlation with clinical outcome. Ann. Neurol. 46: 568–578.

    Article  CAS  PubMed  Google Scholar 

  24. Elting JW, de Jager AE, Teelken AW, et al. (2000) Comparison of serum S-100 protein levels following stroke and traumatic brain injury. J. Neurol. Sci. 181: 104–110.

    Article  CAS  PubMed  Google Scholar 

  25. De Ryck M. (1998) Neuroprotection in animal models of stroke and in clinical stroke trials: a new analysis of infarct size. In Manni C, Delooz H, Della Corte F (eds). First European Congress on Emergency Medicine. Bologna: Monduzzi Editore; 15–22.

    Google Scholar 

  26. Fisher M, Schaebitz W. (2000) An overview of acute stroke therapy: past, present, and future. Arch. Intern. Med. 160: 3196–3206.

    Article  CAS  PubMed  Google Scholar 

  27. Albers GW, Goldstein LB, Hall D, et al. (2001) Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial. JAMA 286: 2673–2682.

    Article  CAS  PubMed  Google Scholar 

  28. Dirnagl U, Iadecola C, Moskowitz MA. (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22: 391–397.

    Article  CAS  PubMed  Google Scholar 

  29. Sasaki C, Kitagawa H, Zhang WR, Warita H, Sakai K, Abe K. (2000) Temporal profile of cytochrome c and caspase-3 immunoreactivities and TUNEL staining after permanent middle cerebral artery occlusion in rats. Neurol. Res. 22: 223–228.

    Article  CAS  PubMed  Google Scholar 

  30. Campana WM, Misasi R, O’Brien JS. (1998) Identification of a neurotrophic sequence in erythropoietin. Int. J. Mol. Med. 1: 235–241.

    PubMed  CAS  Google Scholar 

  31. Marshak DR. (1990) S100 beta as a neurotrophic factor. Prog. Brain Res. 86: 169–181.

    Article  CAS  PubMed  Google Scholar 

  32. Hacke W, Warach S. (2000) Diffusion-weighted MRI as an evolving standard of care in acute stroke. Neurology 54: 1548–1549.

    Article  CAS  PubMed  Google Scholar 

  33. Hacke W, Kaste M, Fieschi C, et al. (1998) Randomised doubleblind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 352: 1245–1251.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work has been supported in part by research grants from the Max-Planck Society and from Ortho Biotech Inc. to Dr Ehrenreich. We wish to thank Dr J. Donald Easton for valuable discussions.

Author information

Authors and Affiliations

  1. Max-Planck-Institute for Experimental Medicine, Departments of Neurology and Psychiatry, Georg-August-University, Hermann-Rein-Str. 3, D-37075, Goettingen, Germany

    Hannelore Ehrenreich, Martin Hasselblatt, Christoph Dembowski, Lukas Cepek, Piotr Lewczuk, Sonja Jacob, Friederike Knerlich, Wolfgang Poser, Eckart Rüther, Hilmar Prange & Anna-Leena Sirén

  2. Departments of Radiology I and III, Georg-August-University, Goettingen, Germany

    Michael Stiefel, Hans-Heino Rustenbeck & Norbert Breiter

  3. Clinical Pharmacy, Georg-August-University, Goettingen, Germany

    Matthias Bohn

  4. Department of Family Medicine, Georg-August-University, Goettingen, Germany

    Michael Kochen

  5. Department of Medical Statistics, University of Erlangen, Erlangen, Germany

    Olaf Gefeller

  6. Department of Clinical Pharmacology, Eberhard-Karls-University, Tuebingen, Germany

    Christoph Gleiter

  7. Janssen Research Foundation, Titusville, NJ, USA

    Thomas C. Wessel

  8. Department of Neuropharmacology, Janssen Research Foundation, Beerse, Belgium

    Marc De Ryck

  9. Ortho Biotech Inc., Raritan, NJ, USA

    Loretta Itri

  10. The Kenneth S. Warren Institute, Kitchawan, New York, NY, USA

    Anthony Cerami & Michael Brines

Authors
  1. Hannelore Ehrenreich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Hasselblatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christoph Dembowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lukas Cepek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Piotr Lewczuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Stiefel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hans-Heino Rustenbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Norbert Breiter
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sonja Jacob
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Friederike Knerlich
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Matthias Bohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Wolfgang Poser
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Eckart Rüther
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Michael Kochen
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Olaf Gefeller
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Christoph Gleiter
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Thomas C. Wessel
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Marc De Ryck
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Loretta Itri
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Hilmar Prange
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Anthony Cerami
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Michael Brines
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Anna-Leena Sirén
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hannelore Ehrenreich.

Additional information

Contributed by A. Cerami.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ehrenreich, H., Hasselblatt, M., Dembowski, C. et al. Erythropoietin Therapy for Acute Stroke Is Both Safe and Beneficial. Mol Med 8, 495–505 (2002). https://doi.org/10.1007/BF03402029

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03402029

Keywords

Search

Navigation