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Emerging biological roles for erythropoietin in the nervous system

Nature Reviews Neuroscience volume 6, pages 484–494 (2005)Cite this article

A Correction to this article was published on 01 August 2005

Abstract

Erythropoietin mediates an evolutionarily conserved, ancient immune response that limits damage to the heart, the nervous system and other tissues following injury. New evidence indicates that erythropoietin specifically prevents the destruction of viable tissue surrounding the site of an injury by signalling through a non-haematopoietic receptor. Engineered derivatives of erythropoietin that have a high affinity for this receptor have been developed, and these show robust tissue-protective effects in diverse preclinical models without stimulating erythropoiesis. A recent successful proof-of-concept clinical trial that used erythropoietin to treat human patients who had suffered a stroke encourages the evaluation of both this cytokine and non-erythropoietic derivatives as therapeutic agents to limit tissue injury.

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Figure 1: Range of erythropoietin concentrations in the serum of healthy individuals and those with moderate anaemia, and the affinities of erythropoietin receptors in different cell types.
Figure 2: The central role of hypoxia-inducible factor in erythropoiesis and tissue protection.
Figure 3: Structure of cytokine receptor subunits that mediate erythropoiesis and cytoprotection.
Figure 4: Intracellular erythropoietin signalling pathways implicated in tissue protection.
Figure 5: Evolution of tissue injury and its modulation by endogenous erythropoietin or exogenous non-erythropoietic tissue-protective cytokines.
Figure 6: In vivo efficacy of non-erythropoietic, tissue-protective erythropoietin derivatives.

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Acknowledgements

Recently, the number and diversity of publications concerning non-erythroid actions of erythropoietin has grown in an exponential manner. We apologize to our many colleagues for omission of their important work due to stringent space limitations in this brief perspective. We especially thank our principal colleagues, T. Coleman, Q.-w. Xie and M. Yamin at Warren Pharmaceuticals; P. Ghezzi, R. Latini and colleagues at the Mario Negri Pharmacological Institute in Milan, Italy; G. Grasso and A. Sfacteria, University of Messina, Sicily, Italy; M. Leist, T. Sager, L. Torup and co-workers at H. Lundbeck A/S, Copenhagen, Denmark; O. Yilmaz, S. Erbayraktar, Z. Erbayraktar and N. Gokmen at Dokuz Eylul University, Izmir, Turkey; and H. Ehrenreich and A. Siren, Max Planck Institute for Experimental Medicine, Gottingen, Germany. M.B. and A.C. are supported by the Kenneth S. Warren Institute and Warren Pharmaceuticals. We are employed by Warren Pharmaceuticals, which is engaged in developing non-erythropoietic tissue protective cytokines for clinical use.

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  1. The Kenneth S. Warren Institute and Warren Pharmaceuticals, Inc., 712 Kitchawan Road, Ossining, 10562, New York, USA

    Michael Brines & Anthony Cerami

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  1. Michael Brines
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Correspondence to Michael Brines.

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Competing interests

M. B. and A. C. are employees of Warren Pharmaceuticals, Inc., which is engaged in developing tissue-protective erythropoietin analogues.

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DATABASES

Entrez Gene

BCL2

BCL-XL

EPO

EPOR

GMCSF

IL-3

IL-5

JAK2

PKB

PI3K

PLCγ

STAT

TNFα

VEGF

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Warren Pharmaceuticals

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Brines, M., Cerami, A. Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci 6, 484–494 (2005). https://doi.org/10.1038/nrn1687

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