Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 9 July 2004:
Vol. 305. no. 5681, pp. 239 - 242
DOI: 10.1126/science.1098313
Prev | Table of Contents | Next

Reports

Derivatives of Erythropoietin That Are Tissue Protective But Not Erythropoietic

Marcel Leist,1* Pietro Ghezzi,2,3* Giovanni Grasso,3,4 Roberto Bianchi,2 Pia Villa,2,5 Maddalena Fratelli,2 Costanza Savino,2 Marina Bianchi,2 Jacob Nielsen,1 Jens Gerwien,1 Pekka Kallunki,1 Anna Kirstine Larsen,1 Lone Helboe,1 Søren Christensen,1 Lars O. Pedersen,1 Mette Nielsen,1 Lars Torup,1 Thomas Sager,1 Alessandra Sfacteria,3,4 Serhat Erbayraktar,3,6 Zubeyde Erbayraktar,3,6 Necati Gokmen,6 Osman Yilmaz,3,6 Carla Cerami-Hand,3,7 Qiao-wen Xie,3,7 Thomas Coleman,3,7 Anthony Cerami,3,7{dagger} Michael Brines3,7

Erythropoietin (EPO) is both hematopoietic and tissue protective, putatively through interaction with different receptors. We generated receptor subtype–selective ligands allowing the separation of EPO's bioactivities at the cellular level and in animals. Carbamylated EPO (CEPO) or certain EPO mutants did not bind to the classical EPO receptor (EPOR) and did not show any hematopoietic activity in human cell signaling assays or upon chronic dosing in different animal species. Nevertheless, CEPO and various nonhematopoietic mutants were cytoprotective in vitro and conferred neuroprotection against stroke, spinal cord compression, diabetic neuropathy, and experimental autoimmune encephalomyelitis at a potency and efficacy comparable to EPO.

1 H. Lundbeck A/S, 2500 Valby, Denmark.
2 Mario Negri Institute of Pharmacological Research, 20157 Milano, Italy.
3 The Kenneth S. Warren Institute, Ossining, NY 10562, USA.
4 University of Messina, 98122 Messina, Italy.
5 Consiglio Nazionale delle Ricerche, Institute of Neuroscience, 20129 Milano, Italy.
6 Dokuz Eylul University School of Medicine, Izmir 35340, Turkey.
7 Warren Pharmaceuticals, Inc., Ossining, NY 10562, USA.



* These authors contributed equally to this study.

{dagger} To whom correspondence should be addressed. E-mail: acerami{at}kswi.org

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Neuroprotective effect of herpes simplex virus-mediated gene transfer of erythropoietin in hyperglycemic dorsal root ganglion neurons.
M. Chattopadhyay, C. Walter, M. Mata, and D. J. Fink (2009)
Brain 132, 879-888
   Abstract »    Full Text »    PDF »
Review: Recombinant human erythropoietin: novel strategies for neuroprotective/neuroregenerative treatment of multiple sclerosis.
C. Bartels, K. Spate, H. Krampe, and H. Ehrenreich (2008)
Therapeutic Advances in Neurological Disorders 1, 193-206
   Abstract »    PDF »
Brain Protection by Erythropoietin: A Manifold Task.
T. Rabie and H. H. Marti (2008)
Physiology 23, 263-274
   Abstract »    Full Text »    PDF »
'O', erythropoietin carbamoylation versus carbamylation.
W. Jelkmann (2008)
Nephrol. Dial. Transplant. 23, 3033
   Full Text »    PDF »
Anemia and Chronic Heart Failure: Implications and Treatment Options.
I. S. Anand (2008)
J. Am. Coll. Cardiol. 52, 501-511
   Abstract »    Full Text »    PDF »
Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin.
M. Brines, N. S. A. Patel, P. Villa, C. Brines, T. Mennini, M. De Paola, Z. Erbayraktar, S. Erbayraktar, B. Sepodes, C. Thiemermann, et al. (2008)
PNAS 105, 10925-10930
   Abstract »    Full Text »    PDF »
Erythropoiesis-Stimulating Agent Use in Cancer: Preclinical and Clinical Perspectives.
M. O. Arcasoy (2008)
Clin. Cancer Res. 14, 4685-4690
   Abstract »    Full Text »    PDF »
Erythropoietin and Its Receptor in Breast Cancer: Putting Together the Pieces of the Puzzle.
F. Mannello and G. A. M. Tonti (2008)
Oncologist 13, 761-768
   Abstract »    Full Text »    PDF »
Antiapoptotic properties of erythropoiesis-stimulating proteins in models of cisplatin-induced acute kidney injury.
A. K. Salahudeen, N. Haider, J. Jenkins, M. Joshi, H. Patel, H. Huang, M. Yang, and H. Zhe (2008)
Am J Physiol Renal Physiol 294, F1354-F1365
   Abstract »    Full Text »    PDF »
Nonerythropoietic derivative of erythropoietin protects against tubulointerstitial injury in a unilateral ureteral obstruction model.
H. Kitamura, Y. Isaka, Y. Takabatake, R. Imamura, C. Suzuki, S. Takahara, and E. Imai (2008)
Nephrol. Dial. Transplant. 23, 1521-1528
   Abstract »    Full Text »    PDF »
High levels of erythropoietin are associated with protection against neurological sequelae in African children with cerebral malaria.
C. Casals-Pascual, R. Idro, N. Gicheru, S. Gwer, B. Kitsao, E. Gitau, R. Mwakesi, D. J. Roberts, and C. R. J. C. Newton (2008)
PNAS 105, 2634-2639
   Abstract »    Full Text »    PDF »
Asialoerythropoietin Prevents Contrast-Induced Nephropathy.
Y. Yokomaku, T. Sugimoto, S. Kume, S.-i. Araki, K. Isshiki, M. Chin-Kanasaki, M. Sakaguchi, N. Nitta, M. Haneda, D. Koya, et al. (2008)
J. Am. Soc. Nephrol. 19, 321-328
   Abstract »    Full Text »    PDF »
Low-dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit.
E. Lipsic, B. D. Westenbrink, P. van der Meer, P. van der Harst, A. A. Voors, D. J. van Veldhuisen, R. G. Schoemaker, and W. H. van Gilst (2008)
Eur J Heart Fail 10, 22-29
   Abstract »    Full Text »    PDF »
The Sonic Hedgehog Pathway Mediates Carbamylated Erythropoietin-enhanced Proliferation and Differentiation of Adult Neural Progenitor Cells.
L. Wang, Z. G. Zhang, S. R. Gregg, R. L. Zhang, Z. Jiao, Y. LeTourneau, X. Liu, Y. Feng, J. Gerwien, L. Torup, et al. (2007)
J. Biol. Chem. 282, 32462-32470
   Abstract »    Full Text »    PDF »
Erythropoietin Inhibits Basal and Stimulated Corticotropin-Releasing Hormone Release from the Rat Hypothalamus via a Nontranscriptional Mechanism.
G. Tringali, G. Pozzoli, L. Lisi, and P. Navarra (2007)
Endocrinology 148, 4711-4715
   Abstract »    Full Text »    PDF »
Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization.
B. D. Westenbrink, E. Lipsic, P. van der Meer, P. van der Harst, H. Oeseburg, G. J. Du Marchie Sarvaas, J. Koster, A. A. Voors, D. J. van Veldhuisen, W. H. van Gilst, et al. (2007)
Eur. Heart J. 28, 2018-2027
   Abstract »    Full Text »    PDF »
Darbepoetin alfa, a long-acting erythropoietin analog, offers novel and delayed cardioprotection for the ischemic heart.
E. Gao, M. Boucher, J. K. Chuprun, R.-H. Zhou, A. D. Eckhart, and W. J. Koch (2007)
Am J Physiol Heart Circ Physiol 293, H60-H68
   Abstract »    Full Text »    PDF »
OPTA: Optimal treatment of anaemia in patients with chronic kidney disease (CKD).
W. H. Horl, Y. Vanrenterghem, P. Aljama, P. Brunet, R. Brunkhorst, L. Gesualdo, I. Macdougall, C. Wanner, and B. Wikstrom (2007)
Nephrol. Dial. Transplant. 22, iii20-iii26
   Full Text »    PDF »
Attenuation of Inflammation and Apoptosis by Pre- and Posttreatment of Darbepoetin-{alpha} in Acute Liver Failure of Mice.
K. Le Minh, K. Klemm, K. Abshagen, C. Eipel, M. D. Menger, and B. Vollmar (2007)
Am. J. Pathol. 170, 1954-1963
   Abstract »    Full Text »    PDF »
Hemoglobin-Independent Organ Protection by EPO in Humans: Amelioration of Cognitive Loss in Chronic Schizophrenia.
H. Ehrenreich, D. Hinze-Selch, S. Stawicki, C. Aust, S. Knolle-Veentjer, S. Wilms, G. Heinz, S. Erdag, H. Jahn, D. Degner, et al. (2007)
J. Am. Soc. Nephrol. 18, 3-6
   Abstract »    Full Text »    PDF »
Protective Effects of Erythropoietin in Cardiac Ischemia: From Bench to Bedside.
E. Lipsic, R. G. Schoemaker, P. van der Meer, A. A. Voors, D. J. van Veldhuisen, and W. H. van Gilst (2006)
J. Am. Coll. Cardiol. 48, 2161-2167
   Abstract »    Full Text »    PDF »
Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia.
M. Fantacci, P. Bianciardi, A. Caretti, T. R. Coleman, A. Cerami, M. Brines, and M. Samaja (2006)
PNAS 103, 17531-17536
   Abstract »    Full Text »    PDF »
In vivo stimulatory effect of erythropoietin on endothelial nitric oxide synthase in cerebral arteries.
A. V. R. Santhanam, L. A. Smith, K. A. Nath, and Z. S. Katusic (2006)
Am J Physiol Heart Circ Physiol 291, H781-H786
   Abstract »    Full Text »    PDF »
Erythropoietin affords additional cardioprotection to preconditioned hearts by enhanced phosphorylation of glycogen synthase kinase-3beta.
M. Nishihara, T. Miura, T. Miki, J. Sakamoto, M. Tanno, H. Kobayashi, Y. Ikeda, K. Ohori, A. Takahashi, and K. Shimamoto (2006)
Am J Physiol Heart Circ Physiol 291, H748-H755
   Abstract »    Full Text »    PDF »
Erythropoietin: Repair of the Failing Heart.
P. van der Meer and E. Lipsic (2006)
J. Am. Coll. Cardiol. 48, 185-186
   Full Text »    PDF »
Anemia in Chronic Heart Failure: Prevalence, Etiology, Clinical Correlates, and Treatment Options.
Y.-D. Tang and S. D. Katz (2006)
Circulation 113, 2454-2461
   Full Text »    PDF »
Protective Effect of Erythropoietin and Its Carbamylated Derivative in Experimental Cisplatin Peripheral Neurotoxicity.
R. Bianchi, M. Brines, G. Lauria, C. Savino, A. Gilardini, G. Nicolini, V. Rodriguez-Menendez, N. Oggioni, A. Canta, P. Penza, et al. (2006)
Clin. Cancer Res. 12, 2607-2612
   Abstract »    Full Text »    PDF »
Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities.
T. R. Coleman, C. Westenfelder, F. E. Togel, Y. Yang, Z. Hu, L. Swenson, H. G. D. Leuvenink, R. J. Ploeg, L. V. d'Uscio, Z. S. Katusic, et al. (2006)
PNAS 103, 5965-5970
   Abstract »    Full Text »    PDF »
Toward a Multimodal Neuroprotective Treatment of Stroke.
M. Fisher, A. Davalos, A. Rogalewski, A. Schneider, E. B. Ringelstein, and W.-R. Schabitz (2006)
Stroke 37, 1129-1136
   Abstract »    Full Text »    PDF »
Important Role of Endogenous Erythropoietin System in Recruitment of Endothelial Progenitor Cells in Hypoxia-Induced Pulmonary Hypertension in Mice.
K. Satoh, Y. Kagaya, M. Nakano, Y. Ito, J. Ohta, H. Tada, A. Karibe, N. Minegishi, N. Suzuki, M. Yamamoto, et al. (2006)
Circulation 113, 1442-1450
   Abstract »    Full Text »    PDF »
Antiapoptotic Effects of Erythropoietin in Differentiated Neuroblastoma SH-SY5Y Cells Require Activation of Both the STAT5 and AKT Signaling Pathways.
M. Um and H. F. Lodish (2006)
J. Biol. Chem. 281, 5648-5656
   Abstract »    Full Text »    PDF »
Erythropoietin, Modified to Not Stimulate Red Blood Cell Production, Retains Its Cardioprotective Properties.
C. Moon, M. Krawczyk, D. Paik, T. Coleman, M. Brines, M. Juhaszova, S. J. Sollott, E. G. Lakatta, and M. I. Talan (2006)
J. Pharmacol. Exp. Ther. 316, 999-1005
   Abstract »    Full Text »    PDF »
A Critical Role of Erythropoietin Receptor in Neurogenesis and Post-Stroke Recovery.
P. T. Tsai, J. J. Ohab, N. Kertesz, M. Groszer, C. Matter, J. Gao, X. Liu, H. Wu, and S. T. Carmichael (2006)
J. Neurosci. 26, 1269-1274
   Abstract »    Full Text »    PDF »
Erythropoietin Biology in Cancer.
M. E. Hardee, M. O. Arcasoy, K. L. Blackwell, J. P. Kirkpatrick, and M. W. Dewhirst (2006)
Clin. Cancer Res. 12, 332-339
   Abstract »    Full Text »    PDF »
Erythropoietin and neuroprotection: a therapeutic perspective.
M. Milano and R. Collomp (2005)
Journal of Oncology Pharmacy Practice 11, 145-149
   Abstract »    PDF »
From The Cover: Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury.
A. Gorio, L. Madaschi, B. Di Stefano, S. Carelli, A. M. Di Giulio, S. De Biasi, T. Coleman, A. Cerami, and M. Brines (2005)
PNAS 102, 16379-16384
   Abstract »    Full Text »    PDF »
Expression of the erythropoietin receptor in human heart.
R. Depping, K. Kawakami, H. Ocker, J. M. Wagner, M. Heringlake, A. Noetzold, H.-H. Sievers, and K. F. Wagner (2005)
J. Thorac. Cardiovasc. Surg. 130, 877
   Full Text »    PDF »
Erythropoietin receptors: their role beyond erythropoiesis.
J. Rossert and K.-U. Eckardt (2005)
Nephrol. Dial. Transplant. 20, 1025-1028
   Full Text »    PDF »
Further Aspects of Anemia, Heart Failure, and Erythropoietin.
J. C. Kovacic (2005)
J. Am. Coll. Cardiol. 45, 1549-1550
   Full Text »    PDF »
A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury.
F. Fiordaliso, S. Chimenti, L. Staszewsky, A. Bai, E. Carlo, I. Cuccovillo, M. Doni, M. Mengozzi, R. Tonelli, P. Ghezzi, et al. (2005)
PNAS 102, 2046-2051
   Abstract »    Full Text »    PDF »
Exciting, Radical, Suicidal: How Brain Cells Die After Stroke.
E. H. Lo, M. A. Moskowitz, and T. P. Jacobs (2005)
Stroke 36, 189-192
   Full Text »    PDF »
Darbepoietin Alfa Potentiates the Efficacy of Radiation Therapy in Mice with Corrected or Uncorrected Anemia.
S. Ning, C. Hartley, G. Molineux, and S. J. Knox (2005)
Cancer Res. 65, 284-290
   Abstract »    Full Text »    PDF »
A Novel Molecule Designed to Keep Bacteria out of the Urinary Tract: A Toll-Like Receptor that Prevents Infection by Uropathogenic Bacteria. Science 303: 1522-1526, 2004.
D. Zhang, G. Zhang, M.S. Hayden, M.B. Greenblatt, C. Bussey, R.A. Flavell, S. Gosh, M. Leist, P. Ghezzi, G. Grasso, et al. (2005)
J. Am. Soc. Nephrol. 16, 4-7
   Full Text »    PDF »
Extracellular Superoxide Dismutase Functions as a Major Repressor of Hypoxia-Induced Erythropoietin Gene Expression.
I. N. Zelko and R. J. Folz (2005)
Endocrinology 146, 332-340
   Abstract »    Full Text »    PDF »
Erythropoietin mediates tissue protection through an erythropoietin and common {beta}-subunit heteroreceptor.
M. Brines, G. Grasso, F. Fiordaliso, A. Sfacteria, P. Ghezzi, M. Fratelli, R. Latini, Q.-w. Xie, J. Smart, C.-j. Su-Rick, et al. (2004)
PNAS 101, 14907-14912
   Abstract »    Full Text »    PDF »
Meet CEPO, a Variant of EPO with Great Therapeutic Potential.
(2004)
Journal Watch (General) 2004, 2
   Full Text »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)