Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo

Serhat Erbayraktar, Giovanni Grasso, Alessandra Sfacteria, Qiao wen Xie, Thomas Coleman, Mads Kreilgaard, Lars Torup, Thomas Sager, Zubeyde Erbayraktar, Necati Gokmen, Osman Yilmaz, Pietro Ghezzi, Pia Villa, Maddalena Fratelli, Simona Casagrande, Marcel Leist, Lone Helboe, Jens Gerwein, Søren Christensen, Marie Aavang GeistLars Østergaard Pedersen, Carla Cerami-Hand, Jean Paul Wuerth, Anthony Cerami, Michael Brines

Research output: Contribution to journalArticle

Abstract

Erythropoietin (EPO) is a tissue-protective cytokine preventing vascular spasm, apoptosis, and inflammatory responses. Although best known for its role in hematopoietic lineages, EPO also affects other tissues, including those of the nervous system. Enthusiasm for recombinant human erythropoietin (rhEPO) as a potential neuroprotective therapeutic must be tempered, however, by the knowledge it also enlarges circulating red cell mass and increases platelet aggregability. Here we examined whether erythropoietic and tissue-protective activities of rhEPO might be dissociated by a variation of the molecule. We demonstrate that asialoerythropoietin (asialoEPO), generated by total enzymatic desialylation of rhEPO, possesses a very short plasma half-life and is fully neuroprotective. In marked contrast with rhEPO, this molecule at doses and frequencies at which rhEPO exhibited erythropoiesis, did not increase the hematocrit of mice or rats, AsialoEPO appeared promptly within the cerebrospinal fluid after i.v. administration; intravenously administered radioiodine-labeled asialoEPO bound to neurons within the hippocampus and cortex in a pattern corresponding to the distribution of the EPO receptor. Most importantly, asialoEPO exhibits a broad spectrum of neuroprotective activities, as demonstrated in models of cerebral ischemia, spinal cord compression, and sciatic nerve crush. These data suggest that nonerythropoietic variants of rhEPO can cross the blood-brain barrier and provide neuroprotection.

Original languageEnglish
Pages (from-to)6741-6746
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number11
DOIs
Publication statusPublished - May 27 2003

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ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Erbayraktar, S., Grasso, G., Sfacteria, A., Xie, Q. W., Coleman, T., Kreilgaard, M., Torup, L., Sager, T., Erbayraktar, Z., Gokmen, N., Yilmaz, O., Ghezzi, P., Villa, P., Fratelli, M., Casagrande, S., Leist, M., Helboe, L., Gerwein, J., Christensen, S., ... Brines, M. (2003). Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proceedings of the National Academy of Sciences of the United States of America, 100(11), 6741-6746. https://doi.org/10.1073/pnas.1031753100