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1. Derivatives of Erythropoietin That Are Tissue Protective but Not Erythropoietic

Author

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

Published
2004

2. Asialoerythropoietin Is a Nonerythropoietic Cytokine with Broad Neuroprotective Activity in vivo

Author

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

Published
2003

5. High-dose erythropoietin alters platelet reactivity and bleeding time in rodents in contrast to the neuroprotective variant carbamyl-erythropoietin (CEPO).

Author

Kirkeby, Agnete, Torup, Lars, Bochsen, Louise, Kjalke, Marianne, Abel, Kristin, Theilgaard-Mønch, Kim, Johansson, Pär I, Bjørn, Søren E, Gerwien, Jens, Leist, Marcel, Kirkeby, Agnete, Torup, Lars, Bochsen, Louise, Kjalke, Marianne, Abel, Kristin, Theilgaard-Mønch, Kim, Johansson, Pär I, Bjørn, Søren E, Gerwien, Jens, and Leist, Marcel

Abstract

Udgivelsesdato: 2008-Apr, The haematopoietic hormone erythropoietin (EPO) has neuroprotective properties and is currently being explored for treatment of stroke and other neurological disorders. Short-term, high-dose treatment with EPO seems to improve neurological function of stroke patients but may be associated with increased thrombotic risk, whereas alternative non-erythropoietic neuroprotective derivatives of EPO, such as carbamylated EPO (CEPO), may be devoid of such side-effects. We investigated the effects of short-term, high-dose treatment with EPO and CEPO on platelet function and haemostasis in healthy mice and rats. Animals received three daily doses of EPO or CEPO (50 microg/kg), and blood was compared with respect to alterations in haematology and platelet reactivity. In rats, treatment with EPO increased the haematocrit to >50% and the mean platelet volume by 37%, while CEPO had no effect on these parameters. Platelets from EPO-treated rats showed an increased sensitivity to thrombin receptor agonist peptides and elevated plasma levels of soluble P-selectin (sP-selectin) were found in treated mice. Further indicators of platelet hyperreactivity in EPO, but not CEPO-treated animals, were significantly increased aggregatory responses to collagen in whole blood and platelet-rich plasma (PRP). The increased platelet reactivity was paralleled by a decreased bleeding time after tail transection in rats. Samples from EPO-treated rats showed an attenuated response to ADP in whole blood aggregometry and thrombelastography (TEG) platelet mapping but not in apyrase-treated PRP, suggesting involvement of ADP receptor desensitization. These findings suggest that while EPO affects various aspects of platelet function, CEPO is devoid of such effects.

Published
2008

8. The Sonic Hedgehog Pathway Mediates Carbamylated Erythropoietin-enhanced Proliferation and Differentiation of Adult Neural Progenitor Cells

Author

Wang, Lei, primary, Zhang, Zheng Gang, additional, Gregg, Sara R., additional, Zhang, Rui Lan, additional, Jiao, Zhongxian, additional, LeTourneau, Yvonne, additional, Liu, Xianshuang, additional, Feng, Yifan, additional, Gerwien, Jens, additional, Torup, Lars, additional, Leist, Marcel, additional, Noguchi, Constance Tom, additional, Chen, Zhi-Yong, additional, and Chopp, Michael, additional

Published
2007
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10. The Sonic Hedgehog Pathway Mediates Carbamylated Erythropoietin-enhanced Proliferation and Differentiation of Adult Neural Progenitor Cells.

Author

Lei Wang, Zheng Gang Zhang, Gregg, Sara R., Rui Lan Zhang, Zhongxian Jiao, LeTourneau, Yvonne, Xianshuang Liu, Yifan Feng, Gerwien, Jens, Torup, Lars, Leist, Marcel, Noguchi, Constance Tom, Zhi-Yong Chen, and Chopp, Michael

Subjects
*CELL proliferation, *CELL differentiation, *CELL growth, *TRANSCRIPTION factors, *BIOCHEMICAL genetics, *BIOORGANIC chemistry, *BIOCHEMISTRY
Abstract

Carbamylated erythropoietin (CEPO), a well characterized erythropoietin (EPO) derivative, does not bind to the classical EPO receptor and does not stimulate erythropoiesis. Using neural progenitor cells derived from the subventricular zone of the adult mouse, we investigated the effect of CEPO on neurogenesis and the associated signaling pathways in vitro. We found that CEPO significantly increased neural progenitor cell proliferation and promoted neural progenitor cell differentiation into neurons, which was associated with up-regulation of Sonic hedgehog (Shh), its receptor ptc, and mammalian achaete-scute homolog 1 (Mash1), a pro-neuron basic helix-loop-helix protein transcription factor. Blockage of the Shh signaling pathway with a pharmacological inhibitor, cyclopamine, abolished the CEPO-induced neurogenesis. Attenuation of endogenous Mash1 expression by short-interfering RNA blocked CEPO-promoted neuronal differentiation. In addition, recombinant mouse Shh up-regulated Mash1 expression in neural progenitor cells. These results demonstrate that the Shh signaling pathway mediates CEPO-enhanced neurogenesis and Mash1 is a downstream target of the Shh signaling pathway that regulates CEPO-enhanced neuronal differentiation. [ABSTRACT FROM AUTHOR]

Published
2007
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11. Derivatives of Erythropoietin That Are Tissue ProtectiveBut Not Erythropoietic.

Author

Leist, Marcel, Ghezzi, Pietro, Grasso, Giovanni, Bianchi, Roberto, Villa, Pia, Fratelli, Maddalena, Savino, Costanza, Bianchi, Marina, Nielsen, Jacob, Gerwien, Jens, Kallunki, Pekka, Larsen, Anna Kirstine, Helboe, Lone, Christensen, Søren, Pedersen, Lars O., Nielsen, Mette, Torup, Lars, Sager, Thomas, Sfacteria, Alessandra, and Erbayraktar, Serhat

Subjects
*ERYTHROPOIETIN, *HEMATOPOIETIC growth factors, *GROWTH factors, *GLYCOPROTEINS, *COLONY-stimulating factors (Physiology), *CYTOKINES
Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2004
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