TY - JOUR
T1 - Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo
AU - Erbayraktar, Serhat
AU - Grasso, Giovanni
AU - Sfacteria, Alessandra
AU - Xie, Qiao-wen
AU - Coleman, Thomas
AU - Kreilgaard, Mads
AU - Torup, Lars
AU - Sager, Thomas
AU - Erbayraktar, Zubeyde
AU - Gokmen, Necati
AU - Yilmaz, Osman
AU - Ghezzi, Pietro
AU - Villa, Pia
AU - Fratelli, Maddalena
AU - Casagrande, Simona
AU - Leist, Marcel
AU - Helboe, Lone
AU - Gerwein, Jens
AU - Christensen, Søren
AU - Geist, Marie Aavang
AU - Pedersen, Lars Østergaard
AU - Cerami-Hand, Carla
AU - Wuerth, Jean-Paul
AU - Cerami, Anthony
AU - Brines, Michael
PY - 2003/5/27
Y1 - 2003/5/27
N2 - 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.
AB - 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.
KW - Animals
KW - Brain Ischemia
KW - Erythropoietin
KW - Hemoglobins
KW - Male
KW - Mice
KW - Neuroprotective Agents
KW - Rats
KW - Rats, Sprague-Dawley
U2 - 10.1073/pnas.1031753100
DO - 10.1073/pnas.1031753100
M3 - Journal article
C2 - 12746497
VL - 100
SP - 6741
EP - 6746
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 11
ER -