TY - JOUR
T1 - Delayed administration of erythropoietin and its non-erythropoietic derivatives ameliorates chronic murine autoimmune encephalomyelitis
AU - Savino, Costanza
AU - Pedotti, Rosetta
AU - Baggi, Fulvio
AU - Ubiali, Federica
AU - Gallo, Barbara
AU - Nava, Sara
AU - Bigini, Paolo
AU - Barbera, Sara
AU - Fumagalli, Elena
AU - Mennini, Tiziana
AU - Vezzani, Annamaria
AU - Rizzi, Massimo
AU - Coleman, Thomas
AU - Cerami, Anthony
AU - Brines, Michael
AU - Ghezzi, Pietro
AU - Bianchi, Roberto
PY - 2006/3
Y1 - 2006/3
N2 - Erythropoietin (EPO) mediates a wide range of neuroprotective activities, including amelioration of disease and neuroinflammation in rat models of EAE. However, optimum dosing parameters are currently unknown. In the present study, we used a chronic EAE model induced in mice by immunization with the myelin oligodendrocyte glycoprotein peptide (MOG35-55) to compare the effect of EPO given with different treatment schedules. EPO was administered intraperitoneally at 0.5, 5.0 or 50 μg/kg three times weekly starting from day 3 after immunization (preventive schedule), at the onset of clinical disease (therapeutic schedule) or 15 days after the onset of symptoms (late therapeutic schedule). The results show that EPO is effective even when given after the appearance of clinical signs of EAE, but with a reduced efficacy compared to the preventative schedule. To determine whether this effect requires the homodimeric EPO receptor (EPOR2)-mediated hematopoietic effect of EPO, we studied the effect of carbamylated EPO (CEPO) that does not bind EPOR2. CEPO, ameliorated EAE without changing the hemoglobin concentration. Another non-erythropoietic derivative, asialoEPO was also effective. Both EPO and CEPO equivalently decreased the EAE-associated production of TNF-α, IL-1β and IL-1Ra in the spinal cord, and IFN-γ by peripheral lymphocytes, indicating that their action involves targeting neuroinflammation. The lowest dosage tested appeared fully effective. The possibility to dissociate the anti-neuroinflammatory action of EPO from its hematopoietic action, which may cause undesired side effects in non-anemic patients, present new avenues to the therapy of multiple sclerosis.
AB - Erythropoietin (EPO) mediates a wide range of neuroprotective activities, including amelioration of disease and neuroinflammation in rat models of EAE. However, optimum dosing parameters are currently unknown. In the present study, we used a chronic EAE model induced in mice by immunization with the myelin oligodendrocyte glycoprotein peptide (MOG35-55) to compare the effect of EPO given with different treatment schedules. EPO was administered intraperitoneally at 0.5, 5.0 or 50 μg/kg three times weekly starting from day 3 after immunization (preventive schedule), at the onset of clinical disease (therapeutic schedule) or 15 days after the onset of symptoms (late therapeutic schedule). The results show that EPO is effective even when given after the appearance of clinical signs of EAE, but with a reduced efficacy compared to the preventative schedule. To determine whether this effect requires the homodimeric EPO receptor (EPOR2)-mediated hematopoietic effect of EPO, we studied the effect of carbamylated EPO (CEPO) that does not bind EPOR2. CEPO, ameliorated EAE without changing the hemoglobin concentration. Another non-erythropoietic derivative, asialoEPO was also effective. Both EPO and CEPO equivalently decreased the EAE-associated production of TNF-α, IL-1β and IL-1Ra in the spinal cord, and IFN-γ by peripheral lymphocytes, indicating that their action involves targeting neuroinflammation. The lowest dosage tested appeared fully effective. The possibility to dissociate the anti-neuroinflammatory action of EPO from its hematopoietic action, which may cause undesired side effects in non-anemic patients, present new avenues to the therapy of multiple sclerosis.
KW - Asialoerythropoietin
KW - Carbamylated erythropoietin
KW - Cytokine
KW - EAE
KW - Erythropoietin
KW - Inflammation
KW - Multiple sclerosis
KW - Spinal cord
UR - http://www.scopus.com/inward/record.url?scp=33244474401&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33244474401&partnerID=8YFLogxK
U2 - 10.1016/j.jneuroim.2005.10.016
DO - 10.1016/j.jneuroim.2005.10.016
M3 - Article
C2 - 16337691
AN - SCOPUS:33244474401
VL - 172
SP - 27
EP - 37
JO - Journal of Neuroimmunology
JF - Journal of Neuroimmunology
SN - 0165-5728
IS - 1-2
ER -