title: Delayed administration of erythropoietin and its non-erythropoietic derivatives ameliorates chronic murine autoimmune encephalomyelitis.
abstract: 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 microg/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-alpha, IL-1beta and IL-1Ra in the spinal cord, and IFN-gamma 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.
authors.affiliation: Mario Negri Institute for Pharmacological Research, 20157, Milan, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Savino
authors.forename: Rosetta
authors.initials: R
authors.lastname: Pedotti
authors.forename: Fulvio
authors.initials: F
authors.lastname: Baggi
authors.forename: Federica
authors.initials: F
authors.lastname: Ubiali
authors.forename: Barbara
authors.initials: B
authors.lastname: Gallo
authors.forename: Sara
authors.initials: S
authors.lastname: Nava
authors.forename: Paolo
authors.initials: P
authors.lastname: Bigini
authors.forename: Sara
authors.initials: S
authors.lastname: Barbera
authors.forename: Elena
authors.initials: E
authors.lastname: Fumagalli
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
authors.forename: Annamaria
authors.initials: A
authors.lastname: Vezzani
authors.forename: Massimo
authors.initials: M
authors.lastname: Rizzi
authors.forename: Thomas
authors.initials: T
authors.lastname: Coleman
authors.forename: Anthony
authors.initials: A
authors.lastname: Cerami
authors.forename: Michael
authors.initials: M
authors.lastname: Brines
authors.forename: Pietro
authors.initials: P
authors.lastname: Ghezzi
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianchi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control*; D004921:Erythropoietin / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D005260:Female; D006023:Glycoproteins; D006400:Hematocrit / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010446:Peptide Fragments; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000187:drug effects; D013154:Spleen / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C488171:carbamylated erythropoietin; C445081:myelin oligodendrocyte glycoprotein (35-55); D004921:Erythropoietin