Nonhematopoietic erythropoietin derivatives prevent motoneuron degeneration in vitro and in vivo.
Chronic treatment with asialo erythropoietin (ASIALO-EPO) or carbamylated erythropoietin (CEPO) improved motor behavior and reduced motoneuron loss and astrocyte and microglia activation in the cervical spinal cord of wobbler mice, an animal model of amyotrophic lateral sclerosis, but had no effect on hematocrit values. ASIALO-EPO and CEPO, like the parent compound EPO, protected primary motoneuron cultures from kainate-induced death in vitro. Both EPO receptor and the common CD131 beta chain were expressed in cultured motoneurons and in the anterior horn of wobbler mice spinal cord. Our results strongly support a role for the common beta chain CD131 in the protective effect of EPO derivatives on motoneuron degeneration. Thus CEPO, which does not bind to the classical homodimeric EPO receptor and is devoid of hematopoietic activity, could be effective in chronic treatment aimed at reducing motoneuron degeneration.
Mennini
Tiziana
T
Department of Molecular Biochemistry and Pharmacology, Mario Negri Institute for Pharmacological Research, Milan, Italy.
De Paola
Massimiliano
M
Bigini
Paolo
P
Mastrotto
Cristina
C
Fumagalli
Elena
E
Barbera
Sara
S
Mengozzi
Manuela
M
Viviani
Barbara
B
Corsini
Emanuela
E
Marinovich
Marina
M
Torup
Lars
L
Van Beek
Johan
J
Leist
Marcel
M
Brines
Michael
M
Cerami
Antony
A
Ghezzi
Pietro
P
D000818:Animals; D001212:Asialoglycoproteins / Q000494:pharmacology*; D001522:Behavior, Animal; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053648:Cytokine Receptor Common beta Subunit / Q000378:metabolism; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006410:Hematopoiesis; D006801:Humans; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D008818:Mice, Neurologic Mutants; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000473:pathology*; D009410:Nerve Degeneration / Q000517:prevention & control*; D009414:Nerve Growth Factors / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology / Q000473:pathology
D001212:Asialoglycoproteins; D053648:Cytokine Receptor Common beta Subunit; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; C500605:asialoerythropoietin; C488171:carbamylated erythropoietin; D004921:Erythropoietin; D007608:Kainic Acid