Nonhematopoietic Erythropoietin Derivatives Prevent Motoneuron Degeneration In Vitro and In Vivo

Tiziana Mennini,Pietro Ghezzi,Barbara Viviani,Sara Barbera,Marcel Leist,Michael Brines,Marina Marinovich,Cristina Mastrotto,Elena Fumagalli,Massimiliano De Paola,Lars Torup,Emanuela Corsini,Paolo Bigini,Antony Cerami,Manuela Mengozzi,Johan Van Beek

doi:10.2119/2006-00045.mennini

Abstract

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a degenerative disease of the upper and lower motoneurons leading to progressive motor dysfunction and death within 3 to 5 years from diagnosis [1]
The wobbler mouse, carrying a mutation of Vps54 [18], is considered one of the most useful models for human motoneuron degenerative diseases, such as ALS and infantile spinal muscular atrophy (ISMA); unlike the transgenic mice carrying the human mutated form of SOD1, disease in the wobbler mouse is unrelated to the mutation responsible for a small proportion of the familial cases [22]
An advantage of wobbler mice over the transgenic SOD1 mice is that, in the wobbler mice, the disease has an early onset and rapid progression [17], allowing shorter treatments that can minimize the production of antibodies using human recombinant proteins

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a degenerative disease of the upper and lower motoneurons leading to progressive motor dysfunction and death within 3 to 5 years from diagnosis [1]. Its mechanism of action is not completely understood: in addition to its anti-apoptotic effect [6] EPO inhibits CNS inflammation [4,8], enhances neurogenesis in animal models of stroke and EAE [9,10], and augments BDNF expression in vivo and in vitro [9,11]. We have previously reported that in vitro EPO protects cultured motoneurons from serum-BDNF deprivation or longterm kainate exposure [6]. The latter is a model of chronic excitotoxicity, used for in vitro studies because motoneurons are selectively vulnerable to activation of the AMPA receptor [12]

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Conclusion