title: Erythropoietin is neuroprotective in a transgenic mouse model of multiple system atrophy.
abstract: Multiple system atrophy is a rapidly progressive neurodegenerative disorder with a markedly reduced life expectancy. Failure of symptomatic treatment raises an urgent need for disease-modifying strategies. We have investigated the neuroprotective potential of erythropoietin in (proteolipid protein)-α-synuclein transgenic mice exposed to 3-nitropropionic acid featuring multiple system atrophy-like pathology including oligodendroglial α-synuclein inclusions and selective neuronal degeneration. Mice were treated with erythropoietin starting before (early erythropoietin) and after (late erythropoietin) intoxication with 3-nitropropionic acid. Nonintoxicated animals receiving erythropoietin and intoxicated animals treated with saline served as control groups. Behavioral tests included pole test, open field activity, and motor behavior scale. Immunohistochemistry for tyrosine hydroxylase and dopamine and cyclic adenosine monophosphate-regulated phosphoprotein (DARPP-32) was analyzed stereologically. Animals receiving erythropoietin before and after 3-nitropropionic acid intoxication scored significantly lower on the motor behavior scale and they performed better in the pole test than controls with no significant difference between early and late erythropoietin administration. Similarly, rearing scores were worse in 3-nitropropionic acid-treated animals with no difference between the erythropoietin subgroups. Immunohistochemistry revealed significant attenuation of 3-nitropropionic acid-induced loss of tyrosine hydroxylase and DARPP-32 positive neurons in substantia nigra pars compacta and striatum, respectively, in both erythropoietin-treated groups without significant group difference in the substantia nigra. However, at striatal level, a significant difference between early and late erythropoietin administration was observed. In the combined (proteolipid protein)-α-synuclein 3-nitropropionic acid multiple system atrophy mouse model, erythropoietin appears to rescue dopaminergic and striatal gabaergic projection neurons. This effect is associated with improved motor function. Further studies are warranted to develop erythropoietin as a potential interventional therapy in multiple system atrophy.
authors.affiliation: Division of Clinical Neurobiology, Department of Neurology, Medical University, Innsbruck, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Köllensperger
authors.affiliation: Division of Clinical Neurobiology, Department of Neurology, Medical University, Innsbruck, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Krismer
authors.affiliation: Division of Clinical Neurobiology, Department of Neurology, Medical University, Innsbruck, Austria.
authors.forename: Anton
authors.initials: A
authors.lastname: Pallua
authors.affiliation: Division of Clinical Neurobiology, Department of Neurology, Medical University, Innsbruck, Austria.
authors.forename: Nadia
authors.initials: N
authors.lastname: Stefanova
authors.affiliation: Division of Clinical Neurobiology, Department of Neurology, Medical University, Innsbruck, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.affiliation: Division of Clinical Neurobiology, Department of Neurology, Medical University, Innsbruck, Austria.
authors.forename: Gregor K
authors.initials: GK
authors.lastname: Wenning
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003292:Convulsants / Q000633:toxicity; D003342:Corpus Striatum / Q000473:pathology; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004334:Drug Administration Schedule; D004921:Erythropoietin / Q000627:therapeutic use*; D005106:Exploratory Behavior / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D019578:Multiple System Atrophy / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D018991:Myelin Proteolipid Protein / Q000235:genetics; D009574:Nitro Compounds / Q000633:toxicity; D011422:Propionates / Q000633:toxicity; D013378:Substantia Nigra / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics
chemical_list: D003292:Convulsants; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018991:Myelin Proteolipid Protein; D009574:Nitro Compounds; D011422:Propionates; D051844:alpha-Synuclein; D004921:Erythropoietin; D014446:Tyrosine 3-Monooxygenase; C015392:3-nitropropionic acid