title: Failure of Neuroprotection Despite Microglial Suppression by Delayed-Start Myeloperoxidase Inhibition in a Model of Advanced Multiple System Atrophy: Clinical Implications.
abstract: Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease. Post-mortem hallmarks of MSA neuropathology include oligodendroglial α-synuclein (αSYN) inclusions, striatonigral degeneration, olivopontocerebellar atrophy, and increased microglial activation that accompanies the wide spread neurodegeneration. Recently, we demonstrated upregulation of myeloperoxidase (MPO) in activated microglia and provided evidence for the role of microglial MPO in the mediation of MSA-like neurodegeneration (Stefanova et al. Neurotox Res 21:393-404, 2015). The aim of the current study was to assess the therapeutic potency of MPO inhibition (MPOi) in a model of advanced MSA. We replicated the advanced pathology of MSA by intoxicating transgenic PLP-α-synuclein transgenic mice with 3-nitropropionic acid (3NP). After onset of the full-blown pathology, MSA mice received either MPOi or vehicle over 3 weeks. Motor phenotype and neuropathology were analyzed to assess the therapeutic efficacy of MPOi compared to vehicle treatment in MSA mice. MPOi therapy initiated after the onset of severe MSA-like neuropathology in mice failed to attenuate motor impairments and neuronal loss within the striatum, substantia nigra pars compacta, inferior olives, pontine nuclei, and cerebellar cortex. However, we observed a significant reduction of microglial activation in degenerating brain areas. Further, nitrated αSYN accumulation was reduced in the striatonigral region. In summary, delayed-start MPOi treatment reduced microglial activation and levels of nitrated αSYN in a mouse model of advanced MSA. These effects failed to impact on motor impairments and neuronal loss in contrast to previously reported disease modifying efficacy of early-start therapy with MPOi in MSA.
authors.affiliation: Department of Neurology, Innsbruck Medical University, Anichstraße 35, 6020, Innsbruck, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Kaindlstorfer
authors.forename: Patrick
authors.initials: P
authors.lastname: Sommer
authors.forename: Biljana
authors.initials: B
authors.lastname: Georgievska
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mather
authors.forename: Alan R
authors.initials: AR
authors.lastname: Kugler
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.forename: Gregor K
authors.initials: GK
authors.lastname: Wenning
authors.forename: Nadia
authors.initials: N
authors.lastname: Stefanova
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D019578:Multiple System Atrophy / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009574:Nitro Compounds; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011422:Propionates; D011744:Pyrimidinones / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: C000602652:AZD3241; D004791:Enzyme Inhibitors; D018991:Myelin Proteolipid Protein; D018696:Neuroprotective Agents; D009574:Nitro Compounds; C047516:Plp1 protein, mouse; D011422:Propionates; D011744:Pyrimidinones; D011758:Pyrroles; C497604:SNCA protein, human; D051844:alpha-Synuclein; D009195:Peroxidase; C015392:3-nitropropionic acid