Failure of Neuroprotection Despite Microglial Suppression by Delayed-Start Myeloperoxidase Inhibition in a Model of Advanced Multiple System Atrophy: Clinical Implications.

Christine Kaindlstorfer,Biljana Georgievska,Gregor K Wenning,Patrick Sommer,Werner Poewe,Robert J Mather,Nadia Stefanova,Alan R Kugler

doi:10.1007/s12640-015-9547-7

Christine Kaindlstorfer, Biljana Georgievska + Show 6 more

Open Access

https://doi.org/10.1007/s12640-015-9547-7

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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.

Highlights

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by progressive autonomic failure, cerebellar ataxia, and parkinsonism due to neuronal loss in respective brain areas (Stefanova et al 2009; Fanciulli and Wenning 2015)
We provide preclinical evidence that MPO inhibition in a model of advanced MSA suppresses microglial activation without significant preservation of neurons in the striatonigral or the olivopontocerebellar regions of the brain and no significant behavioral changes compared to vehicletreated MSA mice
We report significant reduction of nitrated aSYN-positive inclusions in substantia nigra pars compacta (SNc) and striatum but not in the olivopontocerebellar pathway, suggesting that nitrated aSYN accumulation in the MSA mouse brain is not exclusively determined by levels of microglial activation

Summary

Introduction

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by progressive autonomic failure, cerebellar ataxia, and parkinsonism due to neuronal loss in respective brain areas (Stefanova et al 2009; Fanciulli and Wenning 2015). Compared to idiopathic Parkinson’s disease (PD), it progresses more rapidly due to failure of levodopa benefit (Krismer et al 2014). The lack of treatment options aiming to modify the underlying pathophysiology and the rapid deterioration of disease determine a major need for developing disease modification strategies. The underlying pathomechanisms of MSA are poorly understood, but the core feature of MSA pathology, i.e., abundant aggregates of a-synuclein (aSYN) within oligodendrocytes— referred to as glial cytoplasmic inclusions (GCIs)—led to the idea that MSA is a primary

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