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

Kaindlstorfer C, Sommer P, Georgievska B, Mather RJ, Kugler AR, Poewe W, Wenning GK, Stefanova N - Neurotox Res (2015)

Bottom Line: However, we observed a significant reduction of microglial activation in degenerating brain areas.Further, nitrated αSYN accumulation was reduced in the striatonigral region.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Innsbruck Medical University, Anichstraße 35, 6020, Innsbruck, Austria.

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.

No MeSH data available.


Related in: MedlinePlus

a The daily clinical motor score served to evaluate the time course of the motor impairment induced by 3NP treatment (day 1–day 8) and its course over the treatment period with AZD3241 or vehicle (day 9–day 30). b Mean clinical motor score per group over the total experimental time indicated lack of effect of AZD3241 treatment (MPOi) on the general motor disability in MSA mice. c Stride length was not changed under MPOi treatment of MSA mice compared to vehicle-treated ones. d, e Rearing and horizontal open field activities were not affected by the MPOi treatment of MSA mice compared to vehicle-treated MSA mice. Data are presented as mean ± SEM. MSA + vehicle group, n = 15, MSA + MPOi group, n = 14
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Fig1: a The daily clinical motor score served to evaluate the time course of the motor impairment induced by 3NP treatment (day 1–day 8) and its course over the treatment period with AZD3241 or vehicle (day 9–day 30). b Mean clinical motor score per group over the total experimental time indicated lack of effect of AZD3241 treatment (MPOi) on the general motor disability in MSA mice. c Stride length was not changed under MPOi treatment of MSA mice compared to vehicle-treated ones. d, e Rearing and horizontal open field activities were not affected by the MPOi treatment of MSA mice compared to vehicle-treated MSA mice. Data are presented as mean ± SEM. MSA + vehicle group, n = 15, MSA + MPOi group, n = 14

Mentions: Daily evaluation of CMS following 3NP intoxication showed progressive impairment in all animals within the first 8 days of the experiment followed by a period of disability over the next 3 weeks (effect of time: F(3,1) = 143; p < 0.001). After day 9, when the drug treatment was initiated, the disability showed similar severity and temporal evolution in both MPOi and vehicle-treated MSA mice (effect of treatment: F(1,3) = 2.05; p > 0.05). After 20 consecutive days of treatment with MPOi, no significant treatment effect associated with MPOi therapy could be detected (Fig. 1a, b). A similar lack of effect of MPOi on motor performance as determined by stride length (Fig. 1c) and open field activity (Fig. 1d, e) was evident at the end of the treatment period.Fig. 1


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

Kaindlstorfer C, Sommer P, Georgievska B, Mather RJ, Kugler AR, Poewe W, Wenning GK, Stefanova N - Neurotox Res (2015)

a The daily clinical motor score served to evaluate the time course of the motor impairment induced by 3NP treatment (day 1–day 8) and its course over the treatment period with AZD3241 or vehicle (day 9–day 30). b Mean clinical motor score per group over the total experimental time indicated lack of effect of AZD3241 treatment (MPOi) on the general motor disability in MSA mice. c Stride length was not changed under MPOi treatment of MSA mice compared to vehicle-treated ones. d, e Rearing and horizontal open field activities were not affected by the MPOi treatment of MSA mice compared to vehicle-treated MSA mice. Data are presented as mean ± SEM. MSA + vehicle group, n = 15, MSA + MPOi group, n = 14
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556742&req=5

Fig1: a The daily clinical motor score served to evaluate the time course of the motor impairment induced by 3NP treatment (day 1–day 8) and its course over the treatment period with AZD3241 or vehicle (day 9–day 30). b Mean clinical motor score per group over the total experimental time indicated lack of effect of AZD3241 treatment (MPOi) on the general motor disability in MSA mice. c Stride length was not changed under MPOi treatment of MSA mice compared to vehicle-treated ones. d, e Rearing and horizontal open field activities were not affected by the MPOi treatment of MSA mice compared to vehicle-treated MSA mice. Data are presented as mean ± SEM. MSA + vehicle group, n = 15, MSA + MPOi group, n = 14
Mentions: Daily evaluation of CMS following 3NP intoxication showed progressive impairment in all animals within the first 8 days of the experiment followed by a period of disability over the next 3 weeks (effect of time: F(3,1) = 143; p < 0.001). After day 9, when the drug treatment was initiated, the disability showed similar severity and temporal evolution in both MPOi and vehicle-treated MSA mice (effect of treatment: F(1,3) = 2.05; p > 0.05). After 20 consecutive days of treatment with MPOi, no significant treatment effect associated with MPOi therapy could be detected (Fig. 1a, b). A similar lack of effect of MPOi on motor performance as determined by stride length (Fig. 1c) and open field activity (Fig. 1d, e) was evident at the end of the treatment period.Fig. 1

Bottom Line: However, we observed a significant reduction of microglial activation in degenerating brain areas.Further, nitrated αSYN accumulation was reduced in the striatonigral region.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Innsbruck Medical University, Anichstraße 35, 6020, Innsbruck, Austria.

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.

No MeSH data available.


Related in: MedlinePlus