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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

DARPP32-positive medium spiny neurons of the striatum of MSA + vehicle (n = 9) (a) and MSA + MPOi group (n = 7) (b). There was no significant effect of AZD3241 treatment on the number of striatal DARPP32 positive neurons in MSA mice (c). TH-positive dopaminergic neurons in SNc of MSA + vehicle (n = 14) (d) and MSA + MPOi group (n = 13) (e). MPOi treatment showed no significant neuroprotective effect on nigral TH neurons in MSA mice (f). Further, no neuroprotective efficacy of MPOi could be registered in the inferior olives (nvehicle = 6, nMPOi = 6) (g), the pontine nuclei (nvehicle = 5, nMPOi = 7) (h), and the Purkinje cells in the cerebellar cortex (nvehicle = 6, nMPOi = 8) (i). Data are presented as mean ± SEM
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Fig2: DARPP32-positive medium spiny neurons of the striatum of MSA + vehicle (n = 9) (a) and MSA + MPOi group (n = 7) (b). There was no significant effect of AZD3241 treatment on the number of striatal DARPP32 positive neurons in MSA mice (c). TH-positive dopaminergic neurons in SNc of MSA + vehicle (n = 14) (d) and MSA + MPOi group (n = 13) (e). MPOi treatment showed no significant neuroprotective effect on nigral TH neurons in MSA mice (f). Further, no neuroprotective efficacy of MPOi could be registered in the inferior olives (nvehicle = 6, nMPOi = 6) (g), the pontine nuclei (nvehicle = 5, nMPOi = 7) (h), and the Purkinje cells in the cerebellar cortex (nvehicle = 6, nMPOi = 8) (i). Data are presented as mean ± SEM

Mentions: To assess the efficacy of MPOi treatment in a model of advanced MSA, we measured neuronal numbers in SNc, striatum, pontine nuclei, inferior olives, and cerebellar cortex (Purkinje cells). Neuronal numbers remained unaffected by the MPOi treatment compared to vehicle in all studied regions (Fig. 2). However, a strong biological effect of the MPOI treatment was detected on microglial activation being significantly reduced in SNc (p = 0.027), pontine nuclei (p = 0.0018), inferior olives (p = 0.02), and corpus callosum (p = 0.0056). There was significant correlation between the levels of microglial activation and the number of nigral neurons (R2 = 0.1686, p = 0.0334). Although there was a numerical decrease in the ROD of microglial activation in the striatum after MPOi treatment (MSA + vehicle, 0.14 ± 0.018 vs. MSA + MPOi, 0.11 ± 0.012), the difference to vehicle-treated mice did not reach statistical significance (p = 0.1632) (Fig. 3). Furthermore, the treatment with MPOi resulted in significantly reduced density of nitrated αSYN inclusions compared to vehicle-treated MSA mice in SNc (p = 0.0022) and striatum (p = 0.016) but not in the inferior olives (p = 0.47), pontine nuclei (p = 0.53), or the cerebellar cortex (p = 0.55) (Fig. 4).Fig. 2


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)

DARPP32-positive medium spiny neurons of the striatum of MSA + vehicle (n = 9) (a) and MSA + MPOi group (n = 7) (b). There was no significant effect of AZD3241 treatment on the number of striatal DARPP32 positive neurons in MSA mice (c). TH-positive dopaminergic neurons in SNc of MSA + vehicle (n = 14) (d) and MSA + MPOi group (n = 13) (e). MPOi treatment showed no significant neuroprotective effect on nigral TH neurons in MSA mice (f). Further, no neuroprotective efficacy of MPOi could be registered in the inferior olives (nvehicle = 6, nMPOi = 6) (g), the pontine nuclei (nvehicle = 5, nMPOi = 7) (h), and the Purkinje cells in the cerebellar cortex (nvehicle = 6, nMPOi = 8) (i). Data are presented as mean ± SEM
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Fig2: DARPP32-positive medium spiny neurons of the striatum of MSA + vehicle (n = 9) (a) and MSA + MPOi group (n = 7) (b). There was no significant effect of AZD3241 treatment on the number of striatal DARPP32 positive neurons in MSA mice (c). TH-positive dopaminergic neurons in SNc of MSA + vehicle (n = 14) (d) and MSA + MPOi group (n = 13) (e). MPOi treatment showed no significant neuroprotective effect on nigral TH neurons in MSA mice (f). Further, no neuroprotective efficacy of MPOi could be registered in the inferior olives (nvehicle = 6, nMPOi = 6) (g), the pontine nuclei (nvehicle = 5, nMPOi = 7) (h), and the Purkinje cells in the cerebellar cortex (nvehicle = 6, nMPOi = 8) (i). Data are presented as mean ± SEM
Mentions: To assess the efficacy of MPOi treatment in a model of advanced MSA, we measured neuronal numbers in SNc, striatum, pontine nuclei, inferior olives, and cerebellar cortex (Purkinje cells). Neuronal numbers remained unaffected by the MPOi treatment compared to vehicle in all studied regions (Fig. 2). However, a strong biological effect of the MPOI treatment was detected on microglial activation being significantly reduced in SNc (p = 0.027), pontine nuclei (p = 0.0018), inferior olives (p = 0.02), and corpus callosum (p = 0.0056). There was significant correlation between the levels of microglial activation and the number of nigral neurons (R2 = 0.1686, p = 0.0334). Although there was a numerical decrease in the ROD of microglial activation in the striatum after MPOi treatment (MSA + vehicle, 0.14 ± 0.018 vs. MSA + MPOi, 0.11 ± 0.012), the difference to vehicle-treated mice did not reach statistical significance (p = 0.1632) (Fig. 3). Furthermore, the treatment with MPOi resulted in significantly reduced density of nitrated αSYN inclusions compared to vehicle-treated MSA mice in SNc (p = 0.0022) and striatum (p = 0.016) but not in the inferior olives (p = 0.47), pontine nuclei (p = 0.53), or the cerebellar cortex (p = 0.55) (Fig. 4).Fig. 2

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