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Gregor K Wenning - One of the best experts on this subject based on the ideXlab platform.
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l dopa response pattern in a rat model of mild Striatonigral Degeneration
PLOS ONE, 2019Co-Authors: Christine Kaindlstorfer, Kurt A. Jellinger, Nadia Stefanova, Joanna Garcia, Florian Krismer, Máté D. Döbrössy, Georg Göbel, Roberta Granata, Gregor K WenningAbstract:Background Unresponsiveness to dopaminergic therapies is a key feature in the diagnosis of multiple system atrophy (MSA) and a major unmet need in the treatment of MSA patients caused by combined Striatonigral Degeneration (SND). Transgenic, alpha-synuclein animal models do not recapitulate this lack of levodopa responsiveness. In order to preclinically study interventions including striatal cell grafts, models that feature SND are required. Most of the previous studies focused on extensive nigral and striatal lesions corresponding to advanced MSA-P/SND. The aim of the current study was to replicate mild stage MSA-P/SND with L-dopa failure. Methods and results Two different striatal quinolinic acid (QA) lesions following a striatal 6-OHDA lesion replicating mild and severe MSA-P/SND, respectively, were investigated and compared to 6-OHDA lesioned animals. After the initial 6-OHDA lesion there was a significant improvement of motor performance after dopaminergic stimulation in the cylinder and stepping test (p<0.001). Response to L-dopa treatment declined in both MSA-P/SND groups reflecting striatal damage of lateral motor areas in contrast to the 6-OHDA only lesioned animals (p<0.01). The remaining striatal volume correlated strongly with contralateral apomorphine induced rotation behaviour and contralateral paw use during L-dopa treatment in cylinder and stepping test (p<0.001). Conclusion Our novel L-dopa response data suggest that L-dopa failure can be induced by restricted lateral striatal lesions combined with dopaminergic denervation. We propose that this sequential striatal double-lesion model replicates a mild stage of MSA-P/SND and is suitable to address neuro-regenerative therapies aimed at restoring dopaminergic responsiveness.
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L-dopa response pattern in a rat model of mild Striatonigral Degeneration.
PloS one, 2019Co-Authors: Christine Kaindlstorfer, Kurt A. Jellinger, Nadia Stefanova, Joanna Garcia, Florian Krismer, Máté D. Döbrössy, Georg Göbel, Roberta Granata, Gregor K WenningAbstract:Background Unresponsiveness to dopaminergic therapies is a key feature in the diagnosis of multiple system atrophy (MSA) and a major unmet need in the treatment of MSA patients caused by combined Striatonigral Degeneration (SND). Transgenic, alpha-synuclein animal models do not recapitulate this lack of levodopa responsiveness. In order to preclinically study interventions including striatal cell grafts, models that feature SND are required. Most of the previous studies focused on extensive nigral and striatal lesions corresponding to advanced MSA-P/SND. The aim of the current study was to replicate mild stage MSA-P/SND with L-dopa failure. Methods and results Two different striatal quinolinic acid (QA) lesions following a striatal 6-OHDA lesion replicating mild and severe MSA-P/SND, respectively, were investigated and compared to 6-OHDA lesioned animals. After the initial 6-OHDA lesion there was a significant improvement of motor performance after dopaminergic stimulation in the cylinder and stepping test (p
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riluzole improves motor deficits and attenuates loss of striatal neurons in a sequential double lesion rat model of Striatonigral Degeneration parkinson variant of multiple system atrophy
Journal of Neural Transmission, 2005Co-Authors: Christoph Scherfler, Elsa Diguet, Zoe Puschban, François Tison, Nadia Stefanova, T. Sather, W. Poewe, Gregor K WenningAbstract:We investigated neuroprotective effects of riluzole, an anti-glutamatergic agent that is FDA approved for disease-modifying therapy in amyotrophic lateral sclerosis (ALS), in an established double lesion rat model of Striatonigral Degeneration (SND), the neuropathological substrate of parkinsonism associated with MSA (MSA-P). Riluzole was administered prior to and consecutively for ten days following double lesion placement in the left-sided medial forebrain bundle and ipsilateral striatum. Assessment of motor behaviour using a flex field system showed a significant reduction of motor disturbance in animals with Striatonigral lesions treated with riluzole compared to lesioned but untreated animals (P<0.001). DARPP-32 immunohistochemistry revealed a significant reduction of absolute striatal lesion volume in riluzole treated animals compared to lesioned but untreated animals (P<0.01). No significant difference in counts of nigral dopaminergic neurons was found in treated versus untreated double-lesioned animals. The results of our study indicate that riluzole mediates neuroprotective effects in the double lesion rat model of MSA-P. Whether riluzole also protects autonomic and cerebellar pathways that are frequently affected in MSA remains to be determined. Nonetheless, our study is the first to provide an experimental rationale for exploring possible neuroprotective effects of riluzole in MSA.
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Failure of caspase inhibition in the double-lesion rat model of Striatonigral Degeneration (multiple system atrophy)
ACTA NEUROPATHOL, 2005Co-Authors: Gregor K WenningAbstract:In the present study we assessed the neuroprotective effects of the pan-caspase inhibitor z-VAD.fmk [N-benzyloxycarbony-valine-alanine-aspartate-(OMe)-fluoromethylketone], and the caspase-3 inhibitor Ac-DEVD.CHO (acetyl-aspartate-chloromethylketone) in the double-lesion rat model of Striatonigral Degeneration (SND), the core pathology underlying levodopa-unresponsive parkinsonism associated with multiple system atrophy (MSA). Male Wistar rats were divided into three groups, receiving either Ac-DEVD.CHO, z-VAD.fmk or normal saline before lesion surgery, comprising a sequential unilateral quinolinic acid (QA) lesion of the striatum followed by a 6-hydroxydopamine (6-OHDA) lesion of the ipsilateral medial forebrain bundle. At 2 weeks post lesion, all rats underwent testing of spontaneous nocturnal locomotor behavior in an automated Photobeam Activity System (FlexField). Immunohistochemistry was performed with tyrosine hydroxylase, dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein and glial fibrillary acidic protein antibodies. Morphometry was performed using computerized image analysis. Behavioral and morphological analysis failed to show striatal or nigral protection in caspase inhibitor-treated animals. Our findings suggest that anti-apoptotic strategies are unrewarding in the SND rat model and, therefore, alternative neuroprotective interventions such as anti-glutamatergic agents or inhibitors of microglial activation should be explored instead.
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Failure of neuronal protection by inhibition of glial activation in a rat model of Striatonigral Degeneration.
Journal of neuroscience research, 2004Co-Authors: Nadia Stefanova, Elsa Diguet, François Tison, Werner Poewe, Imad Ghorayeb, Monika Mitschnigg, Felix Geser, Gregor K WenningAbstract:Previous studies in rodent models of neurodegenerative disorders have demonstrated that minocycline exerts neuroprotective effects unrelated to its antimicrobial action. The purpose of the present study was to analyze whether minocycline exhibits neuroprotective activity in a rat model of Striatonigral Degeneration (SND), the core pathology underlying levodopa-unresponsive parkinsonism associated with multiple system atrophy (MSA). We observed no significant effect of minocycline on locomotor impairment in double-lesioned SND rats. Minocycline significantly suppressed astroglial and microglial activation (P < 0.01); however, 3'5'-monophosphate-regulated phosphoprotein (DARPP 32) immunohistochemistry revealed no significant differences in striatal lesion volume of minocycline-treated versus untreated control SND rats. Furthermore, there was no protection of nigral dopaminergic neurons in the double-lesion model. We conclude that despite its astrocytic and microglial suppression, minocycline failed to attenuate lesion-induced neuronal damage in the SND rat model.
François Tison - One of the best experts on this subject based on the ideXlab platform.
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riluzole improves motor deficits and attenuates loss of striatal neurons in a sequential double lesion rat model of Striatonigral Degeneration parkinson variant of multiple system atrophy
Journal of Neural Transmission, 2005Co-Authors: Christoph Scherfler, Elsa Diguet, Zoe Puschban, François Tison, Nadia Stefanova, T. Sather, W. Poewe, Gregor K WenningAbstract:We investigated neuroprotective effects of riluzole, an anti-glutamatergic agent that is FDA approved for disease-modifying therapy in amyotrophic lateral sclerosis (ALS), in an established double lesion rat model of Striatonigral Degeneration (SND), the neuropathological substrate of parkinsonism associated with MSA (MSA-P). Riluzole was administered prior to and consecutively for ten days following double lesion placement in the left-sided medial forebrain bundle and ipsilateral striatum. Assessment of motor behaviour using a flex field system showed a significant reduction of motor disturbance in animals with Striatonigral lesions treated with riluzole compared to lesioned but untreated animals (P<0.001). DARPP-32 immunohistochemistry revealed a significant reduction of absolute striatal lesion volume in riluzole treated animals compared to lesioned but untreated animals (P<0.01). No significant difference in counts of nigral dopaminergic neurons was found in treated versus untreated double-lesioned animals. The results of our study indicate that riluzole mediates neuroprotective effects in the double lesion rat model of MSA-P. Whether riluzole also protects autonomic and cerebellar pathways that are frequently affected in MSA remains to be determined. Nonetheless, our study is the first to provide an experimental rationale for exploring possible neuroprotective effects of riluzole in MSA.
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Failure of neuronal protection by inhibition of glial activation in a rat model of Striatonigral Degeneration.
Journal of neuroscience research, 2004Co-Authors: Nadia Stefanova, Elsa Diguet, François Tison, Werner Poewe, Imad Ghorayeb, Monika Mitschnigg, Felix Geser, Gregor K WenningAbstract:Previous studies in rodent models of neurodegenerative disorders have demonstrated that minocycline exerts neuroprotective effects unrelated to its antimicrobial action. The purpose of the present study was to analyze whether minocycline exhibits neuroprotective activity in a rat model of Striatonigral Degeneration (SND), the core pathology underlying levodopa-unresponsive parkinsonism associated with multiple system atrophy (MSA). We observed no significant effect of minocycline on locomotor impairment in double-lesioned SND rats. Minocycline significantly suppressed astroglial and microglial activation (P < 0.01); however, 3'5'-monophosphate-regulated phosphoprotein (DARPP 32) immunohistochemistry revealed no significant differences in striatal lesion volume of minocycline-treated versus untreated control SND rats. Furthermore, there was no protection of nigral dopaminergic neurons in the double-lesion model. We conclude that despite its astrocytic and microglial suppression, minocycline failed to attenuate lesion-induced neuronal damage in the SND rat model.
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mptp potentiates 3 nitropropionic acid induced striatal damage in mice reference to Striatonigral Degeneration
Experimental Neurology, 2004Co-Authors: Pierre-olivier Fernagut, Elsa Diguet, Bernard Bioulac, François TisonAbstract:Striatonigral Degeneration (SND) is a parkinsonian disorder due to the combined Degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and striatal output neurons. The aims of this study were to explore (1) the behavioral and histopathological consequences of combined MPTP plus 3-nitropropionic acid (3-NP) intoxication in C57/Bl6 mice and (2) its ability to reproduce the neuropathological hallmarks of SND. 3-NP was administered i.p. every 12 h (total dose = 450 mg/kg in 9 days) and MPTP i.p. at 10 mg/(kg day) (total dose = 90 mg/kg in 9 days). Four groups of mice (n = 10) were compared: control, 3-NP alone, MPTP alone, MPTP + 3-NP. Mice intoxicated with 3-NP and MPTP + 3-NP developed motor symptoms, including hindlimb dystonia and clasping, truncal dystonia and impaired balance adjustments. The severity of motor disorder was worse and lasted longer in MPTP + 3-NP-treated mice compared to 3-NP alone, MPTP alone and controls. 3-NP and MPTP + 3-NP-treated mice also displayed altered gait patterns, impaired motor performance on the pole test, rotarod and traversing a beam tasks and activity parameters. Several of these sensorimotor deficits were also more severe and lasted longer in MPTP + 3-NP-treated mice. Histology demonstrated increased neuronal loss along with astrocytic activation (glial fibrillary acid protein, GFAP) and a higher incidence of circumscribed striatal lateral lesions in MPTP + 3-NP-treated mice compared to 3-NP. Neuronal loss and astrocytic activation were increased in the lateral part of the striatum in 3-NP-intoxicated mice while observed both in the medial and lateral part in MPTP + 3-NP-intoxicated mice. There was also a significant loss of SNc dopaminergic neurons and striatal terminals, similar to that in MPTP-treated mice. Altogether, these results suggest that MPTP potentiates striatal damage and behavioral impairments induced by 3-NP intoxication in mice and constitutes a useful model of the motor disorder and its histopathological correlates in SND.
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Effects of pulsatile L-DOPA treatment in the double lesion rat model of Striatonigral Degeneration (multiple system atrophy)
Neurobiology of disease, 2004Co-Authors: Nadia Stefanova, François Tison, W. Poewe, Martin Lundblad, M. A. Cenci, Gregor K WenningAbstract:We examined the role of a striatal lesion in the development of L-DOPA-induced abnormal involuntary movements (AIMs) using the double lesion rat model of Striatonigral Degeneration (SND), the underlying neuropathological substrate of parkinsonism associated with multiple system atrophy (MSA-P), in comparison to a Parkinson's disease (PD) rat model. L-DOPA administration reliably induced AIMs in SND and PD rats in a dose-dependent fashion. AIMs occurred significantly earlier in SND compared to PD rats. There was a mild, but significant, transient increase of orolingual AIMs during the first week of low-dose L-DOPA treatment in SND. Whereas L-DOPA significantly improved contralateral forelimb akinesia in PD rats, there was no beneficial effect in SND rats. Striatal FosB/Delta FosB up-regulation in SND and PD rats correlated with the severity of L-DOPA-induced dyskinesias. Pulsatile L-DOPA administration in the double lesion SND rat model replicates salient features of the human disease MSA-P, including loss of the anti-akinetic L-DOPA response and induction of dyskinesias with transient orolingual predominance.
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Neuropathological and behavioral changes induced by various treatment paradigms with MPTP and 3-nitropropionic acid in mice: towards a model of Striatonigral Degeneration (multiple system atrophy)
Acta neuropathologica, 2003Co-Authors: Nadia Stefanova, Pierre-olivier Fernagut, Zoe Puschban, Kurt A. Jellinger, François Tison, Werner Poewe, Emmanuel Brouillet, Markus Reindl, Gregor K WenningAbstract:We characterized two models of dual nigral and striatal lesions replicating the lesion pattern of Striatonigral Degeneration, the neuropathological hallmark of parkinsonism associated with multiple system atrophy (SND/MSA-P). For this purpose, we used systemic administration of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3-NP) in C57BL mice. One group of animals was first injected with MPTP followed by 3NP (MPTP+3-NP model). In the second group 3-NP was injected first, followed by MPTP (3-NP+MPTP model). The behavioral and neuropathological characteristics of these two models were compared to those observed after single 3-NP or MPTP intoxication. Results showed that, compared to control mice, spontaneous nocturnal locomotor activity was preserved in the MPTP+3-NP model, whereas it was reduced by 27% ( P
Werner Poewe - One of the best experts on this subject based on the ideXlab platform.
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Progressive Striatonigral Degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies
Acta Neuropathologica Communications, 2018Co-Authors: Violetta Refolo, Francesco Bez, Daniela Kuzdas-wood, Edith Sturm, Martina Kamaratou, M. Angela Cenci, Leonidas Stefanis, Werner Poewe, Alexia Polissidis, Marina Romero-ramosAbstract:Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective vulnerability and disease progression in the transgenic PLP-α-syn mouse model of MSA characterized by targeted oligodendroglial α-synuclein overexpression aiming to provide a neuropathological correlate of motor deterioration. We show progressive motor deficits that emerge at 6 months of age and deteriorate up to 18 months of follow-up. The motor phenotype was associated with dopaminergic cell loss in the substantia nigra pars compacta at 6 months, followed by loss of striatal dopaminergic terminals and DARPP32-positive medium sized projection neurons at 12 months. Olivopontocerebellar motor loops remained spared in the PLP-α-syn model of MSA. These findings replicate progressive Striatonigral Degeneration underlying Parkinson-variant MSA. The initiation of the degenerative process was linked to an increase of soluble oligomeric α-synuclein species between 2 and 6 months. Early region-specific α-synuclein-associated activation profile of microglia was found in MSA substantia nigra. The role of abnormal neuroinflammatory signalling in disease progression was further supported by increased levels of CD68, CCL3, CCL5 and M-CSF with a peak in aged PLP-α-syn mice. In summary, transgenic PLP-α-syn mice show a distinctive oligodendroglial α-synucleinopathy that is associated with progressive Striatonigral Degeneration linked to abnormal neuroinflammatory response. The model provides a relevant tool for preclinical therapeutic target discovery for human Parkinson-variant MSA.
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Progressive Striatonigral Degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies.
Acta neuropathologica communications, 2018Co-Authors: Violetta Refolo, Francesco Bez, Daniela Kuzdas-wood, Edith Sturm, Martina Kamaratou, Leonidas Stefanis, Werner Poewe, Alexia Polissidis, M. Angela Cenci, Marina Romero-ramosAbstract:Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective vulnerability and disease progression in the transgenic PLP-α-syn mouse model of MSA characterized by targeted oligodendroglial α-synuclein overexpression aiming to provide a neuropathological correlate of motor deterioration. We show progressive motor deficits that emerge at 6 months of age and deteriorate up to 18 months of follow-up. The motor phenotype was associated with dopaminergic cell loss in the substantia nigra pars compacta at 6 months, followed by loss of striatal dopaminergic terminals and DARPP32-positive medium sized projection neurons at 12 months. Olivopontocerebellar motor loops remained spared in the PLP-α-syn model of MSA. These findings replicate progressive Striatonigral Degeneration underlying Parkinson-variant MSA. The initiation of the degenerative process was linked to an increase of soluble oligomeric α-synuclein species between 2 and 6 months. Early region-specific α-synuclein-associated activation profile of microglia was found in MSA substantia nigra. The role of abnormal neuroinflammatory signalling in disease progression was further supported by increased levels of CD68, CCL3, CCL5 and M-CSF with a peak in aged PLP-α-syn mice. In summary, transgenic PLP-α-syn mice show a distinctive oligodendroglial α-synucleinopathy that is associated with progressive Striatonigral Degeneration linked to abnormal neuroinflammatory response. The model provides a relevant tool for preclinical therapeutic target discovery for human Parkinson-variant MSA.
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Failure of neuronal protection by inhibition of glial activation in a rat model of Striatonigral Degeneration.
Journal of neuroscience research, 2004Co-Authors: Nadia Stefanova, Elsa Diguet, François Tison, Werner Poewe, Imad Ghorayeb, Monika Mitschnigg, Felix Geser, Gregor K WenningAbstract:Previous studies in rodent models of neurodegenerative disorders have demonstrated that minocycline exerts neuroprotective effects unrelated to its antimicrobial action. The purpose of the present study was to analyze whether minocycline exhibits neuroprotective activity in a rat model of Striatonigral Degeneration (SND), the core pathology underlying levodopa-unresponsive parkinsonism associated with multiple system atrophy (MSA). We observed no significant effect of minocycline on locomotor impairment in double-lesioned SND rats. Minocycline significantly suppressed astroglial and microglial activation (P < 0.01); however, 3'5'-monophosphate-regulated phosphoprotein (DARPP 32) immunohistochemistry revealed no significant differences in striatal lesion volume of minocycline-treated versus untreated control SND rats. Furthermore, there was no protection of nigral dopaminergic neurons in the double-lesion model. We conclude that despite its astrocytic and microglial suppression, minocycline failed to attenuate lesion-induced neuronal damage in the SND rat model.
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Neuropathological and behavioral changes induced by various treatment paradigms with MPTP and 3-nitropropionic acid in mice: towards a model of Striatonigral Degeneration (multiple system atrophy)
Acta neuropathologica, 2003Co-Authors: Nadia Stefanova, Pierre-olivier Fernagut, Zoe Puschban, Kurt A. Jellinger, François Tison, Werner Poewe, Emmanuel Brouillet, Markus Reindl, Gregor K WenningAbstract:We characterized two models of dual nigral and striatal lesions replicating the lesion pattern of Striatonigral Degeneration, the neuropathological hallmark of parkinsonism associated with multiple system atrophy (SND/MSA-P). For this purpose, we used systemic administration of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3-NP) in C57BL mice. One group of animals was first injected with MPTP followed by 3NP (MPTP+3-NP model). In the second group 3-NP was injected first, followed by MPTP (3-NP+MPTP model). The behavioral and neuropathological characteristics of these two models were compared to those observed after single 3-NP or MPTP intoxication. Results showed that, compared to control mice, spontaneous nocturnal locomotor activity was preserved in the MPTP+3-NP model, whereas it was reduced by 27% ( P
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neuropathological and behavioral changes induced by various treatment paradigms with mptp and 3 nitropropionic acid in mice towards a model of Striatonigral Degeneration multiple system atrophy
Acta Neuropathologica, 2003Co-Authors: Nadia Stefanova, Pierre-olivier Fernagut, Zoe Puschban, Kurt A. Jellinger, François Tison, Werner Poewe, Emmanuel Brouillet, Markus Reindl, Gregor K WenningAbstract:We characterized two models of dual nigral and striatal lesions replicating the lesion pattern of Striatonigral Degeneration, the neuropathological hallmark of parkinsonism associated with multiple system atrophy (SND/MSA-P). For this purpose, we used systemic administration of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3-NP) in C57BL mice. One group of animals was first injected with MPTP followed by 3NP (MPTP+3-NP model).In the second group 3-NP was injected first, followed by MPTP (3-NP+MPTP model). The behavioral and neuropathological characteristics of these two models were compared to those observed after single 3-NP or MPTP intoxication. Results showed that, compared to control mice, spontaneous nocturnal locomotor activity was preserved in the MPTP+3-NP model, whereas it was reduced by 27% (P<0.05) in the 3-NP+MPTP model and in animals treated with either 3-NP (27%, P<0.05) or MPTP (23%, P<0.05) alone. Quantitative histological evaluation based on Nissl staining and DARPP-32 immunohistochemistry revealed that 3-NP alone and 3-NP+MPTP treatment produced a marked (greater than 50%) loss of striatal neurons, whereas MPTP+3-NP treatment attenuated loss of striatal neurons by 43%. Further, loss of tyrosine hydroxylase-positive neurons in substantia nigra pars compacta (SNc) was attenuated after 3-NP+MPTP treatment compared to that observed after MPTP (40% vs 74%, P<0.001) and MPTP+3NP treatment (55% vs 74%, P<0.01). Our results show that MPTP-induced nigral lesions attenuate 3-NP toxicity and, reciprocally, that 3-NP-induced striatal lesions reduce MPTP toxicity. This suggests that complex integrative mechanisms are likely to regulate the vulnerability of the striatum and SNc to cell death in SND/MSA-P.
Nadia Stefanova - One of the best experts on this subject based on the ideXlab platform.
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L-dopa response pattern in a rat model of mild Striatonigral Degeneration.
PloS one, 2019Co-Authors: Christine Kaindlstorfer, Kurt A. Jellinger, Nadia Stefanova, Joanna Garcia, Florian Krismer, Máté D. Döbrössy, Georg Göbel, Roberta Granata, Gregor K WenningAbstract:Background Unresponsiveness to dopaminergic therapies is a key feature in the diagnosis of multiple system atrophy (MSA) and a major unmet need in the treatment of MSA patients caused by combined Striatonigral Degeneration (SND). Transgenic, alpha-synuclein animal models do not recapitulate this lack of levodopa responsiveness. In order to preclinically study interventions including striatal cell grafts, models that feature SND are required. Most of the previous studies focused on extensive nigral and striatal lesions corresponding to advanced MSA-P/SND. The aim of the current study was to replicate mild stage MSA-P/SND with L-dopa failure. Methods and results Two different striatal quinolinic acid (QA) lesions following a striatal 6-OHDA lesion replicating mild and severe MSA-P/SND, respectively, were investigated and compared to 6-OHDA lesioned animals. After the initial 6-OHDA lesion there was a significant improvement of motor performance after dopaminergic stimulation in the cylinder and stepping test (p
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l dopa response pattern in a rat model of mild Striatonigral Degeneration
PLOS ONE, 2019Co-Authors: Christine Kaindlstorfer, Kurt A. Jellinger, Nadia Stefanova, Joanna Garcia, Florian Krismer, Máté D. Döbrössy, Georg Göbel, Roberta Granata, Gregor K WenningAbstract:Background Unresponsiveness to dopaminergic therapies is a key feature in the diagnosis of multiple system atrophy (MSA) and a major unmet need in the treatment of MSA patients caused by combined Striatonigral Degeneration (SND). Transgenic, alpha-synuclein animal models do not recapitulate this lack of levodopa responsiveness. In order to preclinically study interventions including striatal cell grafts, models that feature SND are required. Most of the previous studies focused on extensive nigral and striatal lesions corresponding to advanced MSA-P/SND. The aim of the current study was to replicate mild stage MSA-P/SND with L-dopa failure. Methods and results Two different striatal quinolinic acid (QA) lesions following a striatal 6-OHDA lesion replicating mild and severe MSA-P/SND, respectively, were investigated and compared to 6-OHDA lesioned animals. After the initial 6-OHDA lesion there was a significant improvement of motor performance after dopaminergic stimulation in the cylinder and stepping test (p<0.001). Response to L-dopa treatment declined in both MSA-P/SND groups reflecting striatal damage of lateral motor areas in contrast to the 6-OHDA only lesioned animals (p<0.01). The remaining striatal volume correlated strongly with contralateral apomorphine induced rotation behaviour and contralateral paw use during L-dopa treatment in cylinder and stepping test (p<0.001). Conclusion Our novel L-dopa response data suggest that L-dopa failure can be induced by restricted lateral striatal lesions combined with dopaminergic denervation. We propose that this sequential striatal double-lesion model replicates a mild stage of MSA-P/SND and is suitable to address neuro-regenerative therapies aimed at restoring dopaminergic responsiveness.
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riluzole improves motor deficits and attenuates loss of striatal neurons in a sequential double lesion rat model of Striatonigral Degeneration parkinson variant of multiple system atrophy
Journal of Neural Transmission, 2005Co-Authors: Christoph Scherfler, Elsa Diguet, Zoe Puschban, François Tison, Nadia Stefanova, T. Sather, W. Poewe, Gregor K WenningAbstract:We investigated neuroprotective effects of riluzole, an anti-glutamatergic agent that is FDA approved for disease-modifying therapy in amyotrophic lateral sclerosis (ALS), in an established double lesion rat model of Striatonigral Degeneration (SND), the neuropathological substrate of parkinsonism associated with MSA (MSA-P). Riluzole was administered prior to and consecutively for ten days following double lesion placement in the left-sided medial forebrain bundle and ipsilateral striatum. Assessment of motor behaviour using a flex field system showed a significant reduction of motor disturbance in animals with Striatonigral lesions treated with riluzole compared to lesioned but untreated animals (P<0.001). DARPP-32 immunohistochemistry revealed a significant reduction of absolute striatal lesion volume in riluzole treated animals compared to lesioned but untreated animals (P<0.01). No significant difference in counts of nigral dopaminergic neurons was found in treated versus untreated double-lesioned animals. The results of our study indicate that riluzole mediates neuroprotective effects in the double lesion rat model of MSA-P. Whether riluzole also protects autonomic and cerebellar pathways that are frequently affected in MSA remains to be determined. Nonetheless, our study is the first to provide an experimental rationale for exploring possible neuroprotective effects of riluzole in MSA.
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Failure of neuronal protection by inhibition of glial activation in a rat model of Striatonigral Degeneration.
Journal of neuroscience research, 2004Co-Authors: Nadia Stefanova, Elsa Diguet, François Tison, Werner Poewe, Imad Ghorayeb, Monika Mitschnigg, Felix Geser, Gregor K WenningAbstract:Previous studies in rodent models of neurodegenerative disorders have demonstrated that minocycline exerts neuroprotective effects unrelated to its antimicrobial action. The purpose of the present study was to analyze whether minocycline exhibits neuroprotective activity in a rat model of Striatonigral Degeneration (SND), the core pathology underlying levodopa-unresponsive parkinsonism associated with multiple system atrophy (MSA). We observed no significant effect of minocycline on locomotor impairment in double-lesioned SND rats. Minocycline significantly suppressed astroglial and microglial activation (P < 0.01); however, 3'5'-monophosphate-regulated phosphoprotein (DARPP 32) immunohistochemistry revealed no significant differences in striatal lesion volume of minocycline-treated versus untreated control SND rats. Furthermore, there was no protection of nigral dopaminergic neurons in the double-lesion model. We conclude that despite its astrocytic and microglial suppression, minocycline failed to attenuate lesion-induced neuronal damage in the SND rat model.
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Effects of pulsatile L-DOPA treatment in the double lesion rat model of Striatonigral Degeneration (multiple system atrophy)
Neurobiology of disease, 2004Co-Authors: Nadia Stefanova, François Tison, W. Poewe, Martin Lundblad, M. A. Cenci, Gregor K WenningAbstract:We examined the role of a striatal lesion in the development of L-DOPA-induced abnormal involuntary movements (AIMs) using the double lesion rat model of Striatonigral Degeneration (SND), the underlying neuropathological substrate of parkinsonism associated with multiple system atrophy (MSA-P), in comparison to a Parkinson's disease (PD) rat model. L-DOPA administration reliably induced AIMs in SND and PD rats in a dose-dependent fashion. AIMs occurred significantly earlier in SND compared to PD rats. There was a mild, but significant, transient increase of orolingual AIMs during the first week of low-dose L-DOPA treatment in SND. Whereas L-DOPA significantly improved contralateral forelimb akinesia in PD rats, there was no beneficial effect in SND rats. Striatal FosB/Delta FosB up-regulation in SND and PD rats correlated with the severity of L-DOPA-induced dyskinesias. Pulsatile L-DOPA administration in the double lesion SND rat model replicates salient features of the human disease MSA-P, including loss of the anti-akinetic L-DOPA response and induction of dyskinesias with transient orolingual predominance.
Zoe Puschban - One of the best experts on this subject based on the ideXlab platform.
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Riluzole improves motor deficits and attenuates loss of striatal neurons in a sequential double lesion rat model of Striatonigral Degeneration (parkinson variant of multiple system atrophy)
Journal of Neural Transmission, 2005Co-Authors: Christoph Scherfler, Elsa Diguet, Zoe Puschban, F. Tison, T. Sather, N. Stefanova, W. Poewe, G. K. WenningAbstract:We investigated neuroprotective effects of riluzole, an anti-glutamatergic agent that is FDA approved for disease-modifying therapy in amyotrophic lateral sclerosis (ALS), in an established double lesion rat model of Striatonigral Degeneration (SND), the neuropathological substrate of parkinsonism associated with MSA (MSA-P). Riluzole was administered prior to and consecutively for ten days following double lesion placement in the left-sided medial forebrain bundle and ipsilateral striatum. Assessment of motor behaviour using a flex field system showed a significant reduction of motor disturbance in animals with Striatonigral lesions treated with riluzole compared to lesioned but untreated animals (P
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riluzole improves motor deficits and attenuates loss of striatal neurons in a sequential double lesion rat model of Striatonigral Degeneration parkinson variant of multiple system atrophy
Journal of Neural Transmission, 2005Co-Authors: Christoph Scherfler, Elsa Diguet, Zoe Puschban, François Tison, Nadia Stefanova, T. Sather, W. Poewe, Gregor K WenningAbstract:We investigated neuroprotective effects of riluzole, an anti-glutamatergic agent that is FDA approved for disease-modifying therapy in amyotrophic lateral sclerosis (ALS), in an established double lesion rat model of Striatonigral Degeneration (SND), the neuropathological substrate of parkinsonism associated with MSA (MSA-P). Riluzole was administered prior to and consecutively for ten days following double lesion placement in the left-sided medial forebrain bundle and ipsilateral striatum. Assessment of motor behaviour using a flex field system showed a significant reduction of motor disturbance in animals with Striatonigral lesions treated with riluzole compared to lesioned but untreated animals (P<0.001). DARPP-32 immunohistochemistry revealed a significant reduction of absolute striatal lesion volume in riluzole treated animals compared to lesioned but untreated animals (P<0.01). No significant difference in counts of nigral dopaminergic neurons was found in treated versus untreated double-lesioned animals. The results of our study indicate that riluzole mediates neuroprotective effects in the double lesion rat model of MSA-P. Whether riluzole also protects autonomic and cerebellar pathways that are frequently affected in MSA remains to be determined. Nonetheless, our study is the first to provide an experimental rationale for exploring possible neuroprotective effects of riluzole in MSA.
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Neuropathological and behavioral changes induced by various treatment paradigms with MPTP and 3-nitropropionic acid in mice: towards a model of Striatonigral Degeneration (multiple system atrophy)
Acta neuropathologica, 2003Co-Authors: Nadia Stefanova, Pierre-olivier Fernagut, Zoe Puschban, Kurt A. Jellinger, François Tison, Werner Poewe, Emmanuel Brouillet, Markus Reindl, Gregor K WenningAbstract:We characterized two models of dual nigral and striatal lesions replicating the lesion pattern of Striatonigral Degeneration, the neuropathological hallmark of parkinsonism associated with multiple system atrophy (SND/MSA-P). For this purpose, we used systemic administration of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3-NP) in C57BL mice. One group of animals was first injected with MPTP followed by 3NP (MPTP+3-NP model). In the second group 3-NP was injected first, followed by MPTP (3-NP+MPTP model). The behavioral and neuropathological characteristics of these two models were compared to those observed after single 3-NP or MPTP intoxication. Results showed that, compared to control mice, spontaneous nocturnal locomotor activity was preserved in the MPTP+3-NP model, whereas it was reduced by 27% ( P
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neuropathological and behavioral changes induced by various treatment paradigms with mptp and 3 nitropropionic acid in mice towards a model of Striatonigral Degeneration multiple system atrophy
Acta Neuropathologica, 2003Co-Authors: Nadia Stefanova, Pierre-olivier Fernagut, Zoe Puschban, Kurt A. Jellinger, François Tison, Werner Poewe, Emmanuel Brouillet, Markus Reindl, Gregor K WenningAbstract:We characterized two models of dual nigral and striatal lesions replicating the lesion pattern of Striatonigral Degeneration, the neuropathological hallmark of parkinsonism associated with multiple system atrophy (SND/MSA-P). For this purpose, we used systemic administration of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3-NP) in C57BL mice. One group of animals was first injected with MPTP followed by 3NP (MPTP+3-NP model).In the second group 3-NP was injected first, followed by MPTP (3-NP+MPTP model). The behavioral and neuropathological characteristics of these two models were compared to those observed after single 3-NP or MPTP intoxication. Results showed that, compared to control mice, spontaneous nocturnal locomotor activity was preserved in the MPTP+3-NP model, whereas it was reduced by 27% (P<0.05) in the 3-NP+MPTP model and in animals treated with either 3-NP (27%, P<0.05) or MPTP (23%, P<0.05) alone. Quantitative histological evaluation based on Nissl staining and DARPP-32 immunohistochemistry revealed that 3-NP alone and 3-NP+MPTP treatment produced a marked (greater than 50%) loss of striatal neurons, whereas MPTP+3-NP treatment attenuated loss of striatal neurons by 43%. Further, loss of tyrosine hydroxylase-positive neurons in substantia nigra pars compacta (SNc) was attenuated after 3-NP+MPTP treatment compared to that observed after MPTP (40% vs 74%, P<0.001) and MPTP+3NP treatment (55% vs 74%, P<0.01). Our results show that MPTP-induced nigral lesions attenuate 3-NP toxicity and, reciprocally, that 3-NP-induced striatal lesions reduce MPTP toxicity. This suggests that complex integrative mechanisms are likely to regulate the vulnerability of the striatum and SNc to cell death in SND/MSA-P.
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No functional effects of embryonic neuronal grafts on motor deficits in a 3-nitropropionic acid rat model of advanced Striatonigral Degeneration (multiple system atrophy)
Neuroscience, 2001Co-Authors: Regina Waldner, Zoe Puschban, Christoph Scherfler, Kurt A. Jellinger, Klaus Seppi, Werner Poewe, Gregor K WenningAbstract:Abstract Intrastriatal injection of 3-nitropropionic acid results in secondary excitotoxic local damage and retrograde neuronal cell loss in substantia nigra pars compacta, thus mimicking salient features of Striatonigral Degeneration, the core pathology underlying Parkinsonism associated with multiple system atrophy. We used 3-nitropropionic acid to create a rat model of advanced Striatonigral Degeneration in order to assess the effects of embryonic allografts upon rotational and complex-motor behavioural abnormalities. Following stereotaxic intrastriatal administration of 500 nmol 3-nitropropionic acid in male Wistar rats we observed consistent amphetamine- and apomorphine-induced ipsiversive rotation. Furthermore, there were marked deficits of contralateral paw reaching. Subsequently, animals received intrastriatal implantations of either E14 mesencephalic or striatal or mixed embryonic cell suspensions. In addition, one group received sham injections. Grafted rats were followed for up to 21 weeks and repeated behavioural tests were obtained during this period. Drug-induced rotation asymmetries and complex motor deficits measured by paw reaching tests were not compensated by embryonic grafts. Persistence of drug-induced rotations and of paw reaching deficits following transplantation probably reflects severe atrophy of adult striatum, additional nigral Degeneration as well as glial demarcation of embryonic grafts. We suggest that dopamine rich embryonic grafts fail to induce functional recovery in a novel 3-nitropropionic acid rat model of advanced Striatonigral Degeneration (multiple system atrophy).
