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L-dopa response pattern in a rat model of mild striatonigral degeneration

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 la...

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Autores principales: Kaindlstorfer, Christine, Stefanova, Nadia, Garcia, Joanna, Krismer, Florian, Döbrössy, Máté, Göbel, Georg, Jellinger, Kurt, Granata, Roberta, Wenning, Gregor Karl
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557500/
https://www.ncbi.nlm.nih.gov/pubmed/31181111
http://dx.doi.org/10.1371/journal.pone.0218130
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author Kaindlstorfer, Christine
Stefanova, Nadia
Garcia, Joanna
Krismer, Florian
Döbrössy, Máté
Göbel, Georg
Jellinger, Kurt
Granata, Roberta
Wenning, Gregor Karl
author_facet Kaindlstorfer, Christine
Stefanova, Nadia
Garcia, Joanna
Krismer, Florian
Döbrössy, Máté
Göbel, Georg
Jellinger, Kurt
Granata, Roberta
Wenning, Gregor Karl
author_sort Kaindlstorfer, Christine
collection PubMed
description 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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spelling pubmed-65575002019-06-17 L-dopa response pattern in a rat model of mild striatonigral degeneration Kaindlstorfer, Christine Stefanova, Nadia Garcia, Joanna Krismer, Florian Döbrössy, Máté Göbel, Georg Jellinger, Kurt Granata, Roberta Wenning, Gregor Karl PLoS One Research Article 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. Public Library of Science 2019-06-10 /pmc/articles/PMC6557500/ /pubmed/31181111 http://dx.doi.org/10.1371/journal.pone.0218130 Text en © 2019 Kaindlstorfer et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kaindlstorfer, Christine
Stefanova, Nadia
Garcia, Joanna
Krismer, Florian
Döbrössy, Máté
Göbel, Georg
Jellinger, Kurt
Granata, Roberta
Wenning, Gregor Karl
L-dopa response pattern in a rat model of mild striatonigral degeneration
title L-dopa response pattern in a rat model of mild striatonigral degeneration
title_full L-dopa response pattern in a rat model of mild striatonigral degeneration
title_fullStr L-dopa response pattern in a rat model of mild striatonigral degeneration
title_full_unstemmed L-dopa response pattern in a rat model of mild striatonigral degeneration
title_short L-dopa response pattern in a rat model of mild striatonigral degeneration
title_sort l-dopa response pattern in a rat model of mild striatonigral degeneration
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557500/
https://www.ncbi.nlm.nih.gov/pubmed/31181111
http://dx.doi.org/10.1371/journal.pone.0218130
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