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Time dependent degeneration of the nigrostriatal tract in mice with 6-OHDA lesioned medial forebrain bundle and the effect of activin A on l-Dopa induced dyskinesia

BACKGROUND: Accurately assessing promising therapeutic interventions for human diseases depends, in part, on the reproducibility of preclinical disease models. With the development of transgenic mice, the rapid adaptation of a 6-OHDA mouse model of Parkinson’s disease that was originally described f...

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Autores principales: Rentsch, Peggy, Stayte, Sandy, Morris, Gary P., Vissel, Bryce
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374903/
https://www.ncbi.nlm.nih.gov/pubmed/30760214
http://dx.doi.org/10.1186/s12868-019-0487-7
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author Rentsch, Peggy
Stayte, Sandy
Morris, Gary P.
Vissel, Bryce
author_facet Rentsch, Peggy
Stayte, Sandy
Morris, Gary P.
Vissel, Bryce
author_sort Rentsch, Peggy
collection PubMed
description BACKGROUND: Accurately assessing promising therapeutic interventions for human diseases depends, in part, on the reproducibility of preclinical disease models. With the development of transgenic mice, the rapid adaptation of a 6-OHDA mouse model of Parkinson’s disease that was originally described for the use in rats has come with a lack of a comprehensive characterization of lesion progression. In this study we therefore first characterised the time course of neurodegeneration in the substantia nigra pars compacta and striatum over a 4 week period following 6-OHDA injection into the medial forebrain bundle of mice. We then utilised the model to assess the anti-dyskinetic efficacy of recombinant activin A, a putative neuroprotectant and anti-inflammatory that is endogenously upregulated during the course of Parkinson’s disease. RESULTS: We found that degeneration of fibers in the striatum was fully established within 1 week following 6-OHDA administration, but that the loss of neurons continued to progress over time, becoming fully established 3 weeks after the 6-OHDA injection. In assessing the anti-dyskinetic efficacy of activin A using this model we found that treatment with activin A did not significantly reduce the severity, or delay the time-of-onset, of dyskinesia. CONCLUSION: First, the current study concludes that a 3 week duration is required to establish a complete lesion of the nigrostriatal tract following 6-OHDA injection into the medial forebrain bundle of mice. Second, we found that activin A was not anti-dyskinetic in this model. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12868-019-0487-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-63749032019-02-26 Time dependent degeneration of the nigrostriatal tract in mice with 6-OHDA lesioned medial forebrain bundle and the effect of activin A on l-Dopa induced dyskinesia Rentsch, Peggy Stayte, Sandy Morris, Gary P. Vissel, Bryce BMC Neurosci Research Article BACKGROUND: Accurately assessing promising therapeutic interventions for human diseases depends, in part, on the reproducibility of preclinical disease models. With the development of transgenic mice, the rapid adaptation of a 6-OHDA mouse model of Parkinson’s disease that was originally described for the use in rats has come with a lack of a comprehensive characterization of lesion progression. In this study we therefore first characterised the time course of neurodegeneration in the substantia nigra pars compacta and striatum over a 4 week period following 6-OHDA injection into the medial forebrain bundle of mice. We then utilised the model to assess the anti-dyskinetic efficacy of recombinant activin A, a putative neuroprotectant and anti-inflammatory that is endogenously upregulated during the course of Parkinson’s disease. RESULTS: We found that degeneration of fibers in the striatum was fully established within 1 week following 6-OHDA administration, but that the loss of neurons continued to progress over time, becoming fully established 3 weeks after the 6-OHDA injection. In assessing the anti-dyskinetic efficacy of activin A using this model we found that treatment with activin A did not significantly reduce the severity, or delay the time-of-onset, of dyskinesia. CONCLUSION: First, the current study concludes that a 3 week duration is required to establish a complete lesion of the nigrostriatal tract following 6-OHDA injection into the medial forebrain bundle of mice. Second, we found that activin A was not anti-dyskinetic in this model. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12868-019-0487-7) contains supplementary material, which is available to authorized users. BioMed Central 2019-02-13 /pmc/articles/PMC6374903/ /pubmed/30760214 http://dx.doi.org/10.1186/s12868-019-0487-7 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Rentsch, Peggy
Stayte, Sandy
Morris, Gary P.
Vissel, Bryce
Time dependent degeneration of the nigrostriatal tract in mice with 6-OHDA lesioned medial forebrain bundle and the effect of activin A on l-Dopa induced dyskinesia
title Time dependent degeneration of the nigrostriatal tract in mice with 6-OHDA lesioned medial forebrain bundle and the effect of activin A on l-Dopa induced dyskinesia
title_full Time dependent degeneration of the nigrostriatal tract in mice with 6-OHDA lesioned medial forebrain bundle and the effect of activin A on l-Dopa induced dyskinesia
title_fullStr Time dependent degeneration of the nigrostriatal tract in mice with 6-OHDA lesioned medial forebrain bundle and the effect of activin A on l-Dopa induced dyskinesia
title_full_unstemmed Time dependent degeneration of the nigrostriatal tract in mice with 6-OHDA lesioned medial forebrain bundle and the effect of activin A on l-Dopa induced dyskinesia
title_short Time dependent degeneration of the nigrostriatal tract in mice with 6-OHDA lesioned medial forebrain bundle and the effect of activin A on l-Dopa induced dyskinesia
title_sort time dependent degeneration of the nigrostriatal tract in mice with 6-ohda lesioned medial forebrain bundle and the effect of activin a on l-dopa induced dyskinesia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374903/
https://www.ncbi.nlm.nih.gov/pubmed/30760214
http://dx.doi.org/10.1186/s12868-019-0487-7
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