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Effects of intraventricular methotrexate administration on Cuprizone-induced demyelination in mice
We previously showed that intrathecal administration of methotrexate slowed disability progression in multiple sclerosis (MS) patients with progressive disease. In general MS patients with progressive disease respond poorly to anti-inflammatory therapies. In order to better understand the mechanism...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2013
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797440/ https://www.ncbi.nlm.nih.gov/pubmed/24137109 http://dx.doi.org/10.3389/fnmol.2013.00034 |
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author | Mueller, Andre M. Nassery, Adam Conlon, Hana Liu, Xinhe Jun, Esther Yoon, Bo Hyung Cristofanilli, Massimiliano Sadiq, Saud A. |
author_facet | Mueller, Andre M. Nassery, Adam Conlon, Hana Liu, Xinhe Jun, Esther Yoon, Bo Hyung Cristofanilli, Massimiliano Sadiq, Saud A. |
author_sort | Mueller, Andre M. |
collection | PubMed |
description | We previously showed that intrathecal administration of methotrexate slowed disability progression in multiple sclerosis (MS) patients with progressive disease. In general MS patients with progressive disease respond poorly to anti-inflammatory therapies. In order to better understand the mechanism by which methotrexate is protective in progressive MS, we analyzed its impact on the non-inflammatory cuprizone-induced demyelination model. When low-dose methotrexate was administered intracerebroventricularly it reduced demyelination and accumulation of GFAP+ reactive astrocytes in the corpus callosum. Administration of methotrexate after the withdrawal of cuprizone neither delayed remyelination nor influenced the number of astrocytes in the corpus callosum suggesting that methotrexate does not interfere with repair processes in the CNS. Moreover, methotrexate increased the expression of IGF1 in vitro and in vivo, a factor known to protect oligodendrocytes and limit the activation of astrocytes. Our studies show that methotrexate has an impact on pathogenic process in a demyelination model whose pathophysiological basis is not primarily related to inflammatory mechanisms, similar to neurodegenerative mechanisms associated with progressive MS. The pronounced inhibitory influence of methotrexate on the accumulation of astrocytes in the corpus callosum suggests that intrathecal methotrexate modulates astroglial activation in progressive MS possibly by promoting CNS production of IGF1. |
format | Online Article Text |
id | pubmed-3797440 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-37974402013-10-17 Effects of intraventricular methotrexate administration on Cuprizone-induced demyelination in mice Mueller, Andre M. Nassery, Adam Conlon, Hana Liu, Xinhe Jun, Esther Yoon, Bo Hyung Cristofanilli, Massimiliano Sadiq, Saud A. Front Mol Neurosci Neuroscience We previously showed that intrathecal administration of methotrexate slowed disability progression in multiple sclerosis (MS) patients with progressive disease. In general MS patients with progressive disease respond poorly to anti-inflammatory therapies. In order to better understand the mechanism by which methotrexate is protective in progressive MS, we analyzed its impact on the non-inflammatory cuprizone-induced demyelination model. When low-dose methotrexate was administered intracerebroventricularly it reduced demyelination and accumulation of GFAP+ reactive astrocytes in the corpus callosum. Administration of methotrexate after the withdrawal of cuprizone neither delayed remyelination nor influenced the number of astrocytes in the corpus callosum suggesting that methotrexate does not interfere with repair processes in the CNS. Moreover, methotrexate increased the expression of IGF1 in vitro and in vivo, a factor known to protect oligodendrocytes and limit the activation of astrocytes. Our studies show that methotrexate has an impact on pathogenic process in a demyelination model whose pathophysiological basis is not primarily related to inflammatory mechanisms, similar to neurodegenerative mechanisms associated with progressive MS. The pronounced inhibitory influence of methotrexate on the accumulation of astrocytes in the corpus callosum suggests that intrathecal methotrexate modulates astroglial activation in progressive MS possibly by promoting CNS production of IGF1. Frontiers Media S.A. 2013-10-16 /pmc/articles/PMC3797440/ /pubmed/24137109 http://dx.doi.org/10.3389/fnmol.2013.00034 Text en Copyright © 2013 Mueller, Nassery, Conlon, Liu, Jun, Yoon, Cristofanilli and Sadiq. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Mueller, Andre M. Nassery, Adam Conlon, Hana Liu, Xinhe Jun, Esther Yoon, Bo Hyung Cristofanilli, Massimiliano Sadiq, Saud A. Effects of intraventricular methotrexate administration on Cuprizone-induced demyelination in mice |
title | Effects of intraventricular methotrexate administration on Cuprizone-induced demyelination in mice |
title_full | Effects of intraventricular methotrexate administration on Cuprizone-induced demyelination in mice |
title_fullStr | Effects of intraventricular methotrexate administration on Cuprizone-induced demyelination in mice |
title_full_unstemmed | Effects of intraventricular methotrexate administration on Cuprizone-induced demyelination in mice |
title_short | Effects of intraventricular methotrexate administration on Cuprizone-induced demyelination in mice |
title_sort | effects of intraventricular methotrexate administration on cuprizone-induced demyelination in mice |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797440/ https://www.ncbi.nlm.nih.gov/pubmed/24137109 http://dx.doi.org/10.3389/fnmol.2013.00034 |
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