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Ganaxolone enhances microglial clearance activity and promotes remyelination in focal demyelination in the corpus callosum of ovariectomized rats
AIM: Experimental studies have shown that the progesterone metabolite, allopregnanolone, is endowed with promyelinating effects. The mechanisms underlying these promyelinating effects are not well understood. Therefore, we explored the impact of allopregnanolone's synthetic analogue, ganaxolone...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978248/ https://www.ncbi.nlm.nih.gov/pubmed/31332963 http://dx.doi.org/10.1111/cns.13195 |
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author | Mouihate, Abdeslam Kalakh, Samah |
author_facet | Mouihate, Abdeslam Kalakh, Samah |
author_sort | Mouihate, Abdeslam |
collection | PubMed |
description | AIM: Experimental studies have shown that the progesterone metabolite, allopregnanolone, is endowed with promyelinating effects. The mechanisms underlying these promyelinating effects are not well understood. Therefore, we explored the impact of allopregnanolone's synthetic analogue, ganaxolone, on remyelination and microglial activation following focal demyelination in the corpus callosum of ovariectomized rats. METHODS: Ovariectomized adult Sprague Dawley rats received a stereotaxic injection of 2 µL of 1% lysolecithin solution in the corpus callosum followed by daily injections of either ganaxolone (intraperitoneal injection [i.p.], 2.5 mg/kg) or vehicle. The demyelination lesion was assessed 3 and 7 days postdemyelination insult using Luxol fast blue staining and transmission electron microscopy. The expression levels of myelin proteins (MBP, MAG, MOG, CNPase) were explored using Western blot. The inflammatory response and clearance of damaged myelin were evaluated using immunofluorescent staining (Iba1, dMBP, GFAP) and multiplex enzyme‐linked immunosorbent assay (IL‐1β, TNF‐α, IL‐4, IL‐10, IL‐6). RESULTS: Systemic administration of ganaxolone promoted remyelination of lysolecithin‐induced demyelination, upregulated the expression of major myelin proteins, and enhanced microglial clearance of damaged myelin. Astrocytosis, as well as locally produced pro‐ and antiinflammatory cytokines, was not affected by ganaxolone treatment. CONCLUSION: Ganaxolone promotes remyelination in response to focal demyelination of the corpus callosum of ovariectomized rats. This effect is, at least in part, mediated by enhancing microglial clearance of myelin debris, which creates a conducive environment for a successful remyelination process. |
format | Online Article Text |
id | pubmed-6978248 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-69782482020-01-28 Ganaxolone enhances microglial clearance activity and promotes remyelination in focal demyelination in the corpus callosum of ovariectomized rats Mouihate, Abdeslam Kalakh, Samah CNS Neurosci Ther Original Articles AIM: Experimental studies have shown that the progesterone metabolite, allopregnanolone, is endowed with promyelinating effects. The mechanisms underlying these promyelinating effects are not well understood. Therefore, we explored the impact of allopregnanolone's synthetic analogue, ganaxolone, on remyelination and microglial activation following focal demyelination in the corpus callosum of ovariectomized rats. METHODS: Ovariectomized adult Sprague Dawley rats received a stereotaxic injection of 2 µL of 1% lysolecithin solution in the corpus callosum followed by daily injections of either ganaxolone (intraperitoneal injection [i.p.], 2.5 mg/kg) or vehicle. The demyelination lesion was assessed 3 and 7 days postdemyelination insult using Luxol fast blue staining and transmission electron microscopy. The expression levels of myelin proteins (MBP, MAG, MOG, CNPase) were explored using Western blot. The inflammatory response and clearance of damaged myelin were evaluated using immunofluorescent staining (Iba1, dMBP, GFAP) and multiplex enzyme‐linked immunosorbent assay (IL‐1β, TNF‐α, IL‐4, IL‐10, IL‐6). RESULTS: Systemic administration of ganaxolone promoted remyelination of lysolecithin‐induced demyelination, upregulated the expression of major myelin proteins, and enhanced microglial clearance of damaged myelin. Astrocytosis, as well as locally produced pro‐ and antiinflammatory cytokines, was not affected by ganaxolone treatment. CONCLUSION: Ganaxolone promotes remyelination in response to focal demyelination of the corpus callosum of ovariectomized rats. This effect is, at least in part, mediated by enhancing microglial clearance of myelin debris, which creates a conducive environment for a successful remyelination process. John Wiley and Sons Inc. 2019-07-22 /pmc/articles/PMC6978248/ /pubmed/31332963 http://dx.doi.org/10.1111/cns.13195 Text en © 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Mouihate, Abdeslam Kalakh, Samah Ganaxolone enhances microglial clearance activity and promotes remyelination in focal demyelination in the corpus callosum of ovariectomized rats |
title | Ganaxolone enhances microglial clearance activity and promotes remyelination in focal demyelination in the corpus callosum of ovariectomized rats |
title_full | Ganaxolone enhances microglial clearance activity and promotes remyelination in focal demyelination in the corpus callosum of ovariectomized rats |
title_fullStr | Ganaxolone enhances microglial clearance activity and promotes remyelination in focal demyelination in the corpus callosum of ovariectomized rats |
title_full_unstemmed | Ganaxolone enhances microglial clearance activity and promotes remyelination in focal demyelination in the corpus callosum of ovariectomized rats |
title_short | Ganaxolone enhances microglial clearance activity and promotes remyelination in focal demyelination in the corpus callosum of ovariectomized rats |
title_sort | ganaxolone enhances microglial clearance activity and promotes remyelination in focal demyelination in the corpus callosum of ovariectomized rats |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978248/ https://www.ncbi.nlm.nih.gov/pubmed/31332963 http://dx.doi.org/10.1111/cns.13195 |
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