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HDAC2/3 inhibitor MI192 mitigates oligodendrocyte loss and reduces microglial activation upon injury: A potential role of epigenetics
BACKGROUND: During development, oligodendrocyte (OL) lineage cells are susceptible to injury, leading to life-long clinical neurodevelopmental deficits, which lack effective treatments. Drugs targeting epigenetic modifications that inhibit histone deacetylases (HDACs) protect from many clinical neur...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Faculty of Veterinary Medicine
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541718/ https://www.ncbi.nlm.nih.gov/pubmed/34722210 http://dx.doi.org/10.5455/OVJ.2021.v11.i3.18 |
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author | Al-Griw, Mohamed A. Shmela, Mansur E. Elhensheri, Mohamed M. Bennour, Emad M. |
author_facet | Al-Griw, Mohamed A. Shmela, Mansur E. Elhensheri, Mohamed M. Bennour, Emad M. |
author_sort | Al-Griw, Mohamed A. |
collection | PubMed |
description | BACKGROUND: During development, oligodendrocyte (OL) lineage cells are susceptible to injury, leading to life-long clinical neurodevelopmental deficits, which lack effective treatments. Drugs targeting epigenetic modifications that inhibit histone deacetylases (HDACs) protect from many clinical neurodegenerative disorders. AIM: This study aimed to investigate the therapeutic potential of histone deacetylase 2/3 (HDAC2/3) inhibitor MI192 on white matter (WM) pathology in a model of neonatal rat brain injury. METHODS: Wistar rats (8.5-day-old, n = 32) were used to generate brain tissues. The tissues were cultured and then randomly divided into four groups and treated as following: group I (sham); the tissues were cultured under normoxia, group II (vehicle); DMSO only, group III (injury, INJ); the tissues were exposed to 20 minutes oxygen-glucose deprivation (OGD) insult, and group IV (INJ + MI192); the tissues were subjected to the OGD insult and then treated with the MI192 inhibitor. On culture day 10, the tissues were fixed for biochemical and histological examinations. RESULTS: The results showed that inhibition of HDAC2/3 activity alleviated WM pathology. Specifically, MI192 treatment significantly reduced cell death, minimized apoptosis, and mitigates the loss of the MBP(+) OLs and their precursors (NG(2)(+) OPCs). Additionally, MI192 decreased the density of reactive microglia (OX−42(+)). These findings demonstrate that the inhibition of HDAC2/3 activity post-insult alleviates WM pathology through mechanism(s) including preserving OL lineage cells and suppressing microglial activation. CONCLUSION: The findings of this study suggest that HDAC2/3 inhibition is a rational strategy to preserve WM or reverse its pathology upon newborn brain injury. |
format | Online Article Text |
id | pubmed-8541718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Faculty of Veterinary Medicine |
record_format | MEDLINE/PubMed |
spelling | pubmed-85417182021-10-29 HDAC2/3 inhibitor MI192 mitigates oligodendrocyte loss and reduces microglial activation upon injury: A potential role of epigenetics Al-Griw, Mohamed A. Shmela, Mansur E. Elhensheri, Mohamed M. Bennour, Emad M. Open Vet J Original Research BACKGROUND: During development, oligodendrocyte (OL) lineage cells are susceptible to injury, leading to life-long clinical neurodevelopmental deficits, which lack effective treatments. Drugs targeting epigenetic modifications that inhibit histone deacetylases (HDACs) protect from many clinical neurodegenerative disorders. AIM: This study aimed to investigate the therapeutic potential of histone deacetylase 2/3 (HDAC2/3) inhibitor MI192 on white matter (WM) pathology in a model of neonatal rat brain injury. METHODS: Wistar rats (8.5-day-old, n = 32) were used to generate brain tissues. The tissues were cultured and then randomly divided into four groups and treated as following: group I (sham); the tissues were cultured under normoxia, group II (vehicle); DMSO only, group III (injury, INJ); the tissues were exposed to 20 minutes oxygen-glucose deprivation (OGD) insult, and group IV (INJ + MI192); the tissues were subjected to the OGD insult and then treated with the MI192 inhibitor. On culture day 10, the tissues were fixed for biochemical and histological examinations. RESULTS: The results showed that inhibition of HDAC2/3 activity alleviated WM pathology. Specifically, MI192 treatment significantly reduced cell death, minimized apoptosis, and mitigates the loss of the MBP(+) OLs and their precursors (NG(2)(+) OPCs). Additionally, MI192 decreased the density of reactive microglia (OX−42(+)). These findings demonstrate that the inhibition of HDAC2/3 activity post-insult alleviates WM pathology through mechanism(s) including preserving OL lineage cells and suppressing microglial activation. CONCLUSION: The findings of this study suggest that HDAC2/3 inhibition is a rational strategy to preserve WM or reverse its pathology upon newborn brain injury. Faculty of Veterinary Medicine 2021 2021-08-28 /pmc/articles/PMC8541718/ /pubmed/34722210 http://dx.doi.org/10.5455/OVJ.2021.v11.i3.18 Text en https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Research Al-Griw, Mohamed A. Shmela, Mansur E. Elhensheri, Mohamed M. Bennour, Emad M. HDAC2/3 inhibitor MI192 mitigates oligodendrocyte loss and reduces microglial activation upon injury: A potential role of epigenetics |
title | HDAC2/3 inhibitor MI192 mitigates oligodendrocyte loss and reduces microglial activation upon injury: A potential role of epigenetics |
title_full | HDAC2/3 inhibitor MI192 mitigates oligodendrocyte loss and reduces microglial activation upon injury: A potential role of epigenetics |
title_fullStr | HDAC2/3 inhibitor MI192 mitigates oligodendrocyte loss and reduces microglial activation upon injury: A potential role of epigenetics |
title_full_unstemmed | HDAC2/3 inhibitor MI192 mitigates oligodendrocyte loss and reduces microglial activation upon injury: A potential role of epigenetics |
title_short | HDAC2/3 inhibitor MI192 mitigates oligodendrocyte loss and reduces microglial activation upon injury: A potential role of epigenetics |
title_sort | hdac2/3 inhibitor mi192 mitigates oligodendrocyte loss and reduces microglial activation upon injury: a potential role of epigenetics |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541718/ https://www.ncbi.nlm.nih.gov/pubmed/34722210 http://dx.doi.org/10.5455/OVJ.2021.v11.i3.18 |
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