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MicroRNA-221-3p Suppresses the Microglia Activation and Seizures by Inhibiting of HIF-1α in Valproic Acid-Resistant Epilepsy
One-third of patients with epilepsy suffer from drug-resistant epilepsy (DRE). Valproic acid (VPA) is a classic anticonvulsant drug, and its resistance is a crucial predictor of DRE, but the pathogenesis remain unknown. Most patients with VPA-resistant epilepsy appear distinct inflammatory response...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419275/ https://www.ncbi.nlm.nih.gov/pubmed/34497517 http://dx.doi.org/10.3389/fphar.2021.714556 |
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author | Fu, Meng Zhu, Yiqing Zhang, Junqi Wu, Wei Sun, Yunxia Zhang, Xuemei Tao, Jie Li, Zhiping |
author_facet | Fu, Meng Zhu, Yiqing Zhang, Junqi Wu, Wei Sun, Yunxia Zhang, Xuemei Tao, Jie Li, Zhiping |
author_sort | Fu, Meng |
collection | PubMed |
description | One-third of patients with epilepsy suffer from drug-resistant epilepsy (DRE). Valproic acid (VPA) is a classic anticonvulsant drug, and its resistance is a crucial predictor of DRE, but the pathogenesis remain unknown. Most patients with VPA-resistant epilepsy appear distinct inflammatory response and local hypoxia. Hypoxia-inducible factor (HIF)-1α is an essential effector molecule of hypoxia and inflammation, and may exert therefore a significant effect on the development of VPA-resistant epilepsy. We systematically assess the significance of HIF-1α on children and mice with VPA-resistant epilepsy, and investigated the micro (mi) RNAs that regulate HIF-1α expression. We established models of VPA-sensitive epilepsy and VPA-resistant epilepsy in mice, and confirmed that they had significant differences in epileptic behavior and electroencephalography data. Through proteomics analysis, we identified that HIF-1α was overexpressed in mice with VPA-resistant epilepsy, and regulated the expression of interleukin-1β and tumor necrosis factor-α. Increased expression of HIF-1α led to the increase of microglia and induced their polarization from the M2 phenotype to M1 phenotype, which triggered the release of proinflammatory mediators. Bioinformatics analysis of public databases demonstrated that miR-221-3p was reduced in VPA-resistant epilepsy, and negatively regulated HIF-1α expression. Intervention using miR-221-3p mimics reduced HIF-1α expression markedly and suppressed the activation of microglia and the release of inflammatory mediators, which relieved epileptic seizures of VPA-resistant epilepsy. These observations reveal miR-221-3p/HIF-1α as essential component in pathogenesis of VPA-resistant epilepsy which represent therapeutic antiseizure targets. |
format | Online Article Text |
id | pubmed-8419275 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84192752021-09-07 MicroRNA-221-3p Suppresses the Microglia Activation and Seizures by Inhibiting of HIF-1α in Valproic Acid-Resistant Epilepsy Fu, Meng Zhu, Yiqing Zhang, Junqi Wu, Wei Sun, Yunxia Zhang, Xuemei Tao, Jie Li, Zhiping Front Pharmacol Pharmacology One-third of patients with epilepsy suffer from drug-resistant epilepsy (DRE). Valproic acid (VPA) is a classic anticonvulsant drug, and its resistance is a crucial predictor of DRE, but the pathogenesis remain unknown. Most patients with VPA-resistant epilepsy appear distinct inflammatory response and local hypoxia. Hypoxia-inducible factor (HIF)-1α is an essential effector molecule of hypoxia and inflammation, and may exert therefore a significant effect on the development of VPA-resistant epilepsy. We systematically assess the significance of HIF-1α on children and mice with VPA-resistant epilepsy, and investigated the micro (mi) RNAs that regulate HIF-1α expression. We established models of VPA-sensitive epilepsy and VPA-resistant epilepsy in mice, and confirmed that they had significant differences in epileptic behavior and electroencephalography data. Through proteomics analysis, we identified that HIF-1α was overexpressed in mice with VPA-resistant epilepsy, and regulated the expression of interleukin-1β and tumor necrosis factor-α. Increased expression of HIF-1α led to the increase of microglia and induced their polarization from the M2 phenotype to M1 phenotype, which triggered the release of proinflammatory mediators. Bioinformatics analysis of public databases demonstrated that miR-221-3p was reduced in VPA-resistant epilepsy, and negatively regulated HIF-1α expression. Intervention using miR-221-3p mimics reduced HIF-1α expression markedly and suppressed the activation of microglia and the release of inflammatory mediators, which relieved epileptic seizures of VPA-resistant epilepsy. These observations reveal miR-221-3p/HIF-1α as essential component in pathogenesis of VPA-resistant epilepsy which represent therapeutic antiseizure targets. Frontiers Media S.A. 2021-08-23 /pmc/articles/PMC8419275/ /pubmed/34497517 http://dx.doi.org/10.3389/fphar.2021.714556 Text en Copyright © 2021 Fu, Zhu, Zhang, Wu, Sun, Zhang, Tao and Li. https://creativecommons.org/licenses/by/4.0/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) and the copyright owner(s) 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 | Pharmacology Fu, Meng Zhu, Yiqing Zhang, Junqi Wu, Wei Sun, Yunxia Zhang, Xuemei Tao, Jie Li, Zhiping MicroRNA-221-3p Suppresses the Microglia Activation and Seizures by Inhibiting of HIF-1α in Valproic Acid-Resistant Epilepsy |
title | MicroRNA-221-3p Suppresses the Microglia Activation and Seizures by Inhibiting of HIF-1α in Valproic Acid-Resistant Epilepsy |
title_full | MicroRNA-221-3p Suppresses the Microglia Activation and Seizures by Inhibiting of HIF-1α in Valproic Acid-Resistant Epilepsy |
title_fullStr | MicroRNA-221-3p Suppresses the Microglia Activation and Seizures by Inhibiting of HIF-1α in Valproic Acid-Resistant Epilepsy |
title_full_unstemmed | MicroRNA-221-3p Suppresses the Microglia Activation and Seizures by Inhibiting of HIF-1α in Valproic Acid-Resistant Epilepsy |
title_short | MicroRNA-221-3p Suppresses the Microglia Activation and Seizures by Inhibiting of HIF-1α in Valproic Acid-Resistant Epilepsy |
title_sort | microrna-221-3p suppresses the microglia activation and seizures by inhibiting of hif-1α in valproic acid-resistant epilepsy |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419275/ https://www.ncbi.nlm.nih.gov/pubmed/34497517 http://dx.doi.org/10.3389/fphar.2021.714556 |
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