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Microvascular stabilization via blood-brain barrier regulation prevents seizure activity
Blood-brain barrier (BBB) dysfunction is associated with worse epilepsy outcomes however the underlying molecular mechanisms of BBB dysfunction remain to be elucidated. Tight junction proteins are important regulators of BBB integrity and in particular, the tight junction protein claudin-5 is the mo...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010415/ https://www.ncbi.nlm.nih.gov/pubmed/35422069 http://dx.doi.org/10.1038/s41467-022-29657-y |
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author | Greene, Chris Hanley, Nicole Reschke, Cristina R. Reddy, Avril Mäe, Maarja A. Connolly, Ruairi Behan, Claire O’Keeffe, Eoin Bolger, Isobel Hudson, Natalie Delaney, Conor Farrell, Michael A. O’Brien, Donncha F. Cryan, Jane Brett, Francesca M. Beausang, Alan Betsholtz, Christer Henshall, David C. Doherty, Colin P. Campbell, Matthew |
author_facet | Greene, Chris Hanley, Nicole Reschke, Cristina R. Reddy, Avril Mäe, Maarja A. Connolly, Ruairi Behan, Claire O’Keeffe, Eoin Bolger, Isobel Hudson, Natalie Delaney, Conor Farrell, Michael A. O’Brien, Donncha F. Cryan, Jane Brett, Francesca M. Beausang, Alan Betsholtz, Christer Henshall, David C. Doherty, Colin P. Campbell, Matthew |
author_sort | Greene, Chris |
collection | PubMed |
description | Blood-brain barrier (BBB) dysfunction is associated with worse epilepsy outcomes however the underlying molecular mechanisms of BBB dysfunction remain to be elucidated. Tight junction proteins are important regulators of BBB integrity and in particular, the tight junction protein claudin-5 is the most enriched in brain endothelial cells and regulates size-selectivity at the BBB. Additionally, disruption of claudin-5 expression has been implicated in numerous disorders including schizophrenia, depression and traumatic brain injury, yet its role in epilepsy has not been fully deciphered. Here we report that claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption. We show that targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption. Additionally, inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality. Finally, we identify that RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. Altogether, we propose that BBB stabilizing drugs could represent a new generation of agents to prevent seizure activity in epilepsy patients. |
format | Online Article Text |
id | pubmed-9010415 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90104152022-04-28 Microvascular stabilization via blood-brain barrier regulation prevents seizure activity Greene, Chris Hanley, Nicole Reschke, Cristina R. Reddy, Avril Mäe, Maarja A. Connolly, Ruairi Behan, Claire O’Keeffe, Eoin Bolger, Isobel Hudson, Natalie Delaney, Conor Farrell, Michael A. O’Brien, Donncha F. Cryan, Jane Brett, Francesca M. Beausang, Alan Betsholtz, Christer Henshall, David C. Doherty, Colin P. Campbell, Matthew Nat Commun Article Blood-brain barrier (BBB) dysfunction is associated with worse epilepsy outcomes however the underlying molecular mechanisms of BBB dysfunction remain to be elucidated. Tight junction proteins are important regulators of BBB integrity and in particular, the tight junction protein claudin-5 is the most enriched in brain endothelial cells and regulates size-selectivity at the BBB. Additionally, disruption of claudin-5 expression has been implicated in numerous disorders including schizophrenia, depression and traumatic brain injury, yet its role in epilepsy has not been fully deciphered. Here we report that claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption. We show that targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption. Additionally, inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality. Finally, we identify that RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. Altogether, we propose that BBB stabilizing drugs could represent a new generation of agents to prevent seizure activity in epilepsy patients. Nature Publishing Group UK 2022-04-14 /pmc/articles/PMC9010415/ /pubmed/35422069 http://dx.doi.org/10.1038/s41467-022-29657-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Greene, Chris Hanley, Nicole Reschke, Cristina R. Reddy, Avril Mäe, Maarja A. Connolly, Ruairi Behan, Claire O’Keeffe, Eoin Bolger, Isobel Hudson, Natalie Delaney, Conor Farrell, Michael A. O’Brien, Donncha F. Cryan, Jane Brett, Francesca M. Beausang, Alan Betsholtz, Christer Henshall, David C. Doherty, Colin P. Campbell, Matthew Microvascular stabilization via blood-brain barrier regulation prevents seizure activity |
title | Microvascular stabilization via blood-brain barrier regulation prevents seizure activity |
title_full | Microvascular stabilization via blood-brain barrier regulation prevents seizure activity |
title_fullStr | Microvascular stabilization via blood-brain barrier regulation prevents seizure activity |
title_full_unstemmed | Microvascular stabilization via blood-brain barrier regulation prevents seizure activity |
title_short | Microvascular stabilization via blood-brain barrier regulation prevents seizure activity |
title_sort | microvascular stabilization via blood-brain barrier regulation prevents seizure activity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010415/ https://www.ncbi.nlm.nih.gov/pubmed/35422069 http://dx.doi.org/10.1038/s41467-022-29657-y |
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