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Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage
BACKGROUND: Excitotoxicity is a central pathological pathway in many neurological diseases with blood–brain barrier (BBB) dysfunction. Kainate, an exogenous excitotoxin, induces epilepsy and BBB damage in animal models, but the direct effect of kainate on brain endothelial cells has not been studied...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008534/ https://www.ncbi.nlm.nih.gov/pubmed/32036791 http://dx.doi.org/10.1186/s12987-019-0166-1 |
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author | Barna, Lilla Walter, Fruzsina R. Harazin, András Bocsik, Alexandra Kincses, András Tubak, Vilmos Jósvay, Katalin Zvara, Ágnes Campos-Bedolla, Patricia Deli, Mária A. |
author_facet | Barna, Lilla Walter, Fruzsina R. Harazin, András Bocsik, Alexandra Kincses, András Tubak, Vilmos Jósvay, Katalin Zvara, Ágnes Campos-Bedolla, Patricia Deli, Mária A. |
author_sort | Barna, Lilla |
collection | PubMed |
description | BACKGROUND: Excitotoxicity is a central pathological pathway in many neurological diseases with blood–brain barrier (BBB) dysfunction. Kainate, an exogenous excitotoxin, induces epilepsy and BBB damage in animal models, but the direct effect of kainate on brain endothelial cells has not been studied in detail. Our aim was to examine the direct effects of kainate on cultured cells of the BBB and to test three anti-inflammatory and antioxidant drugs used in clinical practice, simvastatin, edaravone and dexamethasone, to protect against kainate-induced changes. METHODS: Primary rat brain endothelial cell, pericyte and astroglia cultures were used to study cell viability by impedance measurement. BBB permeability was measured on a model made from the co-culture of the three cell types. The production of nitrogen monoxide and reactive oxygen species was followed by fluorescent probes. The mRNA expression of kainate receptors and nitric oxide synthases were studied by PCR. RESULTS: Kainate damaged brain endothelial cells and made the immunostaining of junctional proteins claudin-5 and zonula occludens-1 discontinuous at the cell border indicating the opening of the barrier. The permeability of the BBB model for marker molecules fluorescein and albumin and the production of nitric oxide in brain endothelial cells were increased by kainate. Simvastatin, edaravone and dexamethasone protected against the reduced cell viability, increased permeability and the morphological changes in cellular junctions caused by kainate. Dexamethasone attenuated the elevated nitric oxide production and decreased the inducible nitric oxide synthase (NOS2/iNOS) mRNA expression increased by kainate treatment. CONCLUSION: Kainate directly damaged cultured brain endothelial cells. Simvastatin, edaravone and dexamethasone protected the BBB model against kainate-induced changes. Our results confirmed the potential clinical usefulness of these drugs to attenuate BBB damage. |
format | Online Article Text |
id | pubmed-7008534 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-70085342020-02-13 Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage Barna, Lilla Walter, Fruzsina R. Harazin, András Bocsik, Alexandra Kincses, András Tubak, Vilmos Jósvay, Katalin Zvara, Ágnes Campos-Bedolla, Patricia Deli, Mária A. Fluids Barriers CNS Research BACKGROUND: Excitotoxicity is a central pathological pathway in many neurological diseases with blood–brain barrier (BBB) dysfunction. Kainate, an exogenous excitotoxin, induces epilepsy and BBB damage in animal models, but the direct effect of kainate on brain endothelial cells has not been studied in detail. Our aim was to examine the direct effects of kainate on cultured cells of the BBB and to test three anti-inflammatory and antioxidant drugs used in clinical practice, simvastatin, edaravone and dexamethasone, to protect against kainate-induced changes. METHODS: Primary rat brain endothelial cell, pericyte and astroglia cultures were used to study cell viability by impedance measurement. BBB permeability was measured on a model made from the co-culture of the three cell types. The production of nitrogen monoxide and reactive oxygen species was followed by fluorescent probes. The mRNA expression of kainate receptors and nitric oxide synthases were studied by PCR. RESULTS: Kainate damaged brain endothelial cells and made the immunostaining of junctional proteins claudin-5 and zonula occludens-1 discontinuous at the cell border indicating the opening of the barrier. The permeability of the BBB model for marker molecules fluorescein and albumin and the production of nitric oxide in brain endothelial cells were increased by kainate. Simvastatin, edaravone and dexamethasone protected against the reduced cell viability, increased permeability and the morphological changes in cellular junctions caused by kainate. Dexamethasone attenuated the elevated nitric oxide production and decreased the inducible nitric oxide synthase (NOS2/iNOS) mRNA expression increased by kainate treatment. CONCLUSION: Kainate directly damaged cultured brain endothelial cells. Simvastatin, edaravone and dexamethasone protected the BBB model against kainate-induced changes. Our results confirmed the potential clinical usefulness of these drugs to attenuate BBB damage. BioMed Central 2020-02-10 /pmc/articles/PMC7008534/ /pubmed/32036791 http://dx.doi.org/10.1186/s12987-019-0166-1 Text en © The Author(s) 2020 Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Barna, Lilla Walter, Fruzsina R. Harazin, András Bocsik, Alexandra Kincses, András Tubak, Vilmos Jósvay, Katalin Zvara, Ágnes Campos-Bedolla, Patricia Deli, Mária A. Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage |
title | Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage |
title_full | Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage |
title_fullStr | Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage |
title_full_unstemmed | Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage |
title_short | Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage |
title_sort | simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008534/ https://www.ncbi.nlm.nih.gov/pubmed/32036791 http://dx.doi.org/10.1186/s12987-019-0166-1 |
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