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NLRP3 Inhibition Reduces rt-PA Induced Endothelial Dysfunction under Ischemic Conditions
Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is a mainstay of acute ischemic stroke treatment but is associated with bleeding complications, especially after prolonged large vessel occlusion. Recently, inhibition of the NLRP3 inflammasome led to preserved blood–brain barrier (B...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028140/ https://www.ncbi.nlm.nih.gov/pubmed/35453512 http://dx.doi.org/10.3390/biomedicines10040762 |
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author | Bellut, Maximilian Raimondi, Anthony T. Haarmann, Axel Zimmermann, Lena Stoll, Guido Schuhmann, Michael K. |
author_facet | Bellut, Maximilian Raimondi, Anthony T. Haarmann, Axel Zimmermann, Lena Stoll, Guido Schuhmann, Michael K. |
author_sort | Bellut, Maximilian |
collection | PubMed |
description | Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is a mainstay of acute ischemic stroke treatment but is associated with bleeding complications, especially after prolonged large vessel occlusion. Recently, inhibition of the NLRP3 inflammasome led to preserved blood–brain barrier (BBB) integrity in experimental stroke in vivo. To further address the potential of NLRP3 inflammasome inhibition as adjunct stroke treatment we used immortalized brain derived endothelial cells (bEnd5) as an in vitro model of the BBB. We treated bEnd5 with rt-PA in combination with the NLRP3 specific inhibitor MCC950 or vehicle under normoxic as well as ischemic (OGD) conditions. We found that rt-PA exerted a cytotoxic effect on bEnd5 cells under OGD confirming that rt-PA is harmful to the BBB. This detrimental effect could be significantly reduced by MCC950 treatment. Moreover, under ischemic conditions, the Cell Index—a sensible indicator for a patent BBB—and the protein expression of Zonula occludens 1 stabilized after MCC950 treatment. At the same time, the extent of endothelial cell death and NLRP3 expression decreased. In conclusion, NLRP3 inhibition can protect the BBB from rt-PA-induced damage and thereby potentially increase the narrow time window for safe thrombolysis in stroke. |
format | Online Article Text |
id | pubmed-9028140 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-90281402022-04-23 NLRP3 Inhibition Reduces rt-PA Induced Endothelial Dysfunction under Ischemic Conditions Bellut, Maximilian Raimondi, Anthony T. Haarmann, Axel Zimmermann, Lena Stoll, Guido Schuhmann, Michael K. Biomedicines Communication Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is a mainstay of acute ischemic stroke treatment but is associated with bleeding complications, especially after prolonged large vessel occlusion. Recently, inhibition of the NLRP3 inflammasome led to preserved blood–brain barrier (BBB) integrity in experimental stroke in vivo. To further address the potential of NLRP3 inflammasome inhibition as adjunct stroke treatment we used immortalized brain derived endothelial cells (bEnd5) as an in vitro model of the BBB. We treated bEnd5 with rt-PA in combination with the NLRP3 specific inhibitor MCC950 or vehicle under normoxic as well as ischemic (OGD) conditions. We found that rt-PA exerted a cytotoxic effect on bEnd5 cells under OGD confirming that rt-PA is harmful to the BBB. This detrimental effect could be significantly reduced by MCC950 treatment. Moreover, under ischemic conditions, the Cell Index—a sensible indicator for a patent BBB—and the protein expression of Zonula occludens 1 stabilized after MCC950 treatment. At the same time, the extent of endothelial cell death and NLRP3 expression decreased. In conclusion, NLRP3 inhibition can protect the BBB from rt-PA-induced damage and thereby potentially increase the narrow time window for safe thrombolysis in stroke. MDPI 2022-03-24 /pmc/articles/PMC9028140/ /pubmed/35453512 http://dx.doi.org/10.3390/biomedicines10040762 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Communication Bellut, Maximilian Raimondi, Anthony T. Haarmann, Axel Zimmermann, Lena Stoll, Guido Schuhmann, Michael K. NLRP3 Inhibition Reduces rt-PA Induced Endothelial Dysfunction under Ischemic Conditions |
title | NLRP3 Inhibition Reduces rt-PA Induced Endothelial Dysfunction under Ischemic Conditions |
title_full | NLRP3 Inhibition Reduces rt-PA Induced Endothelial Dysfunction under Ischemic Conditions |
title_fullStr | NLRP3 Inhibition Reduces rt-PA Induced Endothelial Dysfunction under Ischemic Conditions |
title_full_unstemmed | NLRP3 Inhibition Reduces rt-PA Induced Endothelial Dysfunction under Ischemic Conditions |
title_short | NLRP3 Inhibition Reduces rt-PA Induced Endothelial Dysfunction under Ischemic Conditions |
title_sort | nlrp3 inhibition reduces rt-pa induced endothelial dysfunction under ischemic conditions |
topic | Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028140/ https://www.ncbi.nlm.nih.gov/pubmed/35453512 http://dx.doi.org/10.3390/biomedicines10040762 |
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