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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...

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Autores principales: Bellut, Maximilian, Raimondi, Anthony T., Haarmann, Axel, Zimmermann, Lena, Stoll, Guido, Schuhmann, Michael K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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