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Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that severa...

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Autores principales: Daniels, Michael J. D., Rivers-Auty, Jack, Schilling, Tom, Spencer, Nicholas G., Watremez, William, Fasolino, Victoria, Booth, Sophie J., White, Claire S., Baldwin, Alex G., Freeman, Sally, Wong, Raymond, Latta, Clare, Yu, Shi, Jackson, Joshua, Fischer, Nicolas, Koziel, Violette, Pillot, Thierry, Bagnall, James, Allan, Stuart M., Paszek, Pawel, Galea, James, Harte, Michael K., Eder, Claudia, Lawrence, Catherine B., Brough, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987536/
https://www.ncbi.nlm.nih.gov/pubmed/27509875
http://dx.doi.org/10.1038/ncomms12504
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author Daniels, Michael J. D.
Rivers-Auty, Jack
Schilling, Tom
Spencer, Nicholas G.
Watremez, William
Fasolino, Victoria
Booth, Sophie J.
White, Claire S.
Baldwin, Alex G.
Freeman, Sally
Wong, Raymond
Latta, Clare
Yu, Shi
Jackson, Joshua
Fischer, Nicolas
Koziel, Violette
Pillot, Thierry
Bagnall, James
Allan, Stuart M.
Paszek, Pawel
Galea, James
Harte, Michael K.
Eder, Claudia
Lawrence, Catherine B.
Brough, David
author_facet Daniels, Michael J. D.
Rivers-Auty, Jack
Schilling, Tom
Spencer, Nicholas G.
Watremez, William
Fasolino, Victoria
Booth, Sophie J.
White, Claire S.
Baldwin, Alex G.
Freeman, Sally
Wong, Raymond
Latta, Clare
Yu, Shi
Jackson, Joshua
Fischer, Nicolas
Koziel, Violette
Pillot, Thierry
Bagnall, James
Allan, Stuart M.
Paszek, Pawel
Galea, James
Harte, Michael K.
Eder, Claudia
Lawrence, Catherine B.
Brough, David
author_sort Daniels, Michael J. D.
collection PubMed
description Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer's disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer's disease therapeutics.
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spelling pubmed-49875362016-08-30 Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models Daniels, Michael J. D. Rivers-Auty, Jack Schilling, Tom Spencer, Nicholas G. Watremez, William Fasolino, Victoria Booth, Sophie J. White, Claire S. Baldwin, Alex G. Freeman, Sally Wong, Raymond Latta, Clare Yu, Shi Jackson, Joshua Fischer, Nicolas Koziel, Violette Pillot, Thierry Bagnall, James Allan, Stuart M. Paszek, Pawel Galea, James Harte, Michael K. Eder, Claudia Lawrence, Catherine B. Brough, David Nat Commun Article Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer's disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer's disease therapeutics. Nature Publishing Group 2016-08-11 /pmc/articles/PMC4987536/ /pubmed/27509875 http://dx.doi.org/10.1038/ncomms12504 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Daniels, Michael J. D.
Rivers-Auty, Jack
Schilling, Tom
Spencer, Nicholas G.
Watremez, William
Fasolino, Victoria
Booth, Sophie J.
White, Claire S.
Baldwin, Alex G.
Freeman, Sally
Wong, Raymond
Latta, Clare
Yu, Shi
Jackson, Joshua
Fischer, Nicolas
Koziel, Violette
Pillot, Thierry
Bagnall, James
Allan, Stuart M.
Paszek, Pawel
Galea, James
Harte, Michael K.
Eder, Claudia
Lawrence, Catherine B.
Brough, David
Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models
title Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models
title_full Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models
title_fullStr Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models
title_full_unstemmed Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models
title_short Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models
title_sort fenamate nsaids inhibit the nlrp3 inflammasome and protect against alzheimer's disease in rodent models
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987536/
https://www.ncbi.nlm.nih.gov/pubmed/27509875
http://dx.doi.org/10.1038/ncomms12504
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