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

Citation

Daniels, MJD and Rivers-Auty, J and Schilling, T and Spencer, NG and Watremez, W and Fasolino, V and Booth, SJ and White, CS and Baldwin, AG and Freeman, S and Wong, R and Latta, C and Yu, S and Jackson, J and Fischer, N and Koziel, V and Pillot, T and Bagnall, J and Allan, SM and Paszek, P and Galea, J and Harte, MK and Eder, C and Lawrence, CB and Brough, D, Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models, Nature Communications, 7 Article 12504. ISSN 2041-1723 (2016) [Refereed Article]


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Copyright 2016 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License. (CC BY 4.0). 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/

DOI: doi:10.1038/ncomms12504

Abstract

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.

Item Details

Item Type:Refereed Article
Keywords:Alzheimer's disease, NSAID, inflammation, NLRP3
Research Division:Biomedical and Clinical Sciences
Research Group:Immunology
Research Field:Innate immunity
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Rivers-Auty, J (Dr Jack Auty)
ID Code:135821
Year Published:2016
Web of Science® Times Cited:196
Deposited By:Medicine
Deposited On:2019-11-15
Last Modified:2019-12-16
Downloads:13 View Download Statistics

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