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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, 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. and Brough, David 2016. Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models. Nature Communications 7 , 12504. 10.1038/ncomms12504

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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 Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Nature Publishing Group
ISSN: 2041-1723
Date of First Compliant Deposit: 19 March 2018
Date of Acceptance: 6 July 2016
Last Modified: 20 Mar 2018 12:31
URI: http://orca.cf.ac.uk/id/eprint/110003

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