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

Michael J. D. Daniels, Jack Rivers-Auty, Tom Schilling, Nicholas G. Spencer, William Watremez, Victoria Fasolino, Sophie J. Booth, Claire S. White, Alex G. Baldwin, Sally Freeman, Raymond Wong, Clare Latta, Shi Yu, Joshua Jackson, Nicolas Fischer, Violette Koziel, Thierry Pillot, James Bagnall, Stuart M. Allan, Pawel Paszek, James Galea, Michael K. Harte, Claudia Eder, Catherine B. Lawrence and David Brough ()
Additional contact information
Michael J. D. Daniels: Faculty of Biology, Medicine and Health, University of Manchester
Jack Rivers-Auty: Faculty of Biology, Medicine and Health, University of Manchester
Tom Schilling: St. George’s University of London, Institute for Infection and Immunity
Nicholas G. Spencer: St. George’s University of London, Institute for Infection and Immunity
William Watremez: Manchester Pharmacy School, University of Manchester
Victoria Fasolino: Manchester Pharmacy School, University of Manchester
Sophie J. Booth: Faculty of Biology, Medicine and Health, University of Manchester
Claire S. White: Faculty of Biology, Medicine and Health, University of Manchester
Alex G. Baldwin: Manchester Pharmacy School, University of Manchester
Sally Freeman: Manchester Pharmacy School, University of Manchester
Raymond Wong: Faculty of Biology, Medicine and Health, University of Manchester
Clare Latta: Faculty of Biology, Medicine and Health, University of Manchester
Shi Yu: Faculty of Biology, Medicine and Health, University of Manchester
Joshua Jackson: Manchester Pharmacy School, University of Manchester
Nicolas Fischer: SynAging SAS, 24–30 rue Lionnois
Violette Koziel: SynAging SAS, 24–30 rue Lionnois
Thierry Pillot: SynAging SAS, 24–30 rue Lionnois
James Bagnall: Faculty of Biology, Medicine and Health, University of Manchester
Stuart M. Allan: Faculty of Biology, Medicine and Health, University of Manchester
Pawel Paszek: Faculty of Biology, Medicine and Health, University of Manchester
James Galea: Ninewells Medical School, University of Dundee
Michael K. Harte: Manchester Pharmacy School, University of Manchester
Claudia Eder: St. George’s University of London, Institute for Infection and Immunity
Catherine B. Lawrence: Faculty of Biology, Medicine and Health, University of Manchester
David Brough: Faculty of Biology, Medicine and Health, University of Manchester

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12504

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