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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 Wo, 2016. "Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models," Nature Communications, Nature, vol. 7(1), pages 1-10, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12504
    DOI: 10.1038/ncomms12504
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