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 PaszekJames Galea, Michael K. Harte, Claudia Eder, Catherine B. Lawrence, David Brough

    Research output: Contribution to journalArticle

    134 Citations (Scopus)
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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.

    Original languageEnglish
    Article number12504
    Pages (from-to)1-10
    Number of pages10
    JournalNature Communications
    Volume7
    DOIs
    Publication statusPublished - 11 Aug 2016

    Keywords

    • Dementia
    • Drug therapy
    • Inflammasome
    • Neuroimmunology

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