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 & 5 others James Galea, Michael K. Harte, Claudia Eder, Catherine B. Lawrence, David Brough

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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

    Fingerprint

    Fenamates
    Inflammasomes
    rodents
    Rodentia
    Alzheimer Disease
    drugs
    Anti-Inflammatory Agents
    inhibitors
    enzymes
    peritoneum
    Flufenamic Acid
    Mefenamic Acid
    Pharmaceutical Preparations
    interleukins
    Cyclooxygenase 1
    acids
    macrophages
    Macrophages
    Peritoneum
    Memory Disorders

    Keywords

    • Dementia
    • Drug therapy
    • Inflammasome
    • Neuroimmunology

    Cite this

    Daniels, M. J. D., Rivers-Auty, J., Schilling, T., Spencer, N. G., Watremez, W., Fasolino, V., ... Brough, D. (2016). Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models. Nature Communications, 7, 1-10. [12504]. https://doi.org/10.1038/ncomms12504
    Daniels, Michael J. D. ; Rivers-Auty, Jack ; Schilling, Tom ; Spencer, Nicholas G. ; Watremez, William ; Fasolino, Victoria ; Booth, Sophie J. ; White, Claire S. ; Baldwin, Alex G. ; 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. ; Brough, David. / Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models. In: Nature Communications. 2016 ; Vol. 7. pp. 1-10.
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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.",
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    author = "Daniels, {Michael J. D.} and Jack Rivers-Auty and Tom Schilling and Spencer, {Nicholas G.} and William Watremez and Victoria Fasolino and Booth, {Sophie J.} and White, {Claire S.} and Baldwin, {Alex G.} and Sally Freeman and Raymond Wong and Clare Latta and Shi Yu and Joshua Jackson and Nicolas Fischer and Violette Koziel and Thierry Pillot and James Bagnall and Allan, {Stuart M.} and Pawel Paszek and James Galea and Harte, {Michael K.} and Claudia Eder and Lawrence, {Catherine B.} and David Brough",
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    Daniels, MJD, Rivers-Auty, J, Schilling, T, Spencer, NG, Watremez, W, Fasolino, V, Booth, SJ, White, CS, Baldwin, AG, Freeman, S, Wong, R, Latta, C, Yu, S, Jackson, J, Fischer, N, Koziel, V, Pillot, T, Bagnall, J, Allan, SM, Paszek, P, Galea, J, Harte, MK, Eder, C, Lawrence, CB & Brough, D 2016, 'Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models', Nature Communications, vol. 7, 12504, pp. 1-10. https://doi.org/10.1038/ncomms12504

    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 G.; 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.; Brough, David (Lead / Corresponding author).

    In: Nature Communications, Vol. 7, 12504, 11.08.2016, p. 1-10.

    Research output: Contribution to journalArticle

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    AU - Watremez, William

    AU - Fasolino, Victoria

    AU - Booth, Sophie J.

    AU - White, Claire S.

    AU - Baldwin, Alex G.

    AU - Freeman, Sally

    AU - Wong, Raymond

    AU - Latta, Clare

    AU - Yu, Shi

    AU - Jackson, Joshua

    AU - Fischer, Nicolas

    AU - Koziel, Violette

    AU - Pillot, Thierry

    AU - Bagnall, James

    AU - Allan, Stuart M.

    AU - Paszek, Pawel

    AU - Galea, James

    AU - Harte, Michael K.

    AU - Eder, Claudia

    AU - Lawrence, Catherine B.

    AU - Brough, David

    N1 - MJDD is funded by a MRC DTP studentship (MR/K501311/1). C.B.L., J.R.A. and D.B. are funded by the Alzheimer’s Society (211(AS-PG-2013-2007)). P.P. holds a BBSRC David Phillips Research Fellowship (BB/I017976/1). This work also supported by BBSRC grant BB/K003097/1. The work leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2012-2017) under grant agreement no 305564. A.G.B. is funded by the Manchester Pharmacy School and the University of Manchester Presidential Doctoral Scholar award. J.G. is funded by the Stroke Association (TSA 2012/07) and TASC (Tayside Academic Health Science Partnership). C.E. was funded by European Union FP7; Grant number: 279017.

    PY - 2016/8/11

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    N2 - 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.

    AB - 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.

    KW - Dementia

    KW - Drug therapy

    KW - Inflammasome

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    Daniels MJD, Rivers-Auty J, Schilling T, Spencer NG, Watremez W, Fasolino V et al. Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models. Nature Communications. 2016 Aug 11;7:1-10. 12504. https://doi.org/10.1038/ncomms12504