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135821 - Fenamate NSAIDs inhibit the NLRP3 inflammasome.pdf (1.59 MB)

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

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posted on 2023-05-20, 08:21 authored by Daniels, MJD, Jack AutyJack Auty, 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
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.

History

Publication title

Nature Communications

Volume

7

Article number

12504

Number

12504

Pagination

1-10

ISSN

2041-1723

Department/School

Tasmanian School of Medicine

Publisher

Nature Pub. Group

Place of publication

United Kingdom

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Copyright 2016 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License. (CC BY 4.0). The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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  • Open

Socio-economic Objectives

Clinical health not elsewhere classified

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    University Of Tasmania

    Categories

    Keywords

    Alzheimer's diseaseNSAIDinflammationNLRP3

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    In Copyright

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