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Daniels Michael J.D.♦, Rivers-Auty J.♦, Schilling T.♦, Spencer Nicholas G.♦, Watremez W.♦, Fasolino V.♦, Booth Sophie J.♦, White Claire S.♦, Baldwin Alex G.♦, Freeman S.♦, Wong R.♦, Latta C.♦, Yu S.♦, Jackson J.♦, Fischer N.♦, Koziel V.♦, Pillot T.♦, Bagnall J.♦, Allan Stuart M.♦, Paszek P.♦, Galea J.♦, Harte Michael K.♦, Eder C.♦, Lawrence Catherine B.♦, Brough D.♦, Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models,
Nature Communications, ISSN: 2041-1723, DOI: 10.1038/ncomms12504, Vol.7, pp.12504-1-10, 2016 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. Affiliations:
| Daniels Michael J.D. | - | other affiliation | | Rivers-Auty J. | - | other affiliation | | Schilling T. | - | other affiliation | | Spencer Nicholas G. | - | other affiliation | | Watremez W. | - | other affiliation | | Fasolino V. | - | other affiliation | | Booth Sophie J. | - | other affiliation | | White Claire S. | - | other affiliation | | Baldwin Alex G. | - | other affiliation | | Freeman S. | - | other affiliation | | Wong R. | - | other affiliation | | Latta C. | - | other affiliation | | Yu S. | - | other affiliation | | Jackson J. | - | other affiliation | | Fischer N. | - | other affiliation | | Koziel V. | - | other affiliation | | Pillot T. | - | other affiliation | | Bagnall J. | - | other affiliation | | Allan Stuart M. | - | other affiliation | | Paszek P. | - | other affiliation | | Galea J. | - | other affiliation | | Harte Michael K. | - | other affiliation | | Eder C. | - | other affiliation | | Lawrence Catherine B. | - | other affiliation | | Brough D. | - | other affiliation |
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