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Nat Commun. 2016 Aug 11;7:12504. doi: 10.1038/ncomms12504.

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

Author information

1
Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
2
St. George's University of London, Institute for Infection and Immunity, Cranmer Terrace, London SW17 0RE, UK.
3
Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
4
SynAging SAS, 24-30 rue Lionnois, Nancy F-54000, France.
5
Division of Neuroscience, Ninewells Medical School, University of Dundee, Dundee DD1 9SY, UK.

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.

PMID:
27509875
PMCID:
PMC4987536
DOI:
10.1038/ncomms12504
[Indexed for MEDLINE]
Free PMC Article

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