Статья

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

Michael J. DanielsFaculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UKJack Rivers‐AutyFaculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UKTom SchillingSt. George's University of London, Institute for Infection and Immunity, Cranmer Terrace, London SW17 0RE, UKNicholas G. SpencerSt. George's University of London, Institute for Infection and Immunity, Cranmer Terrace, London SW17 0RE, UKWilliam WatremezManchester Pharmacy School, University of Manchester, Manchester M13 9PT, UKVictoria FasolinoManchester Pharmacy School, University of Manchester, Manchester M13 9PT, UKSophie J. BoothFaculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UKClaire WhiteFaculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UKAlex G. BaldwinManchester Pharmacy School, University of Manchester, Manchester M13 9PT, UKSally FreemanManchester Pharmacy School, University of Manchester, Manchester M13 9PT, UKRaymond WongFaculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UKClare LattaFaculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UKYu ShiFaculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UKJoshua JacksonManchester Pharmacy School, University of Manchester, Manchester M13 9PT, UKNicolas FischerSynAging SAS, 24-30 rue Lionnois, Nancy F-54000, FranceViolette KozielSynAging SAS, 24-30 rue Lionnois, Nancy F-54000, FranceThierry PillotSynAging SAS, 24-30 rue Lionnois, Nancy F-54000, FranceJames BagnallFaculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UKStuart M. AllanFaculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UKPawel PaszekFaculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UKJames GaleaDivision of Neuroscience, Ninewells Medical School, University of Dundee, Dundee DD1 9SY, UKMichael HarteManchester Pharmacy School, University of Manchester, Manchester M13 9PT, UKClaudia EderSt. George's University of London, Institute for Infection and Immunity, Cranmer Terrace, London SW17 0RE, UKCatherine B. LawrenceFaculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UKDavid BroughFaculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK

2016en

ABI

Аннотация

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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Идентификаторы

DOI: 10.1038/ncomms12504

Цитирования и источники

Цитирований: 3Использованных источников: 0

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