title: Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models.
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.
authors: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
authors: Michael J D
authors: MJ
authors: Daniels
authors: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
authors: Jack
authors: J
authors: Rivers-Auty
authors: St. George's University of London, Institute for Infection and Immunity, Cranmer Terrace, London SW17 0RE, UK.
authors: Tom
authors: 0000-0002-0274-5482
authors: T
authors: Schilling
authors: St. George's University of London, Institute for Infection and Immunity, Cranmer Terrace, London SW17 0RE, UK.
authors: Nicholas G
authors: NG
authors: Spencer
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: William
authors: 0000-0003-2128-3049
authors: W
authors: Watremez
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: Victoria
authors: V
authors: Fasolino
authors: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
authors: Sophie J
authors: SJ
authors: Booth
authors: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
authors: Claire S
authors: CS
authors: White
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: Alex G
authors: AG
authors: Baldwin
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: Sally
authors: S
authors: Freeman
authors: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
authors: Raymond
authors: R
authors: Wong
authors: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
authors: Clare
authors: C
authors: Latta
authors: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
authors: Shi
authors: 0000-0003-0651-4769
authors: S
authors: Yu
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: Joshua
authors: 0000-0002-9736-2096
authors: J
authors: Jackson
authors: SynAging SAS, 24-30 rue Lionnois, Nancy F-54000, France.
authors: Nicolas
authors: N
authors: Fischer
authors: SynAging SAS, 24-30 rue Lionnois, Nancy F-54000, France.
authors: Violette
authors: V
authors: Koziel
authors: SynAging SAS, 24-30 rue Lionnois, Nancy F-54000, France.
authors: Thierry
authors: T
authors: Pillot
authors: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
authors: James
authors: J
authors: Bagnall
authors: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
authors: Stuart M
authors: SM
authors: Allan
authors: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
authors: Pawel
authors: 0000-0002-0363-0716
authors: P
authors: Paszek
authors: Division of Neuroscience, Ninewells Medical School, University of Dundee, Dundee DD1 9SY, UK.
authors: James
authors: J
authors: Galea
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: Michael K
authors: MK
authors: Harte
authors: St. George's University of London, Institute for Infection and Immunity, Cranmer Terrace, London SW17 0RE, UK.
authors: Claudia
authors: C
authors: Eder
authors: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
authors: Catherine B
authors: CB
authors: Lawrence
authors: Faculty of Biology, Medicine and Health, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
authors: David
authors: D
authors: Brough
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000378:metabolism; D016923:Cell Death; D018118:Chloride Channels / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D005260:Female; D005439:Flufenamic Acid / Q000494:pharmacology*; D005838:Genotype; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008528:Mefenamic Acid / Q000494:pharmacology*; D008569:Memory Disorders / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D010364:Pattern Recognition, Visual / Q000187:drug effects; D051381:Rats
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018118:Chloride Channels; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C573346:Nlrp3 protein, rat; D008528:Mefenamic Acid; D005439:Flufenamic Acid; D003545:Cysteine