Journal Article

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

Booth, Sophie J., Pillot, Thierry, Bagnall, James, Allan, Stuart M., Galea, James, Paszek, Pawel, Harte, Michael K., Yu, Shi, Daniels, Michael J. D., Fasolino, Victoria, Eder, Claudia, Latta, Clare, Jackson, Joshua, Schilling, Tom, Freeman, Sally, Fischer, Nicolas, Baldwin, Alex G., Rivers-Auty, Jack, Brough, David, Koziel, Violette, Lawrence, Catherine B., Wong, Raymond, Spencer, Nicholas G., Watremez, William, White, Claire S.

2016

Overview

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. NSAID-induced analgesia is typically induced by inhibition of COX enzymes. Here the authors show instead that fenamate NSAIDs inhibit the Nlrp3 inflammasome via an effect on volume-regulated anion channel function and also repurpose these drugs for therapeutic effect in rodent models of Alzheimer disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/21 / 13/51 / 14/19 / 631/250/256/2177 / 631/250/371 / 64/110 / 64/60 / 692/699/375/132 / 692/700/565/1436 / 82/29 / 9/74 / 96/31 / 96/95 / Acids / Alzheimer Disease - metabolism / Alzheimer Disease - prevention & control / Alzheimer's disease / Animals / Anti-inflammatory agents / Anti-Inflammatory Agents, Non-Steroidal - pharmacology / Bone Marrow Cells - metabolism / Cell Death / Chloride Channels - metabolism / Cysteine - metabolism / Cytokines / Disease / Enzymes / Female / Flufenamic Acid - pharmacology / Genotype / Humanities and Social Sciences / Inflammasomes - metabolism / Inflammation / Interleukin-1beta - metabolism / Macrophages - metabolism / Mefenamic Acid - pharmacology / Memory Disorders - drug therapy / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / multidisciplinary / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / Nonsteroidal anti-inflammatory drugs / Pattern recognition / Pattern Recognition, Visual - drug effects / Proteins / Rats / Rodents / Science / Science (multidisciplinary)