Nature communications · 2016
Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models.
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Daniels Michael J D, Rivers-Auty Jack, Schilling Tom, Spencer Nicholas G, Watremez William, Fasolino Victoria, Booth Sophie J, White Claire S, Baldwin Alex G, Freeman Sally, Wong Raymond, Latta Clare, Yu Shi, Jackson Joshua, Fischer Nicolas, Koziel Violette, Pillot Thierry, Bagnall James, Allan Stuart M, Paszek Pawel, Galea James, Harte Michael K, Eder Claudia, Lawrence Catherine B, Brough David
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.
Предметные рубрики MeSH
Alzheimer DiseaseAnimalsAnti-Inflammatory Agents, Non-SteroidalBone Marrow CellsCell DeathChloride ChannelsCysteineFemaleFlufenamic AcidGenotypeInflammasomesInflammationInterleukin-1betaMacrophagesMefenamic AcidMemory DisordersMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicNLR Family, Pyrin Domain-Containing 3 ProteinPattern Recognition, VisualRats