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: Michael J D Daniels, Jack Rivers-Auty, Tom Schilling, Nicholas G Spencer, William Watremez, Victoria Fasolino, Sophie J Booth, Claire S White, Alex G Baldwin, Sally Freeman, Raymond Wong, Clare Latta, Shi Yu, Joshua Jackson, Nicolas Fischer, Violette Koziel, Thierry Pillot, James Bagnall, Stuart M Allan, Pawel Paszek, James Galea, Michael K Harte, Claudia Eder, Catherine B Lawrence, David Brough
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 12504 (08 11 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 27509875 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Chloride Channels
• Inflammasomes
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Nlrp3 protein, rat
• Mefenamic Acid
• Flufenamic Acid
• Cysteine

Topics

• Alzheimer Disease (metabolism, prevention & control)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Bone Marrow Cells (metabolism)
• Cell Death
• Chloride Channels (metabolism)
• Cysteine (metabolism)
• Female
• Flufenamic Acid (pharmacology)
• Genotype
• Inflammasomes (metabolism)
• Inflammation
• Interleukin-1beta (metabolism)
• Macrophages (metabolism)
• Mefenamic Acid (pharmacology)
• Memory Disorders (drug therapy)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Pattern Recognition, Visual (drug effects)
• Rats