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

TLDR

NSAIDs inhibit COX‑1 and COX‑2, while the NLRP3 inflammasome processes IL‑1β and is implicated in many inflammatory diseases. The study investigates whether fenamate NSAIDs can selectively inhibit the NLRP3 inflammasome. They do so by blocking the volume‑regulated anion channel in macrophages, independent of COX activity. Flufenamic and mefenamic acids reduced NLRP3‑driven inflammation in rodent air pouch and peritoneum models and improved memory in amyloid‑beta and transgenic Alzheimer’s mouse models, indicating fenamate NSAIDs could be repurposed as NLRP3 inhibitors and Alzheimer’s therapeutics.

Abstract

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.