Fenamate NSAIDs Inhibit the NLRP3 Inflammasome and Protect Against Alzheimer's Disease in Rodent Models

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Aug 12

PMID 27509875

Citations 194

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

Affiliations

Soon will be listed here.

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.

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References

Hua K, Chou J, Ka S, Tasi Y, Chen A, Wu S . Cyclooxygenase-2 regulates NLRP3 inflammasome-derived IL-1β production. J Cell Physiol. 2014; 230(4):863-74. DOI: 10.1002/jcp.24815. View

Heneka M, Carson M, El Khoury J, Landreth G, Brosseron F, Feinstein D . Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015; 14(4):388-405. PMC: 5909703. DOI: 10.1016/S1474-4422(15)70016-5. View

Desbene C, Malaplate-Armand C, Youssef I, Garcia P, Stenger C, Sauvee M . Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit. Neurobiol Aging. 2011; 33(6):1123.e17-29. DOI: 10.1016/j.neurobiolaging.2011.11.008. View

Youssef I, Florent-Bechard S, Malaplate-Armand C, Koziel V, Bihain B, Olivier J . N-truncated amyloid-beta oligomers induce learning impairment and neuronal apoptosis. Neurobiol Aging. 2007; 29(9):1319-33. DOI: 10.1016/j.neurobiolaging.2007.03.005. View

Sanders M, Parsons M, Howard A, Liu J, Fassio S, Martinez J . Single-cell imaging of inflammatory caspase dimerization reveals differential recruitment to inflammasomes. Cell Death Dis. 2015; 6:e1813. PMC: 4650733. DOI: 10.1038/cddis.2015.186. View

Voss F, Ullrich F, Munch J, Lazarow K, Lutter D, Mah N . Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science. 2014; 344(6184):634-8. DOI: 10.1126/science.1252826. View

Small B, McColl B, Allmendinger R, Pahle J, Lopez-Castejon G, Rothwell N . Efficient discovery of anti-inflammatory small-molecule combinations using evolutionary computing. Nat Chem Biol. 2011; 7(12):902-8. PMC: 3223407. DOI: 10.1038/nchembio.689. View

Compan V, Baroja-Mazo A, Lopez-Castejon G, Gomez A, Martinez C, Angosto D . Cell volume regulation modulates NLRP3 inflammasome activation. Immunity. 2012; 37(3):487-500. DOI: 10.1016/j.immuni.2012.06.013. View

Coll R, Robertson A, Chae J, Higgins S, Munoz-Planillo R, Inserra M . A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015; 21(3):248-55. PMC: 4392179. DOI: 10.1038/nm.3806. View

10.

Stauber T . The volume-regulated anion channel is formed by LRRC8 heteromers – molecular identification and roles in membrane transport and physiology. Biol Chem. 2015; 396(9-10):975-90. DOI: 10.1515/hsz-2015-0127. View

11.

Karperien A, Ahammer H, Jelinek H . Quantitating the subtleties of microglial morphology with fractal analysis. Front Cell Neurosci. 2013; 7:3. PMC: 3558688. DOI: 10.3389/fncel.2013.00003. View

12.

Knight E, Martins I, Gumusgoz S, Allan S, Lawrence C . High-fat diet-induced memory impairment in triple-transgenic Alzheimer's disease (3xTgAD) mice is independent of changes in amyloid and tau pathology. Neurobiol Aging. 2014; 35(8):1821-32. PMC: 4024197. DOI: 10.1016/j.neurobiolaging.2014.02.010. View

13.

Hornung V, Bauernfeind F, Halle A, Samstad E, Kono H, Rock K . Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008; 9(8):847-56. PMC: 2834784. DOI: 10.1038/ni.1631. View

14.

Rao P, Knaus E . Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J Pharm Pharm Sci. 2009; 11(2):81s-110s. DOI: 10.18433/j3t886. View

15.

Hoffman H, Scott P, Mueller J, Misaghi A, Stevens S, Yancopoulos G . Role of the leucine-rich repeat domain of cryopyrin/NALP3 in monosodium urate crystal-induced inflammation in mice. Arthritis Rheum. 2010; 62(7):2170-9. PMC: 2929807. DOI: 10.1002/art.27456. View

16.

Guinamard R, Simard C, Del Negro C . Flufenamic acid as an ion channel modulator. Pharmacol Ther. 2013; 138(2):272-84. PMC: 4116821. DOI: 10.1016/j.pharmthera.2013.01.012. View

17.

Dinarello C . Biologic basis for interleukin-1 in disease. Blood. 1996; 87(6):2095-147. View

18.

Lamkanfi M, Dixit V . Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol. 2012; 28:137-61. DOI: 10.1146/annurev-cellbio-101011-155745. View

19.

SOLLE M, Labasi J, Perregaux D, Stam E, Petrushova N, Koller B . Altered cytokine production in mice lacking P2X(7) receptors. J Biol Chem. 2000; 276(1):125-32. DOI: 10.1074/jbc.M006781200. View

20.

Bagnall J, Boddington C, Boyd J, Brignall R, Rowe W, Jones N . Quantitative dynamic imaging of immune cell signalling using lentiviral gene transfer. Integr Biol (Camb). 2015; 7(6):713-25. DOI: 10.1039/c5ib00067j. View