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

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

doi:10.1038/ncomms12504

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

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 PaszekJames Galea, Michael K. Harte, Claudia Eder, Catherine B. Lawrence, David Brough (Lead / Corresponding author)

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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.

Original language	English
Article number	12504
Pages (from-to)	1-10
Number of pages	10
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12504
Publication status	Published - 11 Aug 2016

Keywords

Dementia
Drug therapy
Inflammasome
Neuroimmunology

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Daniels, M. J. D., Rivers-Auty, J., Schilling, T., Spencer, N. G., Watremez, W., Fasolino, V., Booth, S. J., White, C. S., Baldwin, A. G., Freeman, S., Wong, R., Latta, C., Yu, S., Jackson, J., Fischer, N., Koziel, V., Pillot, T., Bagnall, J., Allan, S. M., ... Brough, D. (2016). Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models. Nature Communications, 7, 1-10. Article 12504. https://doi.org/10.1038/ncomms12504

@article{fc24161b711c47af9568f4013853c0d8,

title = "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.",

keywords = "Dementia, Drug therapy, Inflammasome, Neuroimmunology",

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

note = "MJDD is funded by a MRC DTP studentship (MR/K501311/1). C.B.L., J.R.A. and D.B. are funded by the Alzheimer{\textquoteright}s Society (211(AS-PG-2013-2007)). P.P. holds a BBSRC David Phillips Research Fellowship (BB/I017976/1). This work also supported by BBSRC grant BB/K003097/1. The work leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2012-2017) under grant agreement no 305564. A.G.B. is funded by the Manchester Pharmacy School and the University of Manchester Presidential Doctoral Scholar award. J.G. is funded by the Stroke Association (TSA 2012/07) and TASC (Tayside Academic Health Science Partnership). C.E. was funded by European Union FP7; Grant number: 279017.",

year = "2016",

month = aug,

day = "11",

doi = "10.1038/ncomms12504",

language = "English",

volume = "7",

pages = "1--10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Daniels, MJD, Rivers-Auty, J, Schilling, T, Spencer, NG, Watremez, W, Fasolino, V, Booth, SJ, White, CS, Baldwin, AG, Freeman, S, Wong, R, Latta, C, Yu, S, Jackson, J, Fischer, N, Koziel, V, Pillot, T, Bagnall, J, Allan, SM, Paszek, P, Galea, J, Harte, MK, Eder, C, Lawrence, CB & Brough, D 2016, 'Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models', Nature Communications, vol. 7, 12504, pp. 1-10. https://doi.org/10.1038/ncomms12504

TY - JOUR

T1 - Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models

AU - Daniels, Michael J. D.

AU - Rivers-Auty, Jack

AU - Schilling, Tom

AU - Spencer, Nicholas G.

AU - Watremez, William

AU - Fasolino, Victoria

AU - Booth, Sophie J.

AU - White, Claire S.

AU - Baldwin, Alex G.

AU - Freeman, Sally

AU - Wong, Raymond

AU - Latta, Clare

AU - Yu, Shi

AU - Jackson, Joshua

AU - Fischer, Nicolas

AU - Koziel, Violette

AU - Pillot, Thierry

AU - Bagnall, James

AU - Allan, Stuart M.

AU - Paszek, Pawel

AU - Galea, James

AU - Harte, Michael K.

AU - Eder, Claudia

AU - Lawrence, Catherine B.

AU - Brough, David

N1 - MJDD is funded by a MRC DTP studentship (MR/K501311/1). C.B.L., J.R.A. and D.B. are funded by the Alzheimer’s Society (211(AS-PG-2013-2007)). P.P. holds a BBSRC David Phillips Research Fellowship (BB/I017976/1). This work also supported by BBSRC grant BB/K003097/1. The work leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2012-2017) under grant agreement no 305564. A.G.B. is funded by the Manchester Pharmacy School and the University of Manchester Presidential Doctoral Scholar award. J.G. is funded by the Stroke Association (TSA 2012/07) and TASC (Tayside Academic Health Science Partnership). C.E. was funded by European Union FP7; Grant number: 279017.

PY - 2016/8/11

Y1 - 2016/8/11

N2 - 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.

AB - 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.

KW - Dementia

KW - Drug therapy

KW - Inflammasome

KW - Neuroimmunology

U2 - 10.1038/ncomms12504

DO - 10.1038/ncomms12504

M3 - Article

C2 - 27509875

SN - 2041-1723

VL - 7

SP - 1

EP - 10

JO - Nature Communications

JF - Nature Communications

M1 - 12504

ER -

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

Abstract

Keywords

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