Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation.

Proceedings of the National Academy of Sciences of the United States of America
Carlos SolorzanoDaniele Piomelli

Abstract

Identifying points of control in inflammation is essential to discovering safe and effective antiinflammatory medicines. Palmitoylethanolamide (PEA) is a naturally occurring lipid amide that, when administered as a drug, inhibits inflammatory responses by engaging peroxisome proliferator-activated receptor-alpha (PPAR-alpha). PEA is preferentially hydrolyzed by the cysteine amidase N-acylethanolamine-hydrolyzing acid amidase (NAAA), which is highly expressed in macrophages. Here we report the discovery of a potent and selective NAAA inhibitor, N-[(3S)-2-oxo-3-oxetanyl]-3-phenylpropanamide [(S)-OOPP], and show that this inhibitor increases PEA levels in activated leukocytes and blunts responses induced by inflammatory stimuli both in vitro and in vivo. These effects are stereoselective, mimicked by exogenous PEA, and abolished by PPAR-alpha deletion. (S)-OOPP also attenuates inflammation and tissue damage and improves recovery of motor function in mice subjected to spinal cord trauma. The results suggest that PEA activation of PPAR-alpha in leukocytes serves as an early stop signal that contrasts the progress of inflammation. The PEA-hydrolyzing amidase NAAA may provide a previously undescribed target for antiinflammatory medici...Continue Reading

References

Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Feb 7, 1997·The Journal of Biological Chemistry·T BisognoV Di Marzo
Apr 29, 1997·Proceedings of the National Academy of Sciences of the United States of America·S A KliewerJ M Lehmann
Jul 31, 1998·Nature·A CalignanoD Piomelli
Oct 30, 2001·British Journal of Pharmacology·R CapassoV Di Marzo
Mar 2, 2002·The Journal of Organic Chemistry·Manjinder S LallJohn C Vederas
Dec 4, 2002·Nature Medicine·Satish KathuriaDaniele Piomelli
Dec 20, 2002·Nature·Carl Nathan
Jul 13, 2004·Proceedings of the National Academy of Sciences of the United States of America·Benjamin F CravattAron H Lichtman
Jun 15, 2005·Annual Review of Biochemistry·Michele K McKinney, Benjamin F Cravatt
Jun 21, 2005·Life Sciences·Jesse LoVermeDaniele Piomelli
Jan 13, 2006·British Journal of Pharmacology·R J Flower
Feb 24, 2006·Nature Reviews. Immunology·Christopher K Glass, Sumito Ogawa
Aug 30, 2006·Proceedings of the National Academy of Sciences of the United States of America·Jie LiuGeorge Kunos
Sep 26, 2006·The Journal of Pharmacology and Experimental Therapeutics·Jesse LoVermeDaniele Piomelli
Aug 23, 2007·Chemistry & Biodiversity·Kazuhito TsuboiNatsuo Ueda
Nov 6, 2007·Trends in Immunology·Daniel S Straus, Christopher K Glass
Feb 19, 2008·The Journal of Biological Chemistry·Nataly ShtraizentEdward H Schuchman
Mar 28, 2008·The Journal of Pharmacology and Experimental Therapeutics·Tiziana GenoveseSalvatore Cuzzocrea
Apr 26, 2008·Nature Reviews. Immunology·Charles N SerhanThomas E Van Dyke
May 1, 2008·Nature Reviews. Drug Discovery·Vincenzo Di Marzo
May 21, 2008·Nature Reviews. Neuroscience·Phillip G Popovich, Erin E Longbrake
Jul 22, 2008·British Journal of Pharmacology·F D'AcquistoR J Flower
Jul 25, 2008·Nature·Steven J Bensinger, Peter Tontonoz
Nov 11, 2008·Proceedings of the National Academy of Sciences of the United States of America·Stephen E MalawistaCharles N Serhan

❮ Previous
Next ❯

Citations

Apr 10, 2013·Trends in Endocrinology and Metabolism : TEM·Daniele Piomelli
Aug 4, 2012·ACS Chemical Neuroscience·Tatsuya TaiNatsuo Ueda
Nov 2, 2011·Journal of Proteome Research·Jay M WestAlexandros Makriyannis
Mar 15, 2012·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Giuseppe D'AgostinoAntonio Calignano
Oct 31, 2012·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Stephen D Skaper, Laura Facci
Jul 13, 2011·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Kazuhito Tsuboi, Natsuo Ueda
Jun 29, 2012·American Journal of Veterinary Research·Luca CamporaFrancesca Abramo
Jan 30, 2014·Nature Neuroscience·Daniele Piomelli, Oscar Sasso
Nov 2, 2013·Inflammopharmacology·Stephen D SkaperPietro Giusti
May 7, 2014·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Tiziano BandieraDaniele Piomelli
Apr 22, 2014·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Iffat Ara Sonia RahmanNatsuo Ueda
May 20, 2014·Expert Opinion on Investigational Drugs·Mellar P Davis
Nov 21, 2015·Critical Reviews in Biochemistry and Molecular Biology·Silvia PontisDaniele Piomelli
Jan 16, 2016·The Journal of Pharmacology and Experimental Therapeutics·F T BonezziD Piomelli
Feb 10, 2016·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Nicola S OreficeGiuseppe Orefice
Jan 26, 2010·Biochimie·Stefania PetrosinoVincenzo Di Marzo
Mar 12, 2016·Progress in Lipid Research·Fabio Arturo IannottiStefania Petrosino
Jul 24, 2010·The Journal of Comparative Neurology·Sherry Shu-Jung HuAlex Straiker
Dec 24, 2010·British Journal of Pharmacology·Luciano De PetrocellisVincenzo Di Marzo
Sep 17, 2013·Immunology·Stephen D SkaperPietro Giusti
Sep 11, 2014·British Journal of Pharmacology·Francesca BorrelliAngelo A Izzo
Sep 29, 2015·Expert Opinion on Therapeutic Patents·Alessio LodolaSilvia Rivara

❮ Previous
Next ❯

Related Concepts

Related Feeds

Anti-inflammatory Treatments

A drug or substance that reduces inflammation (redness, swelling, and pain) in the body. Anti-inflammatory agents block certain substances in the body that cause inflammation and swelling. Discover the latest research on anti-inflammatory treatments here