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

Carlos Solorzano, Chenggang Zhu, Natalia Battista, Giuseppe Astarita, Alessio Lodola, Silvia Rivara, Marco Mor, Roberto Russo, Mauro Maccarrone, Francesca Antonietti, Andrea Duranti, Andrea Tontini, Salvatore Cuzzocrea, Giorgio Tarzia, Daniele Piomelli

Research output: Contribution to journalArticlepeer-review

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-α (PPAR-α). PEA is preferentially hydrolyzed by the cysteine amidase Nacylethanolamine-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-αdeletion. (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-α 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 medicines.

Original languageEnglish
Pages (from-to)20966-20971
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number49
DOIs
Publication statusPublished - Dec 8 2009

Keywords

  • NAAA
  • Oleoylethanolamide
  • PPAR-α

ASJC Scopus subject areas

  • General

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