Identifying points of control in inflammation is essential to discover safe and effective anti-inflammatory 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 N-acylethanolamine-hydrolyzing acid amidase (NAAA), which is highly expressed in macrophages. Here we report the discovery of the first potent and selective NAAA inhibitor, N-[(3S)-2-oxooxetan-3-yl]-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. The antiinflammatory effects of (S)-OOPP are stereoselective, mimicked by exogenous PEA, and abolished by PPAR-α deletion. The NAAA inhibitor 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.
Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation
ANTONIETTI, FRANCESCA;DURANTI, ANDREA;TONTINI, ANDREA;TARZIA, GIORGIO;
2009
Abstract
Identifying points of control in inflammation is essential to discover safe and effective anti-inflammatory 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 N-acylethanolamine-hydrolyzing acid amidase (NAAA), which is highly expressed in macrophages. Here we report the discovery of the first potent and selective NAAA inhibitor, N-[(3S)-2-oxooxetan-3-yl]-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. The antiinflammatory effects of (S)-OOPP are stereoselective, mimicked by exogenous PEA, and abolished by PPAR-α deletion. The NAAA inhibitor 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
