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Mediates the Anti-Inflammatory Actions of Palmitoylethanolamide
Department of Pharmacology (J.L.V., D.P.), Department of Psychiatry and Human Behavior (J.F., G.A.), and Center for the Neurobiology of Learning and Memory (D.P.), University of California, Irvine, Irvine, California; and Department of Experimental Pharmacology, University of Naples, Naples, Italy (G.L.R., R.R., A.C.)
Palmitoylethanolamide (PEA), the naturally occurring amide of palmitic acid and ethanolamine, reduces pain and inflammation through an as-yet-uncharacterized mechanism. Here, we identify the nuclear receptor peroxisome proliferator-activated receptor-
(PPAR-) as the molecular target responsible for the anti-inflammatory properties of PEA. PEA selectively activates PPAR- in vitro with an EC50 value of 3.1 ± 0.4 µM and induces the expression of PPAR- mRNA when applied topically to mouse skin. In two animal models, carrageenan-induced paw edema and phorbol ester-induced ear edema, PEA attenuates inflammation in wild-type mice but has no effect in mice deficient in PPAR-. The natural PPAR- agonist oleoylethanolamide (OEA) and the synthetic PPAR- agonists GW7647 and Wy-14643 mimic these effects in a PPAR-–dependent manner. These findings indicate that PPAR- mediates the anti-inflammatory effects of PEA and suggest that this fatty-acid ethanolamide may serve, like its analog OEA, as an endogenous ligand of PPAR-.
Address correspondence to: Dr. Daniele Piomelli, Department of Pharmacology, 360 MSRII, University of California, Irvine, California 92697-4625. E-mail: piomelli{at}uci.edu
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