The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide.

Abstract	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-alpha (PPAR-alpha) as the molecular target responsible for the anti-inflammatory properties of PEA. PEA selectively activates PPAR-alpha in vitro with an EC(50) value of 3.1 +/- 0.4 microM and induces the expression of PPAR-alpha 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-alpha. The natural PPAR-alpha agonist oleoylethanolamide (OEA) and the synthetic PPAR-alpha agonists GW7647 and Wy-14643 mimic these effects in a PPAR-alpha-dependent manner. These findings indicate that PPAR-alpha 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-alpha.
Authors	Jesse Lo Verme, Jin Fu, Giuseppe Astarita, Giovanna La Rana, Roberto Russo, Antonio Calignano, Daniele Piomelli
Journal	Molecular pharmacology (Mol Pharmacol) Vol. 67 Issue 1 Pg. 15-9 (Jan 2005) ISSN: 0026-895X [Print] United States
PMID	15465922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Amides Anti-Inflammatory Agents, Non-Steroidal DNA Primers Endocannabinoids Ethanolamines PPAR alpha Palmitic Acids palmidrol Carrageenan Tetradecanoylphorbol Acetate
Topics	Amides Animals Anti-Inflammatory Agents, Non-Steroidal (pharmacology) Base Sequence Carrageenan Crosses, Genetic DNA Primers Edema (chemically induced, physiopathology, prevention & control) Endocannabinoids Ethanolamines HeLa Cells Humans Male Mice Mice, Inbred C57BL Mice, Knockout PPAR alpha (deficiency, genetics, physiology) Palmitic Acids (pharmacology) Polymerase Chain Reaction Tetradecanoylphorbol Acetate

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