The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide.
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.
Department of Pharmacology, 360 MSRII, University of California, Irvine, CA 92697-4625, USA.
Jesse
J
Lo Verme
Jin
J
Fu
Giuseppe
G
Astarita
Giovanna
G
La Rana
Roberto
R
Russo
Antonio
A
Calignano
Daniele
D
Piomelli
D000577:Amides; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001483:Base Sequence; D002351:Carrageenan; D003433:Crosses, Genetic; D017931:DNA Primers; D004487:Edema / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D063388:Endocannabinoids; D004983:Ethanolamines; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010169:Palmitic Acids / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate
D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D017931:DNA Primers; D063388:Endocannabinoids; D004983:Ethanolamines; D047493:PPAR alpha; D010169:Palmitic Acids; C005958:palmidrol; D002351:Carrageenan; D013755:Tetradecanoylphorbol Acetate