The Nuclear Receptor Peroxisome Proliferator-Activated Receptor-α Mediates the Anti-Inflammatory Actions of Palmitoylethanolamide
- Jesse Lo Verme,
- Jin Fu,
- Giuseppe Astarita,
- Giovanna La Rana,
- Roberto Russo,
- Antonio Calignano and
- Daniele Piomelli
- 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.)
- Address correspondence to:
Dr. Daniele Piomelli, Department of Pharmacology, 360 MSRII, University of California, Irvine, California 92697-4625. E-mail: piomelli{at}uci.edu
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-α (PPAR-α) as the molecular target responsible for the anti-inflammatory properties of PEA. PEA selectively activates PPAR-α in vitro with an EC50 value of 3.1 ± 0.4 μM and induces the expression of PPAR-α 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-α. The natural PPAR-α agonist oleoylethanolamide (OEA) and the synthetic PPAR-α agonists GW7647 and Wy-14643 mimic these effects in a PPAR-α–dependent manner. These findings indicate that PPAR-α 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-α.
Footnotes
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This research was supported by the Sandler Program on Asthma Research and the University of California Discovery Grant (to D.P.).
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi: 10.1124/mol.104.006353.
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ABBREVIATIONS: PEA, palmitoylethanolamide; PPAR, peroxisome proliferator-activated receptor; OEA, oleoylethanolamide; TPA, 12-O-tetradecanoylphorbol-13-acetate; DMEM, Dulbecco's modified Eagle's medium; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; CB2, cannabinoid type-2; Wy-14643, 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl)thioacetic acid; SR144528, N-((1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide); GW7647, 2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)-phenyl-thio)-2-methyl-propionic acid.
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- Received August 17, 2004.
- Accepted September 27, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
