Received for publication August 18, 2004.
Revised September 14, 2004.
Accepted for publication September 27, 2004.

The nuclear receptor PPAR- mediates the antiinflammatory actions of palmitoylethanolamide

Abstract

Palmitoylethanolamide (PEA), the naturally occurring amide of palmitic acid and ethanolamine (Kuehl et al., 1957; Bachur et al., 1965), reduces pain and inflammation (Benvenuti et al., 1968; Mazzari et al., 1996; Calignano et al., 1998; Jaggar et al., 1998) through an as-yet-uncharacterized mechanism. Here we identify the nuclear receptor PPAR- (peroxisome proliferator-activated receptor-) as the molecular target responsible for the antiinflammatory properties of PEA. PEA selectively activates PPAR- in vitro with a half-maximal effective concentration (EC₅₀) 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 antiinflammatory effects of PEA and suggest that this fatty-acid ethanolamide may serve, like its analog OEA (Fu et al., 2003) as an endogenous ligand of PPAR-.

Key words: Cannabinoid, PPARs