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First published on June 12, 2007; DOI: 10.1124/jpet.107.123265

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Received for publication March 27, 2007.
Revised June 11, 2007.
Accepted for publication June 11, 2007.

Acute intracerebroventricular administration of palmitoylethanolamide, an endogenous PPAR-{alpha} agonist, modulates carrageenan-induced paw edema in mice

Giuseppe D'Agostino 1, Giovanna La Rana 1, Roberto Russo 1, Oscar Sasso 1, Anna Iacono 1, Emanuela Esposito 2, Giuseppina Mattace Raso 1, Salvatore Cuzzocrea 3, Jesse Lo Verme 4, Daniele Piomelli 4, Rosaria Meli 1, Antonio Calignano 1*

1 Dept Exp Pharmacol University Naples Federico II 2 Dept Exp Pharmacol Univ Naples Federico II; IRCCS Messina 3 Dept Clin & Exp Med and Pharm, School of Medicine, University of Messina/IRCCS 4 Department of Pharmacology, University of California, Irvine, California,USA.

* Address correspondence to: E-mail: calignan{at}unina.it

Abstract

Peroxisome proliferator-activated receptor {alpha} (PPAR-{alpha}) is a nuclear transcription factor. Although the presence of this receptor in different areas of CNS has been reported, its role remains unclear. Palmitoylethanolamide (PEA), a member of the fatty-acid ethanolamide family, acts peripherally as an endogenous PPAR-{alpha} ligand, exerting analgesic and anti-inflammatory effects. High levels of PEA in the CNS have been found, but the specific function of this lipid remains to be clarified. Using carrageenan-induced paw edema in mice, here we show that i.c.v. administration of PEA may control peripheral inflammation through central PPAR-{alpha} activation. A single i.c.v. administration of PEA (0.01-1µg), 30 min before carrageenan injection, reduced edema formation in the mouse carrageenan test. This effect was mimicked by GW7647 (0.01-1µg), a synthetic PPAR-{alpha} agonist. Moreover, central PEA administration significantly reduced the expression of the proinflammatory enzymes COX-2 and iNOS and significantly restored carrageenan-induced PPAR-{alpha} reduction in the spinal cord. To investigate the mechanism by which i.c.v. PEA attenuated the development of carrageenan-induced paw edema, we evaluated IkB-{alpha} degradation and NF-kB p65 activation in the cytosolic or nuclear extracts from spinal cord tissue. PEA prevented IkB-{alpha} degradation and NF-kB nuclear translocation confirming the involvement of this transcriptional factor in the control of peripheral inflammation. The obligatory role of PPAR-{alpha} in mediating PEA's effects was confirmed by the lack of the compounds anti-inflammatory effects in mutant mice lacking PPAR-{alpha}. In conclusion, our data show for the first time that PPAR-{alpha} activation in the CNS can control peripheral inflammation.


Key words: COX-2, PPAR-alpha, acylethanolamide, palmitoylethanolamide, paw edema, spinal cord




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