Acute intracerebroventricular administration of palmitoylethanolamide, an endogenous peroxisome proliferator-activated receptor-alpha agonist, modulates carrageenan-induced paw edema in mice

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 322; no. 3; pp. 1137 - 1143
• Main Authors: D'Agostino, Giuseppe, La Rana, Giovanna, Russo, Roberto, Sasso, Oscar, Iacono, Anna, Esposito, Emanuela, Raso, Giuseppina Mattace, Cuzzocrea, Salvatore, Lo Verme, Jesse, Piomelli, Daniele, Meli, Rosaria, Calignano, Antonio
• Format: Journal Article
• Language: English
• Published: United States 01.09.2007
• Subjects: Animals; Carrageenan; Central Nervous System; Drug Administration Routes; Edema - chemically induced; Edema - drug therapy; Endocannabinoids; Ethanolamines; Inflammation - drug therapy; Mice; Palmitic Acids - administration & dosage; PPAR alpha - agonists
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.107.123265

Peroxisome proliferator-activated receptor (PPAR)-alpha is a nuclear transcription factor. Although the presence of this receptor in different areas of central nervous system (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, 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 0.01 to 1 microg of PEA, 30 min before carrageenan injection, reduced edema formation in the mouse carrageenan test. This effect was mimicked by 0.01 to 1 microg of GW7647 [2-[[4-[2-[[(cyclohexylamino)carbonyl](4-cyclohexylbutyl)amino]ethyl]phenyl]thio]-2-methylpropanoic acid], a synthetic PPAR-alpha agonist. Moreover, central PEA administration significantly reduced the expression of the proinflammatory enzymes cyclooxygenase-2 and inducible nitric-oxide synthase, and it 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 inhibitor kappaB-alpha (I kappa B-alpha) degradation and nuclear factor-kappaB (NF-kappaB) p65 activation in the cytosolic or nuclear extracts from spinal cord tissue. PEA prevented IkB-alpha degradation and NF-kappaB nuclear translocation, confirming the involvement of this transcriptional factor in the control of peripheral inflammation. The obligatory role of PPAR-alpha in mediating the effects of PEA 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.