Acute intracerebroventricular administration of palmitoylethanolamide, an endogenous peroxisome proliferator-activated receptor-alpha agonist, modulates carrageenan-induced paw edema in mice.
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.
D'Agostino
Giuseppe
G
Department of Experimental Pharmacology, University of Naples Federico II, via D. Montesano 49, 80131 Naples, Italy.
La Rana
Giovanna
G
Russo
Roberto
R
Sasso
Oscar
O
Iacono
Anna
A
Esposito
Emanuela
E
Raso
Giuseppina Mattace
GM
Cuzzocrea
Salvatore
S
Lo Verme
Jesse
J
Piomelli
Daniele
D
Meli
Rosaria
R
Calignano
Antonio
A
D000577:Amides; D000818:Animals; D002351:Carrageenan; D002490:Central Nervous System; D004333:Drug Administration Routes; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D063388:Endocannabinoids; D004983:Ethanolamines; D007249:Inflammation / Q000188:drug therapy; D051379:Mice; D047493:PPAR alpha / Q000819:agonists*; D010169:Palmitic Acids / Q000008:administration & dosage*
D000577:Amides; D063388:Endocannabinoids; D004983:Ethanolamines; D047493:PPAR alpha; D010169:Palmitic Acids; C005958:palmidrol; D002351:Carrageenan