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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Acute Intracerebroventricular Administration of Palmitoylethanolamide, an Endogenous Peroxisome Proliferator-Activated Receptor- Agonist, Modulates Carrageenan-Induced Paw Edema in Mice

Department of Experimental Pharmacology, University of Naples "Federico II", Naples, Italy (G.D., G.L.R., R.R., O.S., A.I., E.E., G.M.R., R.M., A.C.); Istituiti di Ricovero e Cura a Carattere Scientifico Centro Neurolesi "Bonino-Pulejo", University of Messina, Messina, Italy (E.E., S.C.); Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy (S.C.); and Department of Pharmacology, University of California, Irvine, California (J.L.V., D.P.)

Peroxisome proliferator-activated receptor (PPAR)- 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- 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- activation. A single i.c.v. administration of 0.01 to 1 µg of PEA, 30 min before carrageenan injection, reduced edema formation in the mouse carrageenan test. This effect was mimicked by 0.01 to 1 µg of GW7647 [2-[[4-[2-[[(cyclohexylamino)carbonyl](4-cyclohexylbutyl)amino]ethyl]phenyl]thio]-2-methylpropanoic acid], a synthetic PPAR- 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- 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 B- (IB-) degradation and nuclear factor-B (NF-B) p65 activation in the cytosolic or nuclear extracts from spinal cord tissue. PEA prevented IkB- degradation and NF-B nuclear translocation, confirming the involvement of this transcriptional factor in the control of peripheral inflammation. The obligatory role of PPAR- in mediating the effects of PEA was confirmed by the lack of the compounds anti-inflammatory effects in mutant mice lacking PPAR-. In conclusion, our data show for the first time that PPAR- activation in the CNS can control peripheral inflammation.

Address correspondence to: Dr. Antonio Calignano, Department of Experimental Pharmacology, University of Naples "Federico II", via D. Montesano 49, 80131 Naples, Italy. E-mail: calignan{at}unina.it