Abstract
Peroxisome proliferator-activated receptor (PPAR)-α 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-α 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-α 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-α 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-α 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 κB-α (IκB-α) degradation and nuclear factor-κB (NF-κB) p65 activation in the cytosolic or nuclear extracts from spinal cord tissue. PEA prevented IkB-α degradation and NF-κB nuclear translocation, confirming the involvement of this transcriptional factor in the control of peripheral inflammation. The obligatory role of PPAR-α in mediating the effects of PEA was confirmed by the lack of the compounds anti-inflammatory effects in mutant mice lacking PPAR-α. In conclusion, our data show for the first time that PPAR-α activation in the CNS can control peripheral inflammation.
Footnotes
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This work was supported, in part, by Programmi di Ricerca di Interesse Nazionale 2003 grant from the Ministero dell'Istruzione, dell'Università e della Ricerca, Italy.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.123265.
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ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor; NF-κB, nuclear factor-κB; CNS, central nervous system; PEA, palmitoylethanolamide; COX, cyclooxygenase; iNOS, inducible nitric-oxide synthase; PBS, phosphate-buffered saline; IκB-α, inhibitor κB-α; Wy-14,643, pirinixic acid; 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl)thioacetic acid; GW7647, 2-[[4-[2-[[(cyclohexylamino)carbonyl](4-cyclohexylbutyl)amino]ethyl]-phenyl]thio]-2-methylpropanoic acid; GW0742, [4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid.
- Received March 27, 2007.
- Accepted June 11, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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