Acute intracerebroventricular administration of palmitoylethanolamide, an endogenous peroxisome proliferator-activated receptor-α 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 mu g of PEA, 30 min before carrageenan injection, reduced edema formation in the mouse carrageenan test. This effect was mimicked by 0.01 to 1 mu g 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 kappa B-alpha (I kappa B-alpha) degradation and nuclear factor-kappa B (NF-kappa B) p65 activation in the cytosolic or nuclear extracts from spinal cord tissue. PEA prevented IkB-alpha degradation and NF-kappa B 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.