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

Giuseppe D'Agostino, Giovanna La Rana, Roberto Russo, Oscar Sasso, Anna Iacono, Emanuela Esposito, Giuseppina Mattace Raso, Salvatore Cuzzocrea, Jesse Lo Verme, Daniele Piomelli, Rosaria Meli, Antonio Calignano

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Abstract

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.
Original languageEnglish
Pages (from-to)1137-43
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume322
Issue number3
Early online date12 Jun 2007
DOIs
Publication statusPublished - Sep 2007

Keywords

  • Animals
  • Carrageenan
  • Central Nervous System
  • Drug Administration Routes
  • Edema
  • Endocannabinoids
  • Ethanolamines
  • Inflammation
  • Mice
  • PPAR alpha
  • Palmitic Acids

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    D'Agostino, G., La Rana, G., Russo, R., Sasso, O., Iacono, A., Esposito, E., Raso, G. M., Cuzzocrea, S., Lo Verme, J., Piomelli, D., Meli, R., & Calignano, A. (2007). Acute intracerebroventricular administration of palmitoylethanolamide, an endogenous peroxisome proliferator-activated receptor-alpha agonist, modulates carrageenan-induced paw edema in mice. Journal of Pharmacology and Experimental Therapeutics, 322(3), 1137-43. https://doi.org/10.1124/jpet.107.123265