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.