2-Pentadecyl-2-oxazoline, the oxazoline of PEA, modulates carrageenan-induced acute inflammation

N-acylethanolamines (NAEs) involve a family of lipid molecules existent in animal and
plant, with N-palmitoylethanolamide (PEA) that arouses great attention owing to its antiinflammatory,
analgesic and neuroprotective activities. Because PEA is produced on
demand and exerts pleiotropic effects, the modulation of specific amidases for NAEs
(and in particular NAE-hydrolyzing acid amidase NAAA, which is more selective for
PEA) could be a condition to preserve its levels. Here we investigate the effect of
2-Pentadecyl-2-oxazoline (PEA-OXA) the oxazoline of PEA, on human recombinant
NAAA in vitro and in an established model of Carrageenan (CAR)-induced rat paw
inflammation. PEA-OXA dose-dependently significantly inhibited recombinant NAAA
and, orally administered to rats (10 mg/kg), limiting histological damage, thermal
hyperalgesia and the increase of infiltrating inflammatory cells after CAR injection in
the rat right hindpaw, compared to ultramicronized PEA given orally at the same dose
(10 mg/kg). These effects were accompanied by elevation of paw PEA levels. Moreover,
PEA-OXA markedly reduced neutrophil infiltration and pro-inflammatory cytokine release
and prevented CAR-induced IkB-α degradation, nuclear translocation of NF-kB p65,
the increase of inducible nitric oxide synthase, cyclooxygenase-2, intercellular adhesion
molecule-1, and mast cell activation. Experiments in PPAR-α knockout mice showed
that the anti-inflammatory effects of PEA-OXA were not dependent on the presence
of PPAR-α receptors. In conclusion, NAAA modulators as PEA-OXA could help to
maximize the tissue availability of PEA by increasing its levels and anti-inflammatory
effects.