Palmitoylethanolamide and luteolin ameliorate development of arthritis caused by injection of collagen type II in mice

Introduction N-palmitoylethanolamine (PEA) is an endogenous fatty acid amide belonging to the family of the N-acylethanolamines (NAEs). Recently, several studies demonstrated that PEA is an important analgesic, anti-inflammatory and neuroprotective mediator. The aim of this study was to investigate the effect of co-ultramicronized PEA + luteolin formulation on the modulation of the inflammatory response in mice subjected to collagen-induced arthritis (CIA). Methods CIA was induced by an intradermally injection of 100 μl of the emulsion (containing 100 μg of bovine type II collagen (CII)) and complete Freund’s adjuvant (CFA) at the base of the tail. On day 21, a second injection of CII in CFA was administered. Mice subjected to CIA were administered with PEA (10 mg/kg 10% ethanol, intraperitoneally (i.p.)) or with coultramicronized PEA + luteolin (1mg/kg, i.p.) every 24 hours, starting from day 25 to 35. Results Mice developed erosive hind paw arthritis when immunized with CII in CFA. Macroscopic clinical evidence of CIA first appeared as peri-articular erythema and edema in the hind paws. The incidence of CIA was 100% by day 28 in the CII challenged mice and the severity of CIA progressed over a 35-day period with a resorption of bone. The histopathology of CIA included erosion of the cartilage at the joint. Treatment with PEA or PEA + luteolin ameliorated the clinical signs at days 26 to 35 and improved histological status in the joint and paw. The degree of oxidative and nitrosative damage was significantly reduced in PEA + luteolin treated mice as indicated by nitrotyrosine and malondialdehyde (MDA) levels. Plasma levels of the pro-inflammatory cytokines and chemokines were significantly reduced by PEA + luteolin treatment. Conclusions We demonstrated PEA co-ultramicronized with luteolin exerts an anti-inflammatory effect during chronic inflammation and ameliorates CI