Open Access Research article

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

Daniela Impellizzeri1, Emanuela Esposito1, Rosanna Di Paola1, Akbar Ahmad1, Michela Campolo1, Angelo Peli2, Valeria Maria Morittu3, Domenico Britti3 and Salvatore Cuzzocrea14*

  • * Corresponding author: Salvatore Cuzzocrea salvator@unime.it

  • † Equal contributors

Author Affiliations

1 Department of Biological and Environmental Sciences, University of Messina, Messina, Italy

2 Clinical Veterinary Department Alma Mater Studiorum, University of Bologna, Bologna, Italy

3 Department of Health Sciences V. le Europa, Campus S. Venuta, Germaneto, 88100 Catanzaro, Italy

4 Manchester Biomedical Research Centre, Manchester Royal Infirmary, University of Manchester, Manchester, UK

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Arthritis Research & Therapy 2013, 15:R192  doi:10.1186/ar4382

Published: 18 November 2013

Abstract

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, antiinflammatory, 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 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 PEA (10 mg/kg 10% ethanol, intraperitoneally (i.p.)) or co-ultramicronized PEA + luteolin (1 mg/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 periarticular erythema and edema in the hindpaws. 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 histologic 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 proinflammatory cytokines and chemokines were significantly reduced by PEA + luteolin treatment.

Conclusions

We demonstrated that PEA co-ultramicronized with luteolin exerts an antiinflammatory effect during chronic inflammation and ameliorates CIA.