Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti-inﬂammatory agent

Francesca Borrelli¹,*,†, Barbara Romano¹,*,†, Stefania Petrosino²,†, Ester Pagano¹,†, Raffaele Capasso¹,†, Diana Coppola³, Giovanni Battista³, Pierangelo Orlando^4,5,†, Vincenzo Di Marzo²,† and Angelo A Izzo¹,†

¹Department of Pharmacy, University of Naples Federico II, Naples, Italy, ²Institute of Biomolecular Chemistry, National Research Council, Naples, Italy, ³Ospedale dei Pellegrini, Department of Diagnostic Services (Anatomy and Pathologic Histology Service), ASL 1, Naples, Italy, 4Institute of Protein Biochemistry, National Research Council, Naples, Italy, and ⁵National Institute of Optics – CNR, Pozzuoli, Italy

Abstract

BACKGROUND AND PURPOSE

Palmitoylethanolamide (PEA) acts via several targets, including cannabinoid CB1 and CB2 receptors, transient receptor potential vanilloid type-1 (TRPV1) ion channels, peroxisome proliferator-activated receptor alpha (PPAR α) and orphan G protein-coupled receptor 55 (GRR55), all involved in the control of intestinal inﬂammation. Here, we investigated the effect of PEA in a murine model of colitis.

EXPERIMENTAL APPROACH

Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Inﬂammation was assessed by evaluating inﬂammatory markers/parameters and by histology; intestinal permeability by a ﬂuorescent method; colonic cell proliferation by immunohistochemistry; PEA and endocannabinoid levels by liquid chromatography mass spectrometry; receptor and enzyme mRNA expression by quantitative RT-PCR.

KEY RESULTS

DNBS administration caused inﬂammatory damage, increased colonic levels of PEA and endocannabinoids, down-regulation of mRNA for TRPV1 and GPR55 but no changes in mRNA for CB1, CB2 and PPARα. Exogenous PEA (i.p. and/or p.o., 1 mg·kg−1)

attenuated inﬂammation and intestinal permeability, stimulated colonic cell proliferation, and increased colonic TRPV1 and CB1 receptor expression. The anti-inﬂammatory effect of PEA was attenuated or abolished by CB2 receptor, GPR55 or PPARα antagonists and further increased by the TRPV1 antagonist capsazepine.

CONCLUSIONS AND IMPLICATIONS

PEA improves murine experimental colitis, the effect being mediated by CB2 receptors, GPR55 and PPARα, and modulated by TRPV1 channels.

Abbreviations

2-AG, 2-arachidonoylglycerol; CB, cannabinoid; DNBS, 2,4,6-dinitrobenzenesulfonic acid; DSS, dextran sodium sulphate; FAAH, fatty acid amide hydrolase; GDE1, glycerophosphodiester PDE 1; IBD, inﬂammatory bowel disease;

MPO, myeloperoxidase; NAAA, N-acylethanolamine-hydrolysing acid amidase; NAPE-PLD,

N-arachidonyl-phosphatidylethanolamine PLD; OEA, oleoylethanolamide; PEA, palmitoylethanolamide; TRPV1, transient receptor potential vanilloid type-1