Adelmidrol, a Palmitoylethanolamide Analogue, as a New Pharmacological Treatment for the Management of Inflammatory Bowel Disease.
Leukocyte infiltration, improved levels of intercellular adhesion molecule 1 (ICAM-1), and oxidative stress in the colon are the principal factors in inflammatory bowel disease. The goal of the current study was to explore the effects of adelmidrol, an analog of the anti-inflammatory fatty acid amide signaling molecule palmitoylethanolamide, in mice subjected to experimental colitis. Additionally, to clarify whether the protective action of adelmidrol is dependent on the activation of peroxisome proliferator-activated receptors (PPARs), we investigated the effects of a PPARγ antagonist, GW9662, on adelmidrol action. Adelmidrol (10 mg/kg daily, o.s.) was tested in a murine experimental model of colitis induced by intracolonic administration of dinitrobenzene sulfonic acid. Nuclear factor-κB translocation, cyclooxygenase-2, and phosphoextracellular signal-regulated kinase, as well as tumor necrosis factor-α and interleukin-1β, were significantly increased in colon tissues after dinitrobenzene sulfonic acid administration. Immunohistochemical staining for ICAM-1, P-selectin, nitrotyrosine, and poly(ADP)ribose showed a positive staining in the inflamed colon. Treatment with adelmidrol decreased diarrhea, body weight loss, and myeloperoxidase activity. Adelmidrol treatment, moreover, reduced nuclear factor-κB translocation, cyclooxygenase-2, and phosphoextracellular signal-regulated kinase expression; proinflammatory cytokine release; and the incidence of nitrotyrosine and poly(ADP)ribose in the colon. It also decreased the upregulation of ICAM-1 and P-selectin. Adelmidrol treatment produced a reduction of Bax and an intensification of Bcl-2 expression. This study clearly demonstrates that adelmidrol exerts important anti-inflammatory effects that are partly dependent on PPARγ, suggesting that this molecule may represent a new pharmacologic approach for inflammatory bowel disease treatment.
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy (M.C., D.I., E.G., R.S., R.C., E.E.,S.C.); and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (S.C.).
Marika
M
Cordaro
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy (M.C., D.I., E.G., R.S., R.C., E.E.,S.C.); and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (S.C.).
Daniela
D
Impellizzeri
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy (M.C., D.I., E.G., R.S., R.C., E.E.,S.C.); and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (S.C.).
Enrico
E
Gugliandolo
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy (M.C., D.I., E.G., R.S., R.C., E.E.,S.C.); and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (S.C.).
Rosalba
R
Siracusa
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy (M.C., D.I., E.G., R.S., R.C., E.E.,S.C.); and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (S.C.).
Rosalia
R
Crupi
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy (M.C., D.I., E.G., R.S., R.C., E.E.,S.C.); and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (S.C.).
Emanuela
E
Esposito
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy (M.C., D.I., E.G., R.S., R.C., E.E.,S.C.); and Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri (S.C.) salvator@unime.it.
Salvatore
S
Cuzzocrea
D000577:Amides; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003998:Dicarboxylic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D004139:Dinitrofluorobenzene / Q000031:analogs & derivatives; D004983:Ethanolamines / Q000737:chemistry*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010169:Palmitic Acids / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000577:Amides; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D003998:Dicarboxylic Acids; D004983:Ethanolamines; D016328:NF-kappa B; D019007:P-Selectin; D047493:PPAR alpha; D047495:PPAR gamma; D010169:Palmitic Acids; D043885:Receptor, Cannabinoid, CB2; D018799:Intercellular Adhesion Molecule-1; C045305:2,4-dinitrofluorobenzene sulfonic acid; C552602:adelmidrol; C002744:3-nitrotyrosine; D014443:Tyrosine; C005958:palmidrol; D004139:Dinitrofluorobenzene; D009195:Peroxidase; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases