Adelmidrol, a palmitoylethanolamide analogue, as a new pharmacological treatment for the management of inflammatory bowel disease

Abstract

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 proliferatoractivated receptors (PPARs), we investigated the effects of a PPARγ antagonist, GW9662, on adelmidrol action. Adelmidrol (10mg/kg daily, o.s.) was tested in a murine experimentalmodel 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.