Pulmonary, Gastrointestinal and Urogenital Pharmacology Dietary supplementation of resveratrol attenuates chronic colonic inflammation in mice Susana Sánchez-Fidalgo ⁎, Ana Cárdeno, Isabel Villegas, Elena Talero, Catalina Alarcón de la Lastra Department of Pharmacology, School of Pharmacy, University of Seville, Spain abstract article info Article history: Received 23 September 2009 Received in revised form 29 December 2009 Accepted 25 January 2010 Available online 2 February 2010 Keywords: Resveratrol Chronic colitis Cytokines COX-2 iNOS p38 Ulcerative colitis is a nonspecific inflammatory disorder characterized by oxidative and nitrosative stress, leucocyte infiltration and upregulation of inflammatory mediators. Resveratrol is a polyphenolic compound found in grapes and wine, with multiple pharmacological actions, mainly anti-inflammatory, antioxidant, antitumour and immunomodulatory activities. The aim of this study was to investigate the effect of dietary resveratrol on chronic dextran sulphate sodium (DSS)-induced colitis. Six-week-old mice were randomized into two dietary groups: one standard diet and the other enriched with resveratrol at 20 mg/kg of diet. After 30 days, mice were exposed to 3% DSS for 5 days developing acute colitis that progressed to severe chronic inflammation after 21 days of water. Our results demonstrated that resveratrol group significantly attenuated the clinical signs such as loss of body weight, diarrhea and rectal bleeding improving results from disease activity index and inflammatory score. Moreover, the totality of resveratrol-fed animals survived and finished the treatment while animals fed with standard diet showed a mortality of 40%. Three weeks after DSS removal, the polyphenol caused substantial reductions of the rise of pro-inflammatory cytokines, TNF-α and IL-1β and an increase of the anti-inflammatory cytokine IL-10. Also resveratrol reduced prostaglandin E synthase-1 (PGES-1), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proteins expression, via downregulation of p38, a mitogen-activated protein kinases (MAPK) signal pathway. We conclude that resveratrol diet represents a novel approach to the treatment of chronic intestinal inflammation. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Inflammatory bowel disease is a chronic pathology by uncon- trolled inflammation of the intestinal mucosa which can affect part of the gastrointestinal tract. Pathophysiological bases of this disease involve genetic factors, immune dysregulation, barrier dysfunction, and a loss of immune tolerance toward the enteric flora (Kucharzik et al., 2006; Sánchez-Muñoz et al., 2008). Increase of inflammatory mediators, including reactive oxygen species such as nitric oxide, prostaglandins and inflammatory cytokines play an important role in immune dysregulation (Kolios et al., 2004; Rojas-Cartagena et al., 2005; Atreya and Neurath, 2005; Ito et al., 2006). Furthermore, reactive oxygen species can activate diverse downstream signalling pathways, for instance mitogen-activated protein kinases (MAPKs) which lead to the activation of transcription factors modulating a number of different steps in the inflammatory cascade. These include production of pro-inflammatory cytokines (tumour necrosis factor alpha (TNF-α), interleukin (IL)-1β, interferon (IFN)-γ, IL-6, IL-12 and IL-17 among others) in different cell-types, degranulation of neu- trophils, as well as the expression of important determining parameters namely prostaglandin E 2 -synthesizing enzymes, including prostaglandin E synthase (PGES)-1 and cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) (Dubuquoy et al., 2002; Collino et al., 2006; Pecchi et al., 2009). Resveratrol (trans-3,4,5-trihydroxystilbene), a natural polyphenol, is found in a large number of plant species including some components of the human diet, such as various fruits and vegetables and is abundant in grapes and in red wines. The last years, it has been the focus of numerous in vitro and in vivo studies where its biological attributes have been investigated, which include essentially antiox- idant and anti-inflammatory activities, anti-platelet aggregation effect, anti-atherogenic property, oestrogen-like growth promoting effect, growth-inhibiting activity, immunomodulation and chemo- prevention (Jang et al., 1997; Bradamante et al., 2004; de la Lastra and Villegas, 2007; Shakibaei et al., 2009). Among the possible mechan- isms responsible for its biological activities are downregulation of the inflammatory response through inhibition of synthesis and release of pro-inflammatory mediators, modification of eicosanoid synthesis, inhibition of Kupffer cells and adhesion molecules, inhibition of activated immune cells, or iNOS and COX-2 downregulation via its European Journal of Pharmacology 633 (2010) 78–84 ⁎ Corresponding author. Department of Pharmacology, School of Pharmacy, University of Seville, Profesor García González Street, 2. 41012-Seville, Spain. Tel.: +34 9 5 4559880; fax: +34 9 5 4556074. E-mail address: fidalgo@us.es (S. Sánchez-Fidalgo). 0014-2999/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2010.01.025 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar