Ellagic acid ameliorates experimental chronic ulcerative colitis.

M Marin, RM Giner-Pons, JL Rios, MC Recio. University of Valencia, Pharmacology 46100, Spain

Introduction. Ulcerative colitis (UC) is characterized by an uncontrolled mucosal immune response influenced by reactive oxygen species (ROS) such as nitric oxide (NO), prostaglandins, and inflammatory cytokines; the main enzymes involved are the inducible isoforms of cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) (Camacho-Barquero et al., 2007). One of the diverse signaling pathways activated by ROS is that of mitogen-activated protein (MAPKs). For its role in controlling inflammation and cell differentiation, growth, death, and malignancy, recent reports support the importance of p38 MAPK in UC (Feng & Li, 2011). Ellagic acid is a naturally occurring dietary polyphenol with proven antioxidant, anti-inflammatory (Hasun et al., 2004; Roserio et al., 2008), and anticarcinogenic (Falsaperla et al., 2005) pharmacological properties. Chronic intestinal inflammation is clearly involved in colorectal cancer (CCR) (Ullman & Itzkowitz, 2011); in fact epidemiological studies have demonstrated that patients with chronic UC have a higher risk for developing CCR than the general population (Clapper et al., 2007). The role of ellagic acid has already been studied in experimental Crohn’s disease (Rosillo et al., 2011), but further investigation in chronic UC is needed.

Experimental Approach. We evaluated the protective effect of 0.5% ellagic acid diet supplements in a dextran sodium sulphate (DSS)-induced experimental model of chronic colitis in C57BL/6 mice. The mice were divided into three groups with 7-10 mice each and chronic colitis was induced by repeated administration of two 7-day cycles of 1% DSS followed by two 7-day cycles of 2% DSS (in drinking water). The DSS phases were interrupted by 1 week periods of treatment with drinking water. On day 56 mice were sacrificed and assessed for disease severity. The colon was removed for macroscopic examination and biochemical assays.

Key results and discussion. Daily ellagic acid treatment significantly improved colonic architecture, lowering the weight/length ratio by 48% (p<0.05) compared to that of untreated mice. In addition, it inhibited NF-κB activation by 41% (p<0.01) and p38 phosphorilation by 65% (p<0.01), thereby down-regulating iNOS and COX-2 expression by 66% (p<0.001) and 84% (p<0.001), respectively. It also almost abolished colonic mRNA expression of IL-6 by 92% (p<0.01). Dates were analyzed by one-way ANOVA and Dunnett’s test. Disease attenuation by ellagic acid is probably associated with the suppression of MAPK signaling pathway activation. Our study reinforces the hypothetical use of ellagic acid as an anti-inflammatory complement to conventional UC treatment and also as a chemopreventive drug against the development of CCR in chronic UC patients.

Acknowledgement. We thank the Spanish Government, MICIIN (SAF 2009-13059-C03-01).

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