P-255 Therapy with Lupeol, a Natural Pentacyclic Triterpenoid, Attenuates Intestinal Inflammation in Rat

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Abstract

Background:

Inflammatory bowel disease (IBD) is a chronic nonspecific intestinal inflammatory disease, including ulcerative colitis (UC) and Crohn's disease (CD). Recent epidemiological data show that its incidence and prevalence have been increasing in many countries, in consequence of altered lifestyles and increased industrialization rate. Current therapeutic strategies for treating IBD have been moderately successful, however, a considerable proportion of patients are still refractory to conventional treatment. Medicinal plants have been introduced for centuries into clinical treatment of many human diseases and, recently, the potential effectiveness of herbs has been suggested for the treatment of UC. Active phytochemical substance from the medicinal plants itself or in combination with conventional therapies would largely benefit patients with UC as shown in some clinical trials. Lupeol, a pentacyclic triterpene found in many plant species, has many biological activities such as antioxidant, antinociceptive and anti-inflammatory. We hypothesize that Lupeol plays a role in controlling inflammatory responses, in hapten-induced colitis via 2,4,6-trinitrobenzene sulfonic acid (TNBS).

Methods:

Colitis was induced by TNBS (10 mg) in 50% ethanol (0.25 mL) given intrarectally to male Unib-Wh rats. Lupeol (1.5, 3.0 and 6.0 mg/kg) was administered orally 2, 24, 48, 72, 96, 120 e 148 hours after the induction of colitis. Non-colitic and colitic control groups received Tween solution 12% orally simultaneously. Animals were sacrificed by CO2 gas 172 hours after the induction of colitis. Macroscopic analysis, weight/length ratio of the colon, the presence of adhesions to adjacent organs and diarrhea were evaluated. Finally, the IFN-γ, TNF-α, IL-1β and IL-12 levels were measured by ELISA to evaluate the action mechanism involving this triterpenoid in the treatment of TNBS inflammation. All experimental procedures were approved by the Institutional Animal Care and Use Committee (CEUA) of State University of Campinas under the license number 2725-1. Animals were kept in accordance with guidelines for animal care prepared by the Committee on Care and Use of Laboratory Animal Resources, National Research Council, USA and Brazilian Arouca Law (number 11.794/2008).

Results:

Rats treated with TNBS showed prostration, piloerection and hypomotility. Macroscopic inspection of the cecum, colon and rectum showed evidence of severe colonic mucosal damage, with edema, deep ulcerations and hemorrhage. In addition, a significant increase in the weight/length ratio (as an indicator of inflammation), presence of adhesions and diarrhea were frequently observed in TNBS-treated rats. On the other hand, Lupeol (1.5, 3.0 and 6.0 mg/kg) treatment significantly reduced the macroscopic inflammation scores (P < 0.001, P < 0.01 and P < 0.05, respectively) and diminished the weight/length of the colon. The colonic injury by TNBS administration was also characterized by an increase in the proinflammatory cytokines IFN-γ, TNF-α, IL-1β and IL-12 levels. In contrast, these levels were significantly lower (P < 0.01, P < 0.001, P < 0.001 and P < 0.001) in the groups treated with Lupeol 1.5 mg/kg, respectively.

Conclusions:

Our studies have effectively demonstrated the therapeutic potential of Lupeol in reducing the severity of colitis and suggest that this plant-derived compound might be a potential molecule in the management of some inflammatory mediators involved in of IBD.

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