Therapeutic action and underlying mechanisms of a combination of two pentacyclic triterpenes, aand Β-amyrin, in a mouse model of colitis

Abstract

Background and purpose: α,Β-amyrin are pentacyclic triterpenes found in plants and are known to exhibit pronounced anti-inflammatory effects. Here, we evaluated the effects of a 1:1 mixture of α,Β-amyrin (α,Β-amyrin) on an experimental model of colitis in mice. Experimental approach: Colitis was induced in Swiss male mice by trinitrobenzene sulphonic acid (TNBS) and followed up to 72 h; animals were treated systemically with a,b-amyrin, dexamethasone or vehicle. Macro-and microscopic damage, myeloperoxidase activity and cytokine levels were assessed in colons. Histological sections were immunostained for cyclooxygenase-2 (COX-2), vascular endothelial growth factor, phospho-p65 nuclear factor-kB (NF-kB) and phospho-cyclic AMP response element-binding protein (CREB) Key results: TNBS-induced colitis was associated with tissue damage, neutrophil infiltration and time-dependent increase of inflammatory mediators. Treatment with α,Β-amyrin (3 mg-kg-1, i.p.) or dexamethasone (1 mg-kg-1, s.c.) consistently improved tissue damage scores and abolished polymorphonuclear cell infiltration. a,b-Amyrin, like dexamethasone, signifi-cantly diminished interleukin (IL)-1b levels and partially restored IL-10 levels in colon tissues 72 h after colitis induction, but only α,Β-amyrin reduced vascular endothelial growth factor expression by immunohistochemistry. The colonic expression of COX-2 at 24 h and that of phospho-NF-kB and phospho-CREB (peaking at 6 h) after colitis induction were consistently inhibited by both α,Β-amyrin and dexamethasone. Conclusions and implications: Systemic administration of a,b-amyrin exerted a marked and rapid inhibition of TNBS-induced colitis, related to the local suppression of inflammatory cytokines and COX-2 levels, possibly via inhibition of NF-kB and CREB-signalling pathways. Taken together, our data suggest a potential use of α,Β-amyrin to control inflammatory responses in bowel disease. © 2009 The British Pharmacological Society All rights reserved.