Novel therapeutic approaches for treatment of irritable bowel syndrome using the multi-herbal drug STW 5

Karen Nieber1, Ulrike Voß1, Heba Abdel-Aziz2, Dieter Weiser2, Olaf Kelber2, Sebastian Michael1. 1University of Leipzig, Institute of Pharmacy, 04103 Leipzig, Germany, 2Steigerwald Arzneimittelwerk GmbH, Scientific Department Darmstadt, Germany

Inflammatory bowel syndrome (IBS) is a disease in which, typically alterations in intestinal motility and visceral hypersensitivity are present, apparently without any organic alteration. Several pathogenic factors responsible for IBS have been suggested. It seems that there are cell factors, which give reason to believe that there is low-grade intestinal inflammation in this pathology. Several cytokines, contribute to the pathogenesis. TNFα has been shown to play a pivotal role in activating the cytokine cascade in many inflammatory diseases and it has been proposed as a therapeutic target for a number of diseases. Consequently, recent strategies for the treatment of intestinal inflammation have primarily targeted the immunopathogenic processes that mediate intestinal inflammation at the cytokine level. A medication which is successfully used in functional dyspepsia and IBS is the fixed herbal combination product STW 5. There is growing evidence that STW 5 besides being effective in functional dyspepsia also improves IBS symptoms. Its mode of action is still not fully understood and a modulation of gastric motility as well as an anti-inflammatory action is hypothesized. These findings provide the basis for investigating STW 5 and its nine components in inflamed small and large intestinal preparations to identify novel anti-inflammatory pathways. The inflammation was induced by intraluminal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS, 0.01 M) in isolated rat jejunum/ileum or transverse colon preparations. Preincubation of STW 5 (64-512µg/ml) or its components in equivalent concentrations together with TNBS prevented the inflammation-induced disturbances in the muscle wall as evidenced by acetylcholine (ACh)-induced contractions. In accordance with these findings, cytotoxicity tests revealed a cell protective effect of STW 5. Using real-time PCA TNBS-induced inflammation was accompanied by an increased TNF-α gene expression. STW 5 (512µg/ml) inhibited the increased gene expression. Additionally, STW 5 in the same concentration reduced significantly the release of TNF-α by activation of adenosine A2A receptors in LPS (100 ng/ml)-stimulated human monocytes, while having no effect in untreated cells. Radioligand binding assays confirmed the affinity of STW 5 but not STW 6 (Iberis amara), a fresh plant component within STW 5 to adenosine A2A receptors. To evaluate the active constituents STW 6 was fractionated and a possible anti-inflammatory effect of the fractions was tested in inflamed preparations. The fractions which contained cucurbitacins E and I prevented the TNBS-induced inhibition of motility. The anti-inflammatory action of cucurbitacins E and I was due to the stimulation of IL-10 gene expression. In conclusion STW 5 reveals significant anti-inflammatory properties which contribute to the reduction of morphological and contractile disturbances. Its mode of action seems to be twofold, inhibition of the TNF-α pathway by activation of adenosine A2A receptors and activation of the IL-10 pathway initiated by cucurbitacins. The described anti-inflammatory mechanisms as well as the cell protective action of STW 5 gives a clear-cut correlation with symptom improvements in clinical trials and highlights the relevance of STW 5 as a novel therapeutic approach in IBS.