ADVANCES IN IBD

C u r r e n t D e v e l o p m e n t s i n t h e Tr e a t m e n t o f I n f l a m m a t o r y B o w e l D i s e a s e s

Section Editor: Stephen B. Hanauer, MD

Understanding the Mechanism of 5-ASA in Treating Colonic Inflammation

Pierre Desreumaux, PhD
Professor of Gastroenterology Department of Hepatogastroenterology and Nutrition Director of Research in Inammatory Digestive Diseases University of Lille, France
with normal ora, and those with humanized ora, and we have shown that in germ-free mice, PPAR levels in the colon are very low but when bacteria are introduced, levels of PPAR expression are raised. In mouse models, PPAR has been similarly stimulated with dierent fractions of live gut bacteria, killed gut bacteria, and lipopolysacchride (LPS), with the understanding that LPS is a key determinant in inducing PPAR expression and activation. Thus emerges a balance achieved between activity of bacteria and activity of LPS, wherein the former induces inammation via the epithelial pathway and the latter enhances PPAR expression activation. G&H How does this balance between bacteriamediated inflammation and LPS-induced PPAR play a part in inflammatory bowel disease manifestation and treatment? PD The expression of PPAR is more closely related to the pathophysiology of ulcerative colitis (UC) than Crohns disease. In patients with UC, there is an unexplained downregulation of expression of PPAR relative to control patients, and it seems that the downregulation of PPAR in the colonic mucosa is indicative of the level of inammation. 5-ASA is a ligand of PPAR, as has been demonstrated in animal models of UC as well as in vitro, utilizing colonic epithelial cells. As a ligand, 5-ASA binds to PPAR, and this binding is functional, leading to activation of PPAR that has an anti-inammatory eect. G&H Are there pharmacokinetic similarities between 5-ASA and diabetes therapies that also target PPAR (ie, thiazolidinediones)? PD There are similarities in the chemical structures of 5-ASA and thiazolidinediones (TZDs). The main difference is that with 5-ASA there is an almost exclusively topical eect on PPAR expressed by the epithelial cells,

G&H How was the link between 5-aminosalicylic acid (5-ASA) and peroxisome proliferatoractivated receptor- (PPAR) initially established? PD The relationship between 5-ASA and PPAR was rst demonstrated in an experimental model utilizing genetically engineered heterozygous knockout mice, in whom colitis symptoms were induced and 5-ASA administered. The anti-inammatory eect of 5-ASA in these mice was compared to that in control mice expressing normal levels of PPAR in the colon. By evaluating microscopic and histologic lesions and levels of tumor necrosis factor- present in the colonic mucosa, it was found that optimal concentration of 5-ASA in the colon had the greatest anti-inammatory eect in control mice. In the PPAR knockout mice, anti-inammatory eects were greatly lessened. Thus, we conclude that the antiinammatory eects of 5-ASA are mediated, at least in part, by PPAR. G&H What is the role of gut flora in the activation of PPAR expression? PD In the colon, PPAR is mainly expressed in epithelial cells. The concentration of PPAR in the colonic mucosa is 100 times greater than that present in the small bowel. This is true in both humans and rodents. We have evaluated PPAR levels in germ-free mice, compared to mice

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patients with UC. As of yet, the etiology of this abnormality remains unknown. It may be due to individual dierences in the make-up of colonic ora or the expression of dierent polyunsaturated fatty acids, which may also regulate levels of PPAR. Each of these concepts requires further investigation in order to better understand the pathophysiology of UC. We also need to nd new compounds that combine the topical activity of 5-ASA with a stronger anity to PPAR. The adverse cardiovascular events that have been associated with TZDs stem from their systemic eects, which activate a number of dierent PPAR-mediated pathways. In order to retain the excellent safety prole enjoyed by 5-ASA formulations, new compounds must remain topically active. G&H What progress has been made toward the development of new, more effective compounds? PD Because we know that 5-ASA is a ligand of PPAR, we should, theoretically, be able to develop new chemical compounds, similar to 5-ASA but with a stronger anity to PPAR with some ease. At present, we have developed several molecules with similarities to 5-ASA, and we have now selected one compound, GED-0507-34 (Giuliani S.p.A., Milan, Italy), which has demonstrated 100150-fold more anti-inammatory activity than 5-ASA. This compound holds great promise in in vitro and in vivo experimental models of colitis, and the specicity of this molecule appears to be very good, avoiding any adverse events. Our current goal is to begin phase I study of this molecule at the beginning of 2009. Suggested Reading
Linard C, Gremy O, Benderitter M. Reduction of peroxisome proliferation-activated receptor gamma expression by gamma-irradiation as a mechanism contributing to inammatory response in rat colon: modulation by the 5-aminosalicylic acid agonist. J Pharmacol Exp Ther. 2008;324:911-920. Desreumaux P, Ghosh S. Review article: mode of action and delivery of 5-aminosalicylic acid - new evidence. Aliment Pharmacol Ther. 2006;24(Suppl 1):2-9. Dubuquoy L, Rousseaux C, Thuru X, Peyrin-Biroulet L, Romano O, et al. PPARgamma as a new therapeutic target in inammatory bowel diseases. Gut. 2006;55:1341-1349. Rousseaux C, Lefebvre B, Dubuquoy L, Lefebvre P, Romano O, et al. Intestinal antiinammatory eect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma. J Exp Med. 2005;201:1205-1215. Alarcon de la Lastra C, Sanchez-Fidalgo S, Villegas I, Motilva V. New pharmacological perspectives and therapeutic potential of PPAR-gamma agonists. Curr Pharm Des. 2004;10:3505-3524.

PPAR
PPRE

RXR

Nucleus

Figure 1. 5-ASA binds to cytoplasmic PPAR, inducing its translocation to the nucleus and conformational change. This re-arrangement promotes the recruitment of the co-activator DRIP and the assembly of the active heterodimer PPAR-RXR, leading to the activation of PPRE.
5-ASA=5-aminosalicylic acid; DRIP=vitamin D receptor-interacting protein; PPAR=peroxisome proliferator-activated receptor; PPRE=PPAR response element; RXR=retinoid X receptor.

with some minor residual eect on PPAR expressed in the lymphocytes or macrophages within the mucosal spaces. The TZDs, in contrast, promote systemic expression of PPAR. 5-ASA, even when orally administered, is mainly concentrated in the terminal and colonic ileum. Even when 5-ASA crosses the gut barrier it is for the most part not free but N-acetylated 5-ASA. Due to this N-acetylation, 5-ASA is not available to bind with and activate PPAR throughout the body. G&H What are the next steps in research of 5-ASA and PPAR as they relate to UC treatment? PD We need to better understand why the downregulation of PPAR expression and activation occurs in

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