DOI: 10.1097/MCG.0b013e318162010c
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PMID: 18838920
Issn Print: 0192-0790
Publication Date: 2009/03/01
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Excerpt
We read with great interest the article by Katz,1 in which the author reviewed in a very objective and comprehensive manner the results from the main placebo-controlled trials evaluating currently available treatment approaches for the management of patients with inflammatory bowel disorders (IBD).
By identifying the so-called gaps (ie, the percentage of patients lacking any benefit) of the current available treatments, the author was able to demonstrate that most drugs will be effective only in 50% of patients, with response rates of 50% to 60% and remission rates of 20% to 30%.
Therefore, the identification of novel therapeutic strategies for patients with IBD is urgently needed. In that sense, we would like to propose that the inhibition of the gastrin-releasing peptide (GRP) receptor-dependent signaling pathway might represent a potentially valuable approach to be exploited in these conditions.
The GRP belongs to the bombesinlike peptide family, mainly found in neurons of the human stomach and intestine. These peptides are responsible for a variety of central and peripheral functions. In the gastrointestinal tract, they promote secretion of hormones (gastrin, somatostatin) and pancreatic enzymes, and stimulate smooth muscle contraction.2,3
Preclinical studies have shown that GRP possesses immune-regulatory functions, such as chemoattraction of macrophages and lymphocytes, and stimulation of cell-mediated cytotoxicity and natural killer activity.4–6 Recently, our group has reported that RC-3095, a synthetic GRP receptor antagonist, was able to attenuate the release of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) in vitro and in vivo, improving survival of rats in a well-established model of sepsis.7 Our findings strongly suggest the involvement of a GRP receptor-dependent signaling pathway in the activation of the inflammatory cascade in sepsis.
On the basis of these observations, we started a series of experiments to evaluate the therapeutic potential of RC-3095 in tumor necrosis factor-dependent and interleukin-1–dependent preclinical models for chronic inflammatory disorders, such as rheumatoid arthritis and ulcerative colitis, with very provocative results. In a rat model for inflammatory colitis, induced by intracolonic administration of 5% acetic acid, daily subcutaneous administration of RC-3095 produced a marked improvement in the inflammatory changes. The lesions were blindly scored according to macroscopic analyses and quantified as ulcer index (Figs. 1, 2). Although histologic and molecular analyses are still pending, the beneficial effect observed in the macroscopic evaluation of the removed colon among animals treated with RC-3095, as compared with animals receiving only intracolonic saline solution, suggests that GRP receptor may be exploited as a potential therapeutic target in future studies evaluating new treatment options for IBD. Further investigations are warranted.
