JPP 2009, 61: 395–397 ß 2009 The Authors Received August 6, 2008 Accepted December 8, 2008 DOI 10.1211/jpp/61.03.0016 ISSN 0022-3573 Correspondence: Professor Mario Baraldi, Dipartimento di Scienze Biomediche, Sezione di Farmacologia, Via Campi 287, I-41100 Modena, Italy. E-mail: mario.baraldi@unimore.it Short Communication Anti-ulcer activity of IAC, a novel free-radical scavenger, in rats Manuela Zavatti, Lorenzo Corsi, Paola Zanoli and Mario Baraldi National InterUniversity Consortium for the Study of Natural Active Principles (CINSPAN), Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy Abstract Objectives We investigated the ability of a novel low-molecular-weight free-radical scavenger, bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC), to protect the gastric mucosa from indometacin-induced ulceration. Methods The pharmacological effects of IAC, administered orally or by intraperitoneal injection, on the gastric mucosa were assessed in a rat model of gastric ulceration induced by indometacin. The effect of IAC on the level of prostaglandin PGE 2 in the gastric mucosa was also investigated. Results IAC, which has no ulcerative activity per se, had a preventive and protective activity against indometacin-induced gastric ulceration. This effect could be only partially attributed to a modulatory effect of IAC on PGE 2 levels; it is more likely to be due to the antioxidant activity of the compound. Conclusions Taking into account the properties of IAC and the mechanisms underlying gastric inflammation elicited by non-steroidal anti-inflammatory drugs, IAC may represent a novel anti-ulcer agent. Keywords IAC; indometacin; gastric ulcer; PGE 2 ; scavengers Introduction The stomach is vulnerable to damage by a variety of insults such as sepsis, trauma, multiple organ failure and non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs such as indometacin are widely used in the treatment of osteoarthritis and rheumatoid arthritis. However, their use is associated with a broad spectrum of side-effects in the gastrointestinal tract, such as bleeding and perforation. [1] Multiple pathogenetic elements underlie the development of these lesions, such as depletion of prostaglandins (PGs) through inhibition of cyclooxygenase (COX), [2–4] disturbances of the gastric microcircula- tion [5] and increased cell death by apoptosis. [6] Approaches to the prevention of gastric damage have included the suppression of acid secretion and the use of prostaglandin analogues, H 2 -histamine receptor antagonists, proton pump (H + /K + ATPase) inhibitors and, most recently, COX-2 inhibitors. [7] NSAID gastropathy has been shown to result from neutrophil activation, [8] the formation of reactive oxygen species (ROS) [9] and the release of nitric oxide, [10] leading to new approaches to the prevention of NSAID-mediated gastric damage. The new molecule bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate, called IAC (Figure 1), rapidly scavenges the majority of radical species involved in oxidative stress. [11] This compound has been shown to cross cell membranes and to distribute into biological environments without altering intracellular components. To date, IAC has been used in the quantitative measurement of ROS in biological samples from athletes [11] and patients with beta-thalassaemia. [12] IAC has been shown to exert a protective effect in vitro in islets isolated from patients with type-2 diabetes, and in vivo in a non-obese diabetic mouse model. [13] Given its antioxidant properties, the drug was tested for its potential anti-inflammatory activity. We have shown that IAC has a consistent effect in different animal models of inflammation (paper in preparation). The main goal of the current work was to study the effect of IAC in the gastrointestinal tract, bearing in mind the well-known NSAID-induced gastropathy. We therefore tested the potential ulcerogenic activity of IAC following oral or intraperitoneal (i.p.) administration to rats. The results of the our earlier experiments prompted us to test the effect of IAC on indometacin-induced ulceration and in turn to evaluate the ability of the compound to 395 Downloaded from https://academic.oup.com/jpp/article/61/3/395/6135932 by guest on 25 June 2022