Elsevier

Free Radical Biology and Medicine

Volume 51, Issue 9, 1 November 2011, Pages 1799-1805
Free Radical Biology and Medicine

Original Contribution
Nitroxides prevent exacerbation of indomethacin-induced gastric damage in adjuvant arthritis rats

https://doi.org/10.1016/j.freeradbiomed.2011.08.010Get rights and content

Abstract

Nonsteroidal anti-inflammatory drugs are the drugs of choice in the treatment of rheumatoid arthritis (RA) because of their rapid analgesic effect. However, they induce severe gastric damage in RA patients and animals by a process mediated by reactive oxygen species (ROS). Nitroxides (nitroxyl radicals) are widely used as imaging agents and antioxidants to explore the role of ROS generation in the pathogenesis of disease. In this study, the effectiveness of the newly synthesized nitroxides 8-aza-7,7,9,9-tetramethyl-1,4-dioxaspiro[4.5]undecan-8-oxyl (compound 1) and 4-oxo-2,2,6,6-tetraethylpiperidine-1-oxyl (compound 2) in the prevention of gastric ulcers in adjuvant arthritis rats treated with indomethacin was evaluated by monitoring the reaction of reactive oxygen species in gastric tissue with Overhauser-enhanced magnetic resonance imaging (OMRI). Pretreatment with all tested nitroxides suppressed the ulcers induced by indomethacin treatment in arthritic rats. OMRI using compounds 1 and 2 as well as 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) demonstrated a redox imbalance in the stomach of these rats. Lipid peroxide and interleukin (IL)-1β levels in the gastric mucosa were significantly suppressed by compound 1 and TEMPOL, whereas CINC/gro, a member of the IL-8 family, was significantly suppressed by compound 1 only. These results suggest that the preventive effects of nitroxides on gastric ulcers may operate by different mechanisms.

Highlights

► Indomethacin exacerbates gastric damage in adjuvant arthritis rats. ► We evaluated new nitroxides as imaging agents and antioxidants. ► OMRI imaging using all tested nitroxides showed a redox imbalance in the stomach. ► Effects of nitroxides on lipid peroxide, IL-1β, and CINC/gro were different.

Section snippets

Chemicals

TEMPOL, heavy oil, indomethacin, and urethane were purchased from Sigma–Aldrich (St. Louis, MO, USA). Heat-killed Mycobacterium tuberculosis H37 RA was obtained from Difco Laboratories (Detroit, MI, USA) and pentobarbital sodium and isoflurane were from Dainippon Sumitomo Pharma (Tokyo, Japan). Purified cyclooxygenase (COX)-1 and COX-2 derived from sheep seminal vesicles were purchased from Meridian Life Science (Saco, ME, USA). All other reagents were from Wako Pure Chemicals Industries Ltd.

Preventive effect of nitroxides on gastric ulcers in AA rats

AA was induced by injection of M. tuberculosis H37 RA into the footpad of the DA rat. Edema occurred on the 9th day and the footpad volume increased up to the 14th day in the AA group, but not in the control (Ctrl) group (Fig. 1A). In the Ctrl group, oral administration of indomethacin (IND) induced a slight gastric mucosal lesion, whereas the lesion in the AA group was markedly exacerbated compared with that in the Ctrl group (Figs. 1B and C). No lesions were observed in the gastric mucosa in

Discussion

This study showed that newly synthesized nitroxides suppressed the gastric mucosal lesions induced by indomethacin treatment in AA rats. Although indomethacin treatment in normal rats induces lesion formation in the gastric mucosa, the effect is exacerbated in AA rats. This enhanced sensitivity to NSAIDs in arthritic rats has previously been reported [4], [34].

The nitroxides showed a dose-dependent protective effect on gastric injury in indomethacin-treated AA rats. Nitroxides are also useful

Acknowledgments

This work was partially supported by the Pharmaceutical Research Foundation, Tokyo; Development of Systems and Technology for Advanced Measurement and Analysis of the Japan Science and Technology Agency; and a Grant-in-Aid for Scientific Research (A) from the Japan Society for the Promotion of Science. Support was also given by the JSPS Core-to-Core Program.

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