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

Hisato Deguchi, Keiji Yasukawa, Toshihide Yamasaki, Fumiya Mito, Yuichi Kinoshita, Tatsuya Naganuma, Suguru Sato, Mayumi Yamato, Kazuhiro Ichikawa, Kiyoshi Sakai, Hideo Utsumi, Ken Ichi Yamada

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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.

Original languageEnglish
Pages (from-to)1799-1805
Number of pages7
JournalFree Radical Biology and Medicine
Volume51
Issue number9
DOIs
Publication statusPublished - Nov 1 2011

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

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    Deguchi, H., Yasukawa, K., Yamasaki, T., Mito, F., Kinoshita, Y., Naganuma, T., Sato, S., Yamato, M., Ichikawa, K., Sakai, K., Utsumi, H., & Yamada, K. I. (2011). Nitroxides prevent exacerbation of indomethacin-induced gastric damage in adjuvant arthritis rats. Free Radical Biology and Medicine, 51(9), 1799-1805. https://doi.org/10.1016/j.freeradbiomed.2011.08.010