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

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 radic...

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Published in:Free radical biology & medicine 2011-11, Vol.51 (9), p.1799-1805
Main Authors: Deguchi, Hisato, Yasukawa, Keiji, Yamasaki, Toshihide, Mito, Fumiya, Kinoshita, Yuichi, Naganuma, Tatsuya, Sato, Suguru, Yamato, Mayumi, Ichikawa, Kazuhiro, Sakai, Kiyoshi, Utsumi, Hideo, Yamada, Ken-ichi
Format: Article
Language:English
Subjects:
analgesic effect
Animals
Anti-Inflammatory Agents, Non-Steroidal - adverse effects
Antioxidants
Antioxidants - metabolism
Arthritis
Arthritis, Experimental - drug therapy
Arthritis, Experimental - metabolism
Arthritis, Experimental - pathology
Free radicals
gastric mucosa
Gastric ulcer
image analysis
indomethacin
Indomethacin - adverse effects
interleukin-8
Magnetic Resonance Imaging
Male
monitoring
Nitrogen Oxides - metabolism
Nitroxide
nonsteroidal anti-inflammatory agents
NSAIDs
pathogenesis
patients
Rats
Rats, Inbred Strains
reactive oxygen species
Reactive Oxygen Species - metabolism
rheumatoid arthritis
Stomach Ulcer - chemically induced
Stomach Ulcer - metabolism
Stomach Ulcer - prevention & control
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Summary: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. ► 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.
ISSN:0891-5849
1873-4596
DOI:10.1016/j.freeradbiomed.2011.08.010