TY - JOUR
T1 - Nitroxides prevent exacerbation of indomethacin-induced gastric damage in adjuvant arthritis rats
AU - Deguchi, Hisato
AU - Yasukawa, Keiji
AU - Yamasaki, Toshihide
AU - Mito, Fumiya
AU - Kinoshita, Yuichi
AU - Naganuma, Tatsuya
AU - Sato, Suguru
AU - Yamato, Mayumi
AU - Ichikawa, Kazuhiro
AU - Sakai, Kiyoshi
AU - Utsumi, Hideo
AU - Yamada, Ken Ichi
N1 - Funding Information:
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.
PY - 2011/11/1
Y1 - 2011/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80053582760&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053582760&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2011.08.010
DO - 10.1016/j.freeradbiomed.2011.08.010
M3 - Article
C2 - 21906674
AN - SCOPUS:80053582760
SN - 0891-5849
VL - 51
SP - 1799
EP - 1805
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 9
ER -