title: Nitroxides prevent exacerbation of indomethacin-induced gastric damage in adjuvant arthritis rats.
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.
authors: Department of Bio-Functional Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors: Hisato
authors: H
authors: Deguchi
authors: Keiji
authors: K
authors: Yasukawa
authors: Toshihide
authors: T
authors: Yamasaki
authors: Fumiya
authors: F
authors: Mito
authors: Yuichi
authors: Y
authors: Kinoshita
authors: Tatsuya
authors: T
authors: Naganuma
authors: Suguru
authors: S
authors: Sato
authors: Mayumi
authors: M
authors: Yamato
authors: Kazuhiro
authors: K
authors: Ichikawa
authors: Kiyoshi
authors: K
authors: Sakai
authors: Hideo
authors: H
authors: Utsumi
authors: Ken-ichi
authors: K
authors: Yamada
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D000975:Antioxidants / Q000378:metabolism; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D007213:Indomethacin / Q000009:adverse effects; D008279:Magnetic Resonance Imaging; D008297:Male; D009589:Nitrogen Oxides / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D017382:Reactive Oxygen Species / Q000378:metabolism; D013276:Stomach Ulcer / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; D007213:Indomethacin