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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Noninvasive Mapping of Reactive Oxygen Species by in Vivo Electron Spin Resonance Spectroscopy in Indomethacin-Induced Gastric Ulcers in Rats

Department of Biofunctional Science, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (H.U., K.Yas., T.S., K.Yam., R.S.); and Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan (T.Y., M.T.)

Reactive oxygen species (ROS) are thought to be involved in the gastric ulcer formation induced by indomethacin, a typical nonsteroidal anti-inflammatory drug. However, the location and the time course of ROS generation remain unknown. To assess the sites of ROS generation, we applied the noninvasive measurement of ROS to indomethacin-treated rats. By giving orally a membrane-permeable or impermeable probe, the spectra were collected as a function of time by in vivo 300-MHz electron spin resonance (ESR) spectroscopy. The ESR signal-decay rates of membrane-permeable probes, hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) and 3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl, in the gastric mucosal region were significantly enhanced 1 h after indomethacin treatment, and they both caused the protection of ulcer formation; however, membrane-impermeable probes, carboxy- and trimethylammonium-TEMPO, which did not exhibit the enhanced signal decay, had no effect on ulcer formation. The enhanced signal decay in the gastric mucosa was suppressed by coadministration of the antioxidants tiron or dimethylthiourea with the nitroxyl probe. The results suggest that the enhanced signal-decay rates in the gastric ulcers observed by in vivo ESR are associated with protective effects. The enhanced signal decay caused by ROS generation in stomach, contributing to the ulcer formation induced by indomethacin, is also suggested to occur at the gastric mucus layer or the interface or the intracellular compartment of epithelial cells. Overall, these results show the potentials of noninvasive assessment of ROS production and the sites of damage by in vivo ESR using nitroxyl probes directed to specific subcellular regions.

Address correspondence to: Prof. Hideo Utsumi, Department of Biofunctional Science, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, 812-8582 Japan. E-mail: utsumi{at}pch.phar.kyushu-u.ac.jp