Introduction
several studies have reported that overproduction of reactive oxygen species (ROS) and 12 an imbalance of important antioxidants exist in the intestine of patients receiving 13 repeated doses of NSAIDs, leading to oxidative damage [8, [11] [12] [13] [14] . Self-sustaining 14 cycles of oxidant production may amplify inflammation and mucosal injury. Thus far, it 15 has been reported that antioxidant compounds and free radical scavengers heal 16 NSAIDs-induced inflammation [15, 16] . However, orally administered 17 low-molecular-weight (LMW) compounds are not sufficiently effective due to their 18 non-specific distribution to the entire body, metabolism in the GI tract, low retention in 1 the lesion area, and undesired adverse effects.
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To address these issues, we have developed a newly designed oral All experiments were carried out using 6-week-old male ICR mice
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(approximately 30 g) purchased from Charles River Japan, Inc. (Yokohama, Japan).
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Mice were maintained in the experimental animal facilities at the University of Tsukuba.
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All experiments were performed according to the Guide for the Care and Use of the jejunum and ileum were longitudinally opened and the mucosa was scraped with a 7 blunt spatula. The animals were given ad libitum access to food and water after the food. The whole small intestine was separated into the duodenum, jejunum, and ileum.
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Five-centimeter lengths of the jejunum and ileum were isolated for hematoxylin and 11 eosin (H&E) staining. The remaining tissues were used for measurements of 12 myeloperoxidase (MPO) activity, superoxide anion production, and malondialdehyde
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(MDA) level. respectively, which were significantly higher than those of LMW TEMPOL (0.09 and 7 0.05 mg·h/mL) ( Table 1) .
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The morphology of RNP O in the small intestine was determined by ESR spectra. 
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This might be one of the reasons preventing its uptake into blood via the mesentery.
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The distribution of RNP O in the small intestine region was further investigated in 17 detail. For this objective, the mucosa and muscle of both jejunum and ileum were administered prior to IND-treated mice, the jejunum area was almost similar to that of 17 control mice ( Figure 4c) ; however, a part of a necrotic villus was observed in the ileum
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(see arrow in Figure 4g ). Since LMW TEMPOL is absorbed from the upper GI tract, 1 most of it might not reach to the ileum area. On the contrary, the histology of the small 2 intestine from RNP O -treated mice showed almost no damage and was similar to that 3 from control mice in both the jejunum and ileum areas (Figures 4d and h ). indicate lumen and serosa, respectively. 

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