Mitsuaki Okayama

Protective effect of lactulose on dextran sulfate sodium-induced colonic inflammation in rats

Promising results have recently been obtained with pre- and probiotic therapy in ulcerative colitis (UC). The prebiotic potential of lactulose is well established, but it has not yet been investigated in experimental colitis models. The purpose of the study was to examine the effect of lactulose on an UC model induced by 3% dextran sulfate sodium (DSS) solution added to drinking water for 7 days in male Wistar rats. Lactulose (300–1000 mg/kg) or 5-aminosalicylic acid (5-ASA; 150 mg/kg) was administered orally twice daily for 6 days. Colonic ulceration area, colon length, body weight changes, diarrhea/bloody feces, colonic mucosal myeloperoxidase activity (MPO), thiobarbituric acid reactive substances (TBARS), and histology were examined. Treatment of animals with DSS for 7 days resulted in severe colonic lesions accompanied by diarrhea, bloody feces, a decrese in body weight, shortening of the colon length, and an increase in MPO activity as well as TBARS, compared to normal rats. Lactulose treatment ameliorated DSS-induced colitis in a dose-dependent manner, and at 1000 mg/kg all of the parameters examined, except TBARS, were shown to improve significantly as compared to controls. Daily administration of 5-ASA also significantly reduced the severity of colonic lesions following DSS treatment. These results demonstrated the protectiv effect of lactulose in this rat colitis model and suggested that the background of this lactulose effect may be due to alterations of colonic microflora.

Aggravation by Selective COX-1 and COX-2 Inhibitors of Dextran Sulfate Sodium (DSS)-Induced Colon Lesions in Rats

We examined the effect of cyclooxygenase (COX) inhibitors on dextran sulfate sodium (DSS)-induced ulcerative colitis in rats and investigated the role of COX isozymes in the pathogenesis of this model. Experimental colitis was induced by treatment with 2.5% DSS in drinking water for 6 days. Indomethacin (a nonselective COX inhibitor), SC-560 (a selective COX-1 inhibitor), or celecoxib (a selective COX-2 inhibitor) was given PO twice daily for 6 days, during the first 3 or last 3 days of the experimental period. Daily treatment with 2.5% DSS for 6 days caused damage to the colon, with a decrease in body weight gain and colon length as well as an increase of myeloperoxidase (MPO) activity. All COX inhibitors given for 6 days significantly worsened the severity of DSS-induced colonic damage with increased MPO activity. The aggravation was also observed by SC-560 given for the first 3 days or by celecoxib given for the last 3 days. The expression of COX-2 mRNA in the colon was upregulated on day 3 during DSS treatment, with significant increase of prostaglandin E2 PGE2 production. The PGE2 content on day 3 during DSS treatment was inhibited by both indomethacin and SC-560, but not by celecoxib; on day 6 it was suppressed by both indomethacin and celecoxib, but not SC-560. These results suggest that endogenous prostaglandins (PGs) afford protection against colonic ulceration, yet the COX isozyme responsible for the production of PGs differs depending on the stage of ulceration; COX-1 in the early stage and COX-2 in the late stage.

Protective effect of lafutidine, a novel histamine H2-receptor antagonist, on dextran sulfate sodium-induced colonic inflammation through capsaicin-sensitive afferent neurons in rats.

Lafutidine, a histamine H2-receptor antagonist, exhibits gastric mucosal protective action mediated by capsaicin-sensitive afferent neurons, in addition to a potent antisecretory effect. In this study we examined the effect of lafutidine on dextran sulfate Na (DSS) -induced ulcerative colitis in rats, in relation to capsaicin-sensitive afferent neurons. Experimental colitis was induced in rats by daily treatment with 3% DSS in drinking water for 7 days. Lafutidine, capsaicin, and cimetidine were administered per os twice daily for 6 days. The ulceration area, colon length, and myeloperoxidase (MPO) activity were measured on day 7 after the onset of DSS treatment. DSS caused severe mucosal lesions in the colon, accompanied by an increase in MPO activity as well as a decrease in body weight gain and colon length. Daily administration of lafutidine dose-dependently reduced the severity of DSS-induced colitis and significantly mitigated changes in the colon length and MPO activity. The effects of lafutidine were mimicked by daily administration of capsaicin but not cimetidine and were totally abolished by chemical ablation of capsaicin-sensitive afferent neurons. In contrast, desensitization of afferent neurons significantly worsened the colonic inflammation induced by DSS. It was also found that both lafutidine and capsaicin increased the secretion of mucus in the colonic mucosa. These results suggest that lafutidine is effective against the ulcerative colitis induced by DSS through capsaicin-sensitive afferent neurons. This action might be attributable at least partly to the enhancement of colonic mucus secretion.

Protective Effect of Intra-Rectal Administration of Rebamipide on Dextran Sulfate Sodium-Induced Rat Colitis

Background/Aim: Rebamipide, an anti-ulcer drug, has various actions including radical scavenging and mucus-stimulating as well as anti-inflammatory effects, and exhibits both mucosal protective and healing promoting actions in the stomach. In the present study, we examined the effect of rebamipide on an animal model of colitis induced by dextran sulfate sodium (DSS). Methods: Experimental colitis was induced in rats by daily treatment with 3% DSS in drinking water for 7 days. Rebamipide (3–30 mg/kg), 5-aminosalicylic acid (5-ASA: 150 mg/kg) or metronidazole (10 and 30 mg/kg) was administered intra-rectally once daily for 6 days. The ulceration area, colon length, and mucosal myeloperoxidase (MPO) activity as well as thiobarbituric acid-reactive substance (TBARS) were measured on the 7th day after the onset of DSS treatment. The effects of rebamipide on the secretion of mucus in the colon was also examined. Results: DSS treatment caused severe lesions in the colon, accompanied by an increase in MPO activity and TBARS as well as a decrease in body weight gain and colon length. Repeated administration of rebamipide dose-dependently suppressed the colon lesions and improved the pathological changes induced by DSS treatment. Rebamipide significantly increased the mucus contents in the colon. Both 5-ASA and metronidazole also reduced the severity of DSS-induced lesions. Conclusion: These results suggest that intra-rectal administration of rebamipide is effective against DSS-induced colitis. The protective effect of rebamipide may be attributable to both the radical scavenging action and the increase in the production of mucus in the colon, the latter presumably suppressing the process of intestinal bacterial infiltration.

Prophylactic Effect of Restraint Stress on Cerulein-Induced Pancreatitis in Rats: Role of Endogenous Glucocorticoids

Stress is reportedly known to affect the severity of acute pancreatitis, yet the effect has not been without controversy. We investigated the influence of restraint stress on cerulein-induced pancreatitis, especially in relation to endogenous glucocorticoids. In the present study, restraint stress significantly reduced the increase in serum amylase levels but not pancreas weight induced by cerulein, the effect being totally antagonized by pretreatment with mifepristone, a glucocorticoid receptor antagonist. The changes induced by cerulein were prevented by dexamethasone in a dose-dependent manner. Histologically, restraint stress suppressed the intralobular edema, similar to a low dose of dexamethasone, while the latter at a high dose prevented not only the intralobular but also the interlobular edema. These results suggest that restraint stress exerts a beneficial influence on the cerulein-induced pancreatitis, mainly mediated by endogenous glucocorticoids, and it is assumed that short-term steroid therapy has a potential of clinical application for treatment of pancreatitis.

Amelioration of caerulein-induced pancreatitis by restraint stress in the rat

We investigated the influence of restraint stress on caerulein-induced pancreatitis in rats, especially in relation to endogenous glucocorticoids. Pancreatitis was induced by repeated injections of caerulein, and the serum amylase levels, pancreas weight and histological findings were evaluated 6 h later. Restraint stress was performed by immobilizing the animals in Bollman cages from 30 min before the first injection of caerulein, while mifepristone, the glucocorticoid receptor antagonist, was administered s.c. 1 h before. Repeated injections of caerulein produced marked increases in not only the serum amylase levels and pancreas weight but also the intralobular edema of pancreas when determined histologically. Restraint stress significantly reduced the increase in both serum amylase levels and intralobular edema, but not the pancreas weight. The improvement by restraint stress of pancreatitis was totally antagonized by pretreatment with mifepristone. We conclude that restraint stress exerts a beneficial influence on caerulein-induced pancreatitis, mediated by endogenous glucocorticoids.