Search

Chang JY, 2010, CLIN GASTROENTEROL H, V8, P669, DOI 10.1016-j.cgh.2010.04.022; Okpara N, 2009, WORLD J GASTROENTERO, V15, P2975, DOI 10.3748-wig.15.2975; Yan BM, 2009, GUT, V58, P721, DOI 10.1136-gut.2008.165894

Melanin-concentrating hormone (MCH) is localized mainly in the brain, but it is also found in the intestine. MCH plays a clear role in feeding behavior. Recent data suggests that MCH and the MCH receptor 1 mediate intestinal inflammation in mice. Two diverse MCH receptor 1 antagonists (DABA-821 and DABA-822) have been developed for pharmacological testing. DABA-821 penetrates the blood-brain barrier, while DABA-822 does not. Study Aim: Our goal was to test DABA-821 and DABA-822 in a murine model of TNBS colitis. The efficacy of these compounds was compared to Dexamethasone (Dex).Methods: Female BALB/c mice (n=37) were randomized to receive an intracolonic enema of PBS, 50% ethanol/PBS, or 20 mg/kg TNBS in 50% ethanol. On day 1 (five hours after the enemas) mice were given Vehicle, 30 mg/kg of DABA-821, 30 mg/kg of DABA-822, or 1 mg/kg of Dex by orogastric gavage. Test drugs were also administered bid on days 2 through 6. On day 7, mice were euthanized. The colon was analyzed for overall macroscopic damage, ulceration, total length, distal segment weight, MPO activity and histological pathology. Body and spleen weights were also determined. Results:Macroscopic colonic scores (combination of lesions, diarrhea, adhesions, thickness) were significantly increased in TNBS treated mice, as compared to PBS or 50% ethanol treated animals. These scores were attenuated by 53 to 75% in mice treated with the MCH-1 receptor antagonists. Similar efficacy was found with Dex. Colonic ulceration was clearly apparent in the Vehicle/TNBS treatment group, but ulcer severity was significantly reduced in mice treated with the MCH receptor 1 antagonists. Mean colonic ulcer scores were: 4.7 (Vehicle/TNBS), 2.4 (DABA-821), 2.9 (DABA-822) and 2.8 (Dex). As compared to their vehicle treated cohorts, colons were significantly longer, but weighed less, in drug treated mice. Colonic MPO activity was nearly normalized in mice treated with Dex, but only partially attenuated by treatment with the MCH receptor 1 antagonists. Colonic histology scores were significantly reduced (p < 0.05 vs. Vehicle) in all drug treatment groups. Vehicle/TNBS treated mice lost significant weight throughout the study, as compared to PBS treated animals. None of the treatments normalized this weight loss. Reduced spleen weights were observed in Dex treated mice, as well as in mice treated with DABA-821 and 822. Summary: Two diverse MCH receptor 1 antagonists attenuated various parameters of TNBS-induced colitis in mice. The anti-colitis profile of these antagonists was similar to Dex. Conclusion:MCH receptor 1 antagonismmay represent an effective therapeutic approach for intestinal inflammation.

Melanin-concentrating hormone (MCH) is localized mainly in the brain, but it is also found in the intestine. MCH plays a clear role in feeding behavior. Recent data suggests that MCH and the MCH receptor 1 mediate intestinal inflammation in mice. Two diverse MCH receptor 1 antagonists (DABA-821 and DABA-822) have been developed for pharmacological testing. DABA-821 penetrates the blood-brain barrier, while DABA-822 does not. Study Aim: Our goal was to test DABA-821 and DABA-822 in a murine model of TNBS colitis. The efficacy of these compounds was compared to Dexamethasone (Dex).Methods: Female BALB/c mice (n=37) were randomized to receive an intracolonic enema of PBS, 50% ethanol/PBS, or 20 mg/kg TNBS in 50% ethanol. On day 1 (five hours after the enemas) mice were given Vehicle, 30 mg/kg of DABA-821, 30 mg/kg of DABA-822, or 1 mg/kg of Dex by orogastric gavage. Test drugs were also administered bid on days 2 through 6. On day 7, mice were euthanized. The colon was analyzed for overall macroscopic damage, ulceration, total length, distal segment weight, MPO activity and histological pathology. Body and spleen weights were also determined. Results:Macroscopic colonic scores (combination of lesions, diarrhea, adhesions, thickness) were significantly increased in TNBS treated mice, as compared to PBS or 50% ethanol treated animals. These scores were attenuated by 53 to 75% in mice treated with the MCH-1 receptor antagonists. Similar efficacy was found with Dex. Colonic ulceration was clearly apparent in the Vehicle/TNBS treatment group, but ulcer severity was significantly reduced in mice treated with the MCH receptor 1 antagonists. Mean colonic ulcer scores were: 4.7 (Vehicle/TNBS), 2.4 (DABA-821), 2.9 (DABA-822) and 2.8 (Dex). As compared to their vehicle treated cohorts, colons were significantly longer, but weighed less, in drug treated mice. Colonic MPO activity was nearly normalized in mice treated with Dex, but only partially attenuated by treatment with the MCH receptor 1 antagonists. Colonic histology scores were significantly reduced (p < 0.05 vs. Vehicle) in all drug treatment groups. Vehicle/TNBS treated mice lost significant weight throughout the study, as compared to PBS treated animals. None of the treatments normalized this weight loss. Reduced spleen weights were observed in Dex treated mice, as well as in mice treated with DABA-821 and 822. Summary: Two diverse MCH receptor 1 antagonists attenuated various parameters of TNBS-induced colitis in mice. The anti-colitis profile of these antagonists was similar to Dex. Conclusion:MCH receptor 1 antagonismmay represent an effective therapeutic approach for intestinal inflammation.

Background: Trinitrobenzene sulfonic acid (TNBS) is a hapten and its rectal admi nistration with ethanol induce s immunologically mediated colitis (TNBS-induced colitis). The colitis has been extensively used as an animal model for Crohn's disease. On the other hand, several food coloring agents are still popularly used in the world, and they are known to be metabolized into hapten(s) by intestinal bacteria. For example, one of the most popular and commercially available tartrazine is metabol ized into sulfanilic acid which has a typical structure of hapten. Therefore, oral intake of such coloring agents may induce and/or aggrava te the immunologically mediated colitis. Aim: Aims of this study were 10 investigate whether oral administration of tartrazine influences the development of hapten-induced colitis by utilizing its metabolite, sulfanilic acid, in rats. Materials and Methods: 4 week old male SD-rats were used (20 animalsl each group). 25 mg/mllday of tartrazine was gavaged into the stomach for 12 days before the colitis induction in group I. The same amount of distilled water was given for the control animals (group 2). Sulfanili c acid-induced colitis was made by the intracolonic injection of 0.1 ml of saturated sulfanilic acid in 50% ethanol. 6 rats leach group were sacrificed to observe colonic ulcer index on the day 4 after the colitis induction . Then a half of remaining rats (7) in group 1 started to have tartrazine again for 6 additional days and all of the animals were sacrificed for measuring colonic ulcer index on the day 10. A half of the rats (7) in group 2 were also given tartrazine from the day 4 to the day 9 before sacrifice. Results: Rats in group 1 had significantly higher ulcer index than those in group 2 in the acute phase on the day 4 after the co litis induction (2 1.5::'::4.7 vs 4. 1::':: 1.1, p

Experimentally induced ulcerative disease of the large intestine in guinea pigs was significantly mitigated by selective elimination of the aerobic gram-negative intestinal microflora. Lesions were induced with 2 or 5% degraded carrageenan administered in the drinking water for 30 to 44 days. Craterous cecal or colonic ulcers, crypt abscesses, mucosal distortion, mesenteric lymphadenopathy, marked cecal or colonic lymphoid hyperplasia, and other lesions were seen in conventional guinea pigs treated with degraded carrageenan. Other guinea pigs that were treated with 2% degraded carrageenan, but freed of Enterobacteriaceae species by the administration of trimethoprim with sulfamethoxazole, and subsequently maintained in isolators, exhibited virtually no lesions. Enterobacteriaceae-free animals that were treated with 5% degraded carrageenan had significantly fewer lesions than were observed in the conventional degraded carrageenan-treated animals. Biotyping of bacterial isolates indicated that the family of Enterobacteriaceae species generally, and not a single biotype, was associated with the lesions. The bacteria presumably stimulated an immunological response after penetration of the intestinal mucosal barrier; thus, inflammatory bowel disease in guinea pigs, induced with degraded carrageenan, may provide a useful model for investigating immunological aspects of human inflammatory bowel disease.

Severe bleeding from the lower gastrointestinal tract commonly occurs from mucosal lesions such as angiodysplasia and less often from acute ulcerations. Endoscopic coagulation of such lesions is now feasible. Our purpose was to compare the efficacy and histologic injury of bipolar electrocoagulation and argon laser photocoagulation applied at laparotomy in the canine colon. After right colotomy and heparinization in adult mongrel dogs, bleeding standard ulcers were randomly assigned to treatment or control. The colonic ulcers randomized to each group were not significantly different in size or bleeding rate. Efficacy of treatment was evaluated acutely. Adjacent normal mucosa was treated with the same modality as the ulcer to simulate treatment of a mucosal lesion. The same total exposure time (argon laser photocoagulation) or number of pulses (bipolar electrocoagulation) was used for these paired treatments. Gross and histologic injury were determined after 7 days. Both argon laser photocoagulation and bipolar electrocoagulation were uniformly effective in controlling bleeding from standard colonic ulcers and the incidence of full thickness injury was similar, 33%-48%. The histologic damage seen with normal mucosa treatment was consistently less than with standard ulcers for all treatment groups. The difference is easily explained by the reduction in colonic wall thickness of about 50% with creation of standard ulcers. In our opinion, argon laser photocoagulation and bipolar electrocoagulation are safe enough to be used in clinical trials for control of colonic bleeding from mucosal lesions but not acute colonic ulcers.

The role of leukotrienes in the pathogenesis of chronic colitis was investigated using a rat model. Ulceration and inflammation of the distal colon was initiated by the intracolonic administration of the hapten trinitrobenzene sulfonic acid in 50% ethanol. Leukotriene B4 synthesis increased significantly within 4 h after induction of damage, with the greatest increase observed 24-72 h after administration of the hapten. The increase in leukotriene B4 synthesis correlated well (r = 0.88) with an increase in colonic myeloperoxidase activity, a biochemical marker of neutrophil infiltration. Daily intracolonic treatment with a specific 5-lipoxygenase inhibitor, L651,392, during the first 4 days after initiation of colitis, resulted in significant reductions of colonic leukotriene B4 synthesis, colonic damage score, and colon wet weight. When examined 2 wk after initiation of colitis, the group treated with L651,392 (for the first 4 days) showed significantly less colonic damage (assessed macroscopically and histologically) and colonic inflammation (assessed histologically and by measurement of myeloperoxidase activity). The healing produced by treatment with L651,392 was comparable to that observed after treatment with 5-aminosalicylic acid in a similar manner. Although a reduction of colonic damage could be produced in this model by intracolonic pretreatment with a prostaglandin E1 analogue (rioprostil), the mechanism of action of L651,392 did not appear to be through prevention of the initial injury induced by the hapten and ethanol solution. These results demonstrate that inhibition of leukotriene synthesis results in a marked acceleration of the healing of colonic ulcers and resolution of colonic inflammation in this animal model of chronic colitis. The results are therefore consistent with the hypothesis that leukotrienes play an important role in the pathogenesis of intestinal inflammation.