M1651 Melanin-Concentrating Hormone Receptor 1 Antagonists Attenuate TNBS-Induced Colitis in Mice

Abstract

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.