Tetsuya Hirakawa

Chronic Intracerebroventricular Administration of Relaxin-3 Increases Body Weight in Rats

Bolus-administered intracerebroventricular (ICV) relaxin-3 has been reported to increase feeding. In this study, to examine the role of relaxin-3 signaling in energy homeostasis, we studied the effects of chronically administered ICV relaxin-3 on body weight gain and locomotor activity in rats. Two groups of animals received vehicle or relaxin-3 at 600 pmol/head/day, delivered with Alzet osmotic minipumps. In animals receiving relaxin-3, food consumption and weight gain were statistically significantly higher than those in the vehicle group during the 14-day infusion. During the light phase on days 2 and 7 and the dark phase on days 3 and 8, there was no difference in locomotor activity between the two groups. Plasma concentrations of leptin and insulin in rats chronically injected with relaxin-3 were significantly higher than in the vehicle-injected controls. These results indicate that relaxin-3 up-regulates food intake, leading to an increase of body weight and that relaxin-3 antagonists might be candidate antiobesity agents.

Selective corticotropin-releasing factor 1 receptor antagonist E2508 reduces restraint stress-induced defecation and visceral pain in rat models

N-Cyclopropylmethyl-7-(2,6-dimethoxy-4-methoxymethylphenyl)-2-ethyl-N-(tetrahydro-2H-pyran-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-amine tosylate (E2508) is a newly discovered selective corticotropin-releasing factor 1 receptor antagonist. Here, we investigated the effects of E2508 on wrap restraint stress-induced defecation and visceral pain in rats. Oral pretreatment with E2508 dose-dependently decreased stool weights after 20min wrap restraint stress and significant effects were observed at doses of 30 and 100mg/kg. However, E2508 did not affect basal defecation at doses up to 100mg/kg. In contrast, alosetron, a 5-HT3 receptor antagonist, decreased both wrap restraint stress-induced and basal stool output at a dose of 0.1mg/kg. In a rat visceral pain model, subcutaneous injections of both E2508 (0.01 and 0.1mg/kg) and alosetron (0.001 and 0.01mg/kg) significantly decreased the number of abdominal muscle contractions induced by colonic distention, suggesting these drugs reduced visceral pain. Together, these results demonstrate E2508 has the potential to be an effective therapy for the treatment of irritable bowel syndrome with a lower risk of adverse events such as constipation compared with the current clinically used 5-HT3 receptor antagonist.