Effect of J147 on irritable bowel syndrome mouse: Involvement of 5-HT1A-dependent PKA-CREB-BDNF signaling pathway

Purpose: To determine the effect of J147 on depression, anxiety, and gut malfunction triggered by stress in a mouse model exhibiting symptoms of irritable bowel syndrome (IBS). Methods: An IBS mouse model was established by chronic/acute combined stress and housed individually. The stressed mouse was exposed to 21 consecutive days of random chronic unpredictable stress and received 3 h of acute restraint stress on day 2. Forced swimming test (FST) and elevated plus-maze test were used to evaluate depressive and anxiety behaviour, respectively. The intestinal motility and visceral sensitivity of mouse were measured by abdominal withdrawal reflex test (AWR). Also, 8-OH-DPAT (a 5-HT1A receptor agonist) and NAN-190 hydrobromide (a 5-HT1A receptor antagonist) were used in combination with different doses of J147 (2 and 10 mg/kg) for three weeks and AWR test was done. Furthermore, IBS-related protein expression (PKA, pCREB, BDNF) in the hippocampus, colon and ileum was determined by western blotting. Results: After CACS induction, mice showed depression/anxiety-like behaviour along with intestinal allergy, and altered levels of 5-hydroxytryptamine (5-HT) in both the hippocampus and gut. Furthermore, J147 significantly alleviated depression, anxiety, intestinal motility disorders, and intestinal hypersensitivity. Additionally, it normalized abnormal levels of brain-gut 5-HT neurotransmitters observed in IBS mice. Pre-treatment with NAN-190 reversed the effect of J147, whereas the addition of 8-OH-DPAT, augmented the effect of low dose J147 (2 mg/kg) on behavioural abnormalities associated with CACS. Furthermore, J147 significantly increased expression levels of IBS-related proteins in the hippocampus, and decreased their levels in the ileum and colon. Conclusion: J147 inhibits IBS-like depression, anxiety, and visceral hypersensitivity by modulating the 5-HT1A-dependent PKA-CREB-BDNF signaling pathway. Thus, there is need for further studies on the development of J147 in the treatment of irritable bowel syndrome.