Paeoniflorin Improved Constipation in the Loperamide-Induced Rat Model via TGR5/TRPA1 Signaling-Mediated 5-Hydroxytryptamine Secretion

Abstract

Slow transit constipation (STC) is a common type of constipation with a high incidence rate and a large number of patients. We aimed to investigate the therapeutic effects and potential mechanism of paeoniflorin (PAE) on loperamide-induced Sprague Dawley (SD) rat constipation models. Rats with loperamide-induced constipation were orally administered different concentrations of PAE (10, 20, or 40 mg/kg). In vitro, enterochromaffin (EC)-like RIN-14B cells were treated with 20, 40, or 80 μg/ml PAE. We found that PAE treatment significantly improved the symptoms of constipation and increased the intestinal transit rate. Hematoxylin and eosin (H&E) staining showed that PAE alleviated colonic tissue pathological damage. Besides, our results implied that PAE concentration-dependently promoted the content of 5-hydroxytryptamine (5-HT) catalyzed by tryptophan hydroxylase (Tph)-1 in the serum of loperamide-induced rats and in RIN-14B cells. Western blot and immunofluorescence (IF) stain indicated that PAE also promoted the expression of G protein-coupled BA receptor 1 (TGR5), transient receptor potential ankyrin 1 (TRPA1), phospholipase C (PLC)-γ1, and phosphatidylinositol 4,5-bisphosphate (PIP2) in vivo and in vitro. RIN-14B cells were cotreated with a TGR5 inhibitor (SBI-115) to explore the mechanism of PAE in regulating the 5-HT secretion. We observed inhibition of TGR5 reversed the increase of 5-HT secretion induced by PAE in RIN-14B cells. We provided evidence that PAE could promote 5-HT release from EC cells and improve constipation by activating the TRPA1 channel and PLC-γ1/PIP2 signaling. Thus, PAE may provide therapeutic effects for patients with STC.

Improvement of loperamide-hydrochloride-induced intestinal motility disturbance by Platycodon grandiflorum polysaccharides through effects on gut microbes and colonic serotonin

“…Furthermore, paeoniflorin has the ability to alleviate loperamide-induced constipation by mediating G-protein-coupled bile acid receptor/TRPA1 signaling. In our study, the expression of TRPA1 was activated by PGP ( Zhan et al., 2021 ).…”

Dysregulation of the Enteric Nervous System in the Mid Colon of Complement Component 3 Knockout Mice with Constipation Phenotypes

“…A dysfunction of ENS can be considered one of the causes of constipation, reflux, and delayed gastric emptying because it plays a key role in regulating the GI tract motility, movement of water and electrolyte, gastric and pancreatic secretion, and defense reactions [ 24 , 25 , 26 ]. Therefore, it is very important to verify the dysfunction of ENS in the C3 KO mice as a new constipation model.…”

Activation of ASIC3/ERK pathway by paeoniflorin improves intestinal fluid metabolism and visceral sensitivity in slow transit constipated rats

“…Feces were measured in wet weight (WW), then dried at a constant temperature of 60 C for 12 h and weighed as dry weight (DW). The water content of the feces was calculated as follows 7 : [(WW À DW)/ WW] Â 100%.…”

“…5,6 Previous studies demonstrated that PF can treat constipation by activating the PLC-γ1/PIP2 pathway and TRPA1 channel to promote 5-hydroxytryptamine (5-HT) release from enterochromaffin cells. 7 Although the efficacy of PF on STC has been established, its mechanisms of action have yet to be fully elucidated. This is partly due to the complex nature of the pathogenesis of STC and the multi-targeted action of natural drugs.…”