The 5-hydroxytryptamine 4 Receptor Agonist-induced Actions and Enteric Neurogenesis in the Gut

Abstract

We explored a novel effect of 5-hydroxytryptamine 4 receptor (5-HT4R) agonists in vivo to reconstruct the enteric neural circuitry that mediates a fundamental distal gut reflex. The neural circuit insult was performed in guinea pigs and rats by rectal transection and anastomosis. A 5-HT4R-agonist, mosapride citrate (MOS) applied orally and locally at the anastomotic site for 2 weeks promoted the regeneration of the impaired neural circuit or the recovery of the distal gut reflex. MOS generated neurofilament-, 5-HT4R- and 5-bromo-2'-deoxyuridine-positive cells and formed neural network in the granulation tissue at the anastomosis. Possible neural stem cell markers increased during the same time period. These novel actions by MOS were inhibited by specific 5-HT4R-antagonist such as GR113808 (GR) or SB-207266. The activation of enteric neural 5-HT4R promotes reconstruction of an enteric neural circuit that involves possibly neural stem cells. We also succeeded in forming dense enteric neural networks by MOS in a gut differentiated from mouse embryonic stem cells. GR abolished the formation of enteric neural networks. MOS up-regulated the expression of mRNA of 5-HT4R, and GR abolished this upregulation, suggesting MOS differentiated enteric neural networks, mediated via activation of 5-HT4R. In the small intestine in H-line: Thy1 promoter green fluorescent protein (GFP) mice, we obtained clear 3-dimensional imaging of enteric neurons that were newly generated by oral application of MOS after gut transection and anastomosis. All findings indicate that treatment with 5-HT4R-agonists could be a novel therapy for generating new enteric neurons to rescue aganglionic disorders in the whole gut.

Changes in Enteric Neurons of Small Intestine in a Rat Model of Irritable Bowel Syndrome with Diarrhea

“…38 Comparable results occuring in the ENS has begun to accumulate. [39][40][41] We presume that the responsive changes in enteric neurons to CAS stress might contribute to the dysfunction in motility and secretion in IBS-D, and to the symptom of diarrhea. Understanding the pathophysiological mechanisms of IBS from the viewpoint of integrated controlling functions of the ENS could be helpful for future development effective drugs for functional GI disorders.…”

Gene-environment interactions and the enteric nervous system: Neural plasticity and Hirschsprung disease prevention

“…The norepinephrine reuptake transporter (NET) is also required for development of serotonergic neurons and reduced NET activity affects ENS development (Li et al, 2010). Interestingly, in postnatal bowel, serotonin also promotes new neurogenesis and ENS repair, at least partially via 5-HT4 receptor (Gershon, 2012; Matsuyoshi et al, 2010; Takaki et al, 2014). Consistent with these observations, human data based on 35,400 pregnancies suggest that first trimester exposure to tricyclic antidepressants (TCAs) and second or third trimester exposure to selective serotonin reuptake inhibitors (SSRIs) increases the use of laxatives in children after birth up to 10-fold for combined exposures (Nijenhuis et al, 2012).…”

Activation of 5-HT₄ receptors facilitates neurogenesis of injured enteric neurons at an anastomosis in the lower gut

“…(26) with permission. GAB1: GRB2-associated binding protein 1; GDNF: glial cell line-derived neurotrophic factor; GFRα1: GDNF family receptor α1; GRB2: growth factor receptor-bound protein 2; JNK: c-Jun-NH2-terminal kinase; PKC: protein kinase C; S: serine; Y: tyrosine.) (22). …”

“…Therefore, the downstream pathways via AKT and ERK1/2 may be more important than others (see Fig. 7) (22). …”

“…In the literature (22, 25, 26), the detailed downstream has been reported as follows: RET activation results in phosphorylation of several residues, including Y1015 and Y1062. GRB2 (Growth factor receptor-bound protein 2) and PLCγ are required for proliferation and/or differentiation of ENS precursors.…”