Comparison of effects of a selective 5-HT reuptake inhibitor versus a 5-HT₄ receptor agonist on in vivo neurogenesis at the rectal anastomosis in rats

Abstract

It was recently reported that activation of enteric neural 5-HT(4) receptors (SR4) promotes reconstruction of enteric neural circuit injury in distal gut of guinea pigs and that this reconstruction involves neural stem cells. We aimed to explore a novel approach using a selective serotonin reuptake inhibitor (SSRI), which increases endogenous 5-HT, to repair enteric nerve fiber injury in the rat distal gut. Enteric nerve fiber injury was performed by rectal transection and subsequent end-to-end one-layer anastomosis. The SSRI fluvoxamine maleate (100 μmol/l) was applied locally at the anastomotic site to compare with the 5-HT(4) agonist mosapride citrate (100 μmol/l) (applied for patent) applied locally and orally. Unlike mosapride, fluvoxamine failed to promote the regeneration of the nerve fiber tract across the anastomosis. Furthermore, fluvoxamine did not generate anti-distal-less homeobox 2 (DLX2)- and anti-SR4-positive cells (neural stem cells) and/or anti-neurofilament (NF)-positive cells (neural cells) in newly formed granulation tissue at the anastomosis, whereas these cell types were observed in mosapride-treated preparations. In contrast to its effects in guinea pigs, mosapride generated 5-bromo-2'-deoxyuridine (BrdU)-positive neural cells in ganglia sites 3 mm oral and anal from the anastomosis 2 wk after nerve fiber injury. All actions of mosapride were observed after local and or oral applications. These findings indicate that local SSRI treatment does not induce in vivo nerve fiber tract growth across the anastomosis in the rat distal gut. Mosapride induces nerve fiber tract growth across the anastomosis, mediated through enteric neural stem cells possibly from neural crest-derived stem cells or mesenchymal stem cells in the bone marrow.

Protective Actions of Epithelial 5-Hydroxytryptamine 4 Receptors in Normal and Inflamed Colon

“…3 This neuro-protective action has been supported by in vivo studies demonstrating that recovery of the recto-anal reflex is significantly augmented, through neurogenesis and axon outgrowth, by 5-HT 4 receptor treatment following rectal transection and anastomosis. 103738 Furthermore, 5-HT 4 receptor-mediated enteric neurogenesis occurs in colitis, 39 a condition in which bioavailability of 5-HT is increased. 2 Taken together with the results reported here, it is becoming increasingly clear that the 5-HT 4 receptor exerts protective actions in the inner and outer layers of the gut.…”

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

“…HSCR pathogenesis is caused by mutations in genes encoding the Ret receptor tyrosine kinase (RET) and endothelin receptor type B (EDNRB) (11, 15). We have previously reported that MOS increases the mRNA level of RET in the cells mobilized into an implanted gel sponge in a rat subcutaneous model (not a gut model); this increase in RET mRNA was completely blocked by treatment with an SR4-antagonist (12). RET seems to be the target molecule of MOS and RET inhibitors could suppress MOS-induced neurogenesis (16).…”

“…The transplant NSC (PKH+ cells) and host NSC (YFP+ cells) are mobilized to the anastomosed area and either/or survived, proliferated, and finally differentiated into neurons (9, 11, 12). MOS clearly accelerated these processes after surgery (Fig.…”

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

“…Therefore, we subsequently explored a novel approach in vivo to reconstruct the enteric neural circuitry in the distal gut of guinea pigs9 and rats10 by application of an 5-HT 4 R agonist.…”

“…We applied a 5-HT 4 R agonist, mosapride citrate (MOS) locally at the anastomosis in guinea pigs9 or orally by the drinking water in rats10 for 2-4 weeks. Furthermore, we examined neurofilament (NF)-, 5-HT 4 R- and 5-bromo-2'-deoxyuridine (BrdU)-positive cells in the newly formed granulation tissue at the anastomotic site 2-4 weeks after enteric nerve circuit insult.…”