Serotonin and neuroprotection in functional bowel disorders

Abstract

The 5-HT 4 partial agonist tegaserod is effective in the treatment of chronic constipation and constipation predominant irritable bowel syndrome. 5-HT 4 receptors are located on presynaptic terminals in the enteric nervous system. Stimulation of 5-HT 4 receptors enhances the release of acetylcholine and calcitonin gene related peptide from stimulated nerve terminals. This action strengthens neurotransmission in prokinetic pathways, enhancing gastrointestinal motility. The knockout of 5-HT 4 receptors in mice not only slows gastrointestinal activity but also, after 1 month of age, increases the age-related loss of enteric neurons and decreases the size of neurons that survive. 5-HT 4 receptor agonists, tegaserod and RS67506, increase numbers of enteric neurons developing from precursor cells and/or surviving in culture; they also increase neurite outgrowth and decrease apoptosis. The 5-HT 4 receptor antagonist, GR113808, blocks all of these effects, which are thus specific and 5-HT 4 -mediated. 5-HT 4 receptor agonists, therefore, are neuroprotective and neurotrophic for enteric neurons. Because the age-related decline in numbers of enteric neurons may contribute to the dysmotilities of the elderly, the possibility that the neuroprotective actions of 5-HT agonists can be utilized to prevent the occurrence or worsening of these conditions should be investigated. Keywords5-HT 4 receptors; constipation; enteric nervous system; gastrointestinal motility; lubiprostone; tegaserod Enteric Nervous System Development is Incomplete at BirthAlthough the bowel and the enteric nervous system (ENS) of a newborn mammal must be functioning at the time of birth to cope with oral feeding, both the gut and the ENS enlarge as a function of postnatal growth. Enlargement of the ENS is not just a matter of the hypertrophy of existing cells. New neurons must also be generated. As a result, the ENS of a mature mammal contains a larger number of neurons than that of a newborn. 1,2 In mice, the birth of new neurons has been demonstrated to occur at least through postnatal day 21 (P21). 3 The corresponding age has not been ascertained for humans, but extrapolation on the basis of relative life span would suggest that it is ∼3 years. Very little is known about the postnatal generation of new enteric neurons; nevertheless, the postnatal gut has recently been demonstrated to contain stem cells, 4,5 which are a likely source of neurons added to the ENS during postnatal life. It is thus possible that neurons continue to be added to the ENS in adult life, but if so, this addition would have to occur at a rate that is too slow to be detected by the conventional techniques that have thus far been utilized to look for it. Neurons are Lost from the Mature Ens as a Function of AgeThe number of neurons in the bowel increases in postnatal life, reaches a peak and then stabilizes. 2 The age at which the peak number of neurons is achieved in humans is unknown. Ageing, however, is associated with a postpeak decline so that the senescent gut has fe...

Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

“…Studies from 5-HT 4 knockout mice indicate that the density of neurons is not altered at birth, but 5-HT 4 receptor deficiency leads to a postnatal reduction in enteric neurons, and treatment of adult mice with a 5-HT 4 agonists promotes the generation of new enteric neurons 132, 133 . Furthermore, studies of cultured enteric neurons show that stimulation of 5-HT 4 receptors increases the proliferation and/or survival of enteric neurons and enhances neurite outgrowth 132, 133 . The results of these investigations are supported by the studies of Miyako Takaki and colleagues demonstrating that 5-HT 4 receptor stimulation enhances the formation of neural networks in an embryoid body culture system 134 .…”

Abuse, Trauma, and GI Illness: Is There a Link?

“…Recent theories of neurogenesis propose that behavioral and antidepressant treatment may potentially help regrow these neurons, and possibly re-establish normal cortical or even myenteric neuronal growth ( 50,57,64 ), possibly restoring more normal neural function. Within psychiatry, longer treatment with antidepressants is associated with a lower rate of relapse, possibly because it takes more time to restore lost neurons to produce clinical recovery from psychiatric disorders ( 65 ).…”

Gut Microbiota: The Conductor in the Orchestra of Immune–Neuroendocrine Communication

“…Changes in the levels of serotonin were also linked to the pathology of GI disorders, in which modulation of serotonin secretion is proposed as a treatment given its significant role in the enteric nervous system (ENS) and gut motility. 86 Bacterial by-products that come in contact with the gut epithelium stimulate enteroendocrine cells (EECs) to produce several neuropeptides such as peptide YY, neuropeptide Y, cholecystokinin, glucagon-like peptide-1 and -2, and substance P. 87 As an example, the gut senses the bacterial by-product SCFAs through G proteincoupled receptors 41 and 43 expressed on EECs. 88 Upon their secretion by EECs, the neuropeptides presumably diffuse throughout the lamina propria, which is occupied with a variety of immune cells, until they reach the bloodstream or act on the vagal nerve or intrinsic sensory neurons.…”