Serotonin and neuroprotection in functional bowel disorders

Abstract

The 5‐HT₄ partial agonist tegaserod is effective in the treatment of chronic constipation and constipation predominant irritable bowel syndrome. 5‐HT₄ receptors are located on presynaptic terminals in the enteric nervous system. Stimulation of 5‐HT₄ 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‐HT₄ 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‐HT₄ 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‐HT₄ receptor antagonist, GR113808, blocks all of these effects, which are thus specific and 5‐HT₄‐mediated. 5‐HT₄ 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.