Serotonin and neuroprotection in functional bowel disorders.
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.
Gershon
M D
MD
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. mdg4@columbia.edu
Liu
M-T
MT
D000818:Animals; D003109:Colonic Diseases, Functional / Q000188:drug therapy / Q000503:physiopathology*; D003248:Constipation / Q000188:drug therapy; D017615:Enteric Nervous System / Q000502:physiology; D005765:Gastrointestinal Agents / Q000627:therapeutic use; D006801:Humans; D007211:Indoles; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000627:therapeutic use; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure
D005765:Gastrointestinal Agents; D007211:Indoles; D018696:Neuroprotective Agents; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; C105050:tegaserod