title: The TNF-α antagonist etanercept reverses age-related decreases in colonic SERT expression and faecal output in mice.
abstract: Treatment for chronic constipation in older people is challenging and the condition has a major impact on quality of life. A lack of understanding about the causes of this condition has hampered the development of effective treatments. 5-HT is an important pro-kinetic agent in the colon. We examined whether alterations in colonic 5-HT signalling underlie age-related changes in faecal output in mice and whether these changes were due to an increase in TNF-α. Components of the 5-HT signalling system (5-HT, 5-HIAA, SERT) and TNF-α expression were examined in the distal colon of 3, 12, 18 and 24-month old mice and faecal output and water content monitored under control conditions and following the administration of etanercept (TNF-α inhibitor; 1 mg Kg-1). Faecal output and water content were reduced in aged animals. Age increased mucosal 5-HT availability and TNF-α expression and decreased mucosal SERT expression and 5-HIAA. Etanercept treatment of old mice reversed these changes, suggesting that age-related changes in TNFα expression are an important regulator of mucosal 5-HT signalling and pellet output and water content in old mice. These data point to "anti-TNFα" drugs as potential treatments for age-related chronic constipation.
authors.affiliation: School of Pharmacy and Biomolecular Science, University of Brighton, Brighton, BN2 4GJ, UK.
authors.forename: Bhavik Anil
authors.initials: BA
authors.lastname: Patel
authors.affiliation: School of Pharmacy and Biomolecular Science, University of Brighton, Brighton, BN2 4GJ, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Fidalgo
authors.affiliation: Department of Life, Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
authors.forename: Chunfang
authors.initials: C
authors.lastname: Wang
authors.affiliation: School of Pharmacy and Biomolecular Science, University of Brighton, Brighton, BN2 4GJ, UK.
authors.forename: Leena
authors.initials: L
authors.lastname: Parmar
authors.affiliation: School of Pharmacy and Biomolecular Science, University of Brighton, Brighton, BN2 4GJ, UK.
authors.forename: Kasonde
authors.initials: K
authors.lastname: Mandona
authors.affiliation: School of Pharmacy and Biomolecular Science, University of Brighton, Brighton, BN2 4GJ, UK.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Panossian
authors.affiliation: School of Pharmacy and Biomolecular Science, University of Brighton, Brighton, BN2 4GJ, UK.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Flint
authors.affiliation: Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, NE1 8ST, UK.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Ranson
authors.affiliation: Department of Life, Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
authors.forename: M Jill
authors.initials: MJ
authors.lastname: Saffrey
authors.affiliation: School of Pharmacy and Biomolecular Science, University of Brighton, Brighton, BN2 4GJ, UK.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Yeoman
mesh_terms: D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000502:physiology; D003248:Constipation / Q000188:drug therapy* / Q000378:metabolism; D000068800:Etanercept / Q000494:pharmacology / Q000627:therapeutic use*; D005765:Gastrointestinal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D005765:Gastrointestinal Agents; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D012701:Serotonin; D000068800:Etanercept