title: Prucalopride exerts neuroprotection in human enteric neurons.
abstract: Serotonin (5-hydroxytryptamine, 5-HT) and its transporters and receptors are involved in a wide array of digestive functions. In particular, 5-HT4 receptors are known to mediate intestinal peristalsis and recent data in experimental animals have shown their role in neuronal maintenance and neurogenesis. This study has been designed to test whether prucalopride, a well-known full 5-HT4 agonist, exerts protective effects on neurons, including enteric neurons, exposed to oxidative stress challenge. Sulforhodamine B assay was used to determine the survival of SH-SY5Y cells, human enteric neurospheres, and ex vivo submucosal neurons following H2O2 exposure in the presence or absence of prucalopride (1 nM). Specificity of 5-HT4-mediated neuroprotection was established by experiments performed in the presence of GR113808, a 5-HT4 antagonist. Prucalopride exhibited a significant neuroprotective effect. SH-SY5Y cells pretreated with prucalopride were protected from the injury elicited by H2O2 as shown by increased survival (73.5 ± 0.1% of neuronal survival vs. 33.3 ± 0.1%, respectively; P < 0.0001) and a significant reduction of proapoptotic caspase-3 and caspase-9 activation in all neurons tested. The protective effect of prucalopride was reversed by the specific 5-HT4 antagonist GR113808. Prucalopride promotes a significant neuroprotection against oxidative-mediated proapoptotic mechanisms. Our data pave the way for novel therapeutic implications of full 5-HT4 agonists in gut dysmotility characterized by neuronal degeneration, which go beyond the well-known enterokinetic effect.
authors.affiliation: Department of Veterinary Medical Sciences, University of Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianco
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: Bonora
authors.affiliation: Paediatric Gastroenterology, UCL Institute of Child Health, London, UK;
authors.forename: Dipa
authors.initials: D
authors.lastname: Natarajan
authors.affiliation: BioNanoGenLab Health Sciences and Technologies-Interdepartmental Center for Industrial Research, University of Bologna, Italy;
authors.forename: Manuela
authors.initials: M
authors.lastname: Vargiolu
authors.affiliation: BioNanoGenLab Health Sciences and Technologies-Interdepartmental Center for Industrial Research, University of Bologna, Italy;
authors.forename: Nikhil
authors.initials: N
authors.lastname: Thapar
authors.affiliation: Department of Digestive System, St. Orsola-Malpighi Hospital, Bologna, Italy; and.
authors.forename: Francesco
authors.initials: F
authors.lastname: Torresan
authors.affiliation: Department of Veterinary Medical Sciences, University of Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Italy;
authors.forename: Fiorella
authors.initials: F
authors.lastname: Giancola
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Italy;
authors.forename: Elisa
authors.initials: E
authors.lastname: Boschetti
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Italy;
authors.forename: Umberto
authors.initials: U
authors.lastname: Volta
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Italy;
authors.forename: Franco
authors.initials: F
authors.lastname: Bazzoli
authors.affiliation: Department of Veterinary Medical Sciences, University of Bologna, Italy;
authors.forename: Maurizio
authors.initials: M
authors.lastname: Mazzoni
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.affiliation: Department of Veterinary Medical Sciences, University of Bologna, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: Clavenzani
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Italy;
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Stanghellini
authors.affiliation: Departments of Medicine and Neurobiology, David Geffen School of Medicine, UCLA, Los Angeles, California.
authors.forename: Catia
authors.initials: C
authors.lastname: Sternini
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Italy; roberto.degiorgio@unibo.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: De Giorgio
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D001572:Benzofurans / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007422:Intestines / Q000166:cytology / Q000294:innervation*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology*
chemical_list: D001572:Benzofurans; D018696:Neuroprotective Agents; D058828:Serotonin 5-HT4 Receptor Agonists; C406662:prucalopride
keywords: 5-HT4 full agonist; enterokinetic drug; prucalopride; serotonin