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.

Localization of the 5‐hydroxytryptamine 4 receptor in equine enteric neurons and extrinsic sensory fibers

“…Tissue was thawed and homogenized. Total protein content from human (SH‐SY5Y) and murine (Neuro 2A) neuroblastoma cell lines were included as positive and negative controls, respectively …”

“…From this, different 5‐HT 4 agonists have been developed and used in humans as prokinetic agents for the treatment of chronic constipation . Among them, a selective 5‐HT 4 full agonist, prucalopride, stimulates intestinal propulsion, mucosal secretion, and exhibits enteric neuroprotective properties …”

Non-conventional features of peripheral serotonin signalling — the gut and beyond

“…Consistent with this, mice with an overactive form of SERT have altered motility that is associated with fewer enteric neurons, and these deficits are reversed by 5-HT4 receptor agonist treatment 33 . Agonists of the 5-HT 4 receptor also protect enteric neurons from oxidative stress-induced injury and cell death 34 . In a DSS mouse model of injury, colitis and its associated increase in 5-HT promoted enteric neurogenesis, and this effect was attributed to the 5-HT 4 receptor as it was blocked by an antagonist 35 .…”

Enteric Neuronal Regulation of Intestinal Inflammation

“…They also illustrate the great, but as yet not fully exploited, therapeutic potential of neuroactive compounds. With respect to IBD, it is known that inflammation is destructive of enteric neurons; therefore it is possible that 5-HT 4 -promoted neuroprotection or stimulation of adult neurogenesis [48,105,106,108] would be helpful in treating patients with IBD. The large stockpile of neuroactive drugs in clinical use may thus hold a few gems that, once explored, might help to alleviate the suffering of patients with IBD and other GI ailments.…”