Contractile dysfunction and nitrergic dysregulation in small intestine of a primate model of Parkinson’s disease

Abstract

Bowel dysfunction is a common non-motor symptom in Parkinson’s disease (PD). The main contractile neurotransmitter in the GI tract is acetylcholine (ACh), while nitric oxide (NO) causes the relaxation of smooth muscle in addition to modulating ACh release. The aim of this study was to characterise functional and neurochemical changes in the isolated ileum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmoset, an established model of PD motor dysfunction. While NO-synthase inhibitor L-NAME concentration dependently augmented the neurogenically-evoked contractions and inhibited the relaxations in normal tissues, it had no effects on the MPTP ileum. Immunohistochemical analyses of the myenteric plexus showed that ChAT-immunoreactivity (-ir) was significantly reduced and the density of the enteric glial cells as shown by SOX-10-ir was increased. However, no change in TH-, 5-HT-, VIP- or nNOS-ir was observed in the MPTP tissues. The enhancement of the neurogenically-evoked contractions and the inhibition of the relaxation phase by L-NAME in the control tissues is in line with NO’s direct relaxing effect on smooth muscle and its indirect inhibitory effect on ACh release. The absence of the relaxation and the inefficacy of L-NAME in the MPTP tissues suggests that central dopaminergic loss dopamine may eventually lead to the impairment of NO signal coupling that affects bowel function, and this may be the result of a complex dysregulation at the level of the neuroeffector junction.

Dysregulation of epithelial ion transport and neurochemical changes in the colon of a parkinsonian primate

“…Previously Natale et al 29 reported a reduction in murine enteric dopaminergic neurons 1 week after MPTP treatment in the duodenum but not in the colon. Whilst we found no change in the number of TH-ir neurons in the colon, we have previously reported generalised reduction in the intensity of TH-ir staining in the ileum but not the actual cell numbers 27 suggesting that these neurons may not be as susceptible to the toxic effects of MPTP as the dopaminergic neurons of the substantia nigra were, or were better able to repair over time. However, because TH is a common enzyme in the biosynthesis of both dopamine and noradrenaline much of the sparse TH immunoreactivity in the colon is likely to be associated with the extrinsic sympathetic innervation 30 , which may explain why the selective dopaminergic toxin MPTP did not alter the TH-immunoreactivity in the myenteric plexus of the common marmosets.…”

“…In the current study we observed a significant but low-level inflammation exemplified by the lack of change in SOX-10 glial markers and an increase in GFAP- and S100β in the proximal but not in the distal colon. In our previous study 27 we did observe a modest but significant increase in the number of SOX-10-ir cells in the ileum following MPTP treatment, but the lack of change in the proximal and distal colon in this study may suggest a regional pattern in the expression of inflammation.…”

“…While anecdotally we have some evidence of marked bowel dysfunction following very early stages of MPTP treatment, it has not always been possible to systematically study gut dysfunction throughout the life of these primates because the main focus of investigations in MPTP-treated common marmosets has been movement disorders. Previously, Chaumette et al 26 identified a reduction in TH-, and an increase in nNOS-immunoreactive (-ir) neurons in the MPTP-treated macaques, and we have shown a dysregulation of nitric oxide signal coupling in the ileum of MPTP-treated common marmosets, accompanied by a selective reduction in enteric cholinergic neurons 26 , 27 . However, there have been no studies of the changes in mucosal ion transport in the colon or the contractility of colonic tissue in isolated preparations, or accompanying changes in neuronal populations.…”

“…All animals received a wash out period of at least 2 months prior to this study and there were no overt contractile differences between tissues obtained from these animals. Immunohistochemical studies showed >70% TH cell loss in the substantia nigra pars compacta compared to the naïve controls 27 .…”

Characterization of Gastrointestinal Symptom Type and Severity in Parkinson's Disease: A Case–Control Study in an Australian Cohort

“…These symptoms can all be related to constipation, which is a particularly troublesome NMS, and a well‐studied symptom of prodromal PD 5,7–11 . Constipation in PD is reported to involve a dysfunctional colonic musculature which causes slowed movement of bowl contents through the colon, and prolonged transit time has been reported previously in PwP 8,39,40 . In addition, there is an outlet type obstruction and difficulty with rectal expulsion.…”