Physiological and Functional Changes in the Colon of MPTP-Treated Common Marmosets

Abstract

Objective: To determine changes in colon pathophysiology in MPTP-treated common marmosets. Background: Constipation is a common premotor symptom of Parkinson's disease (PD) and may be the result of changes in colonic innervation and function. However, this has not been fully investigated. We report neurochemical and functional changes in mucosal ion transport and muscle contractility in the colon of MPTP-treated common marmosets. Methods: Colon from pentobarbitone euthanized naive (n=8) or MPTP-treated common marmosets (n=7) was used for immunohistochemistry, and to measure mucosal ion transport and longitudinal muscle contraction. To investigate changes in the myenteric plexus, whole mounts were stained for HuC/HuD-, ChAT-, VIP- and nNOS-immunoreactivity. Using transverse colon preparations voltage-clamped at 0 mV, basal resistances and short-circuit current (Isc) were measured. Changes in Isc were measured following vehicle or combinations of 1 µM atropine, 10 µM, carbachol (CCh), 200 µM hexamethonium and 1mM N-nitro-L-arginine (LNNA), or following depolarisation of enteric nerves with 30 µM veratridine (VER). To investigate the spontaneous and CCh-evoked contractions, isometric contractile force of isolated longitudinal muscle was measured. Data were analysed by 1 or 2-way ANOVA and Dunnet's test or Student's t-test. Results: In MPTP-treated animals there were reduced numbers of ChAT+ve cell bodies in the proximal and distal colon, an increased number of VIP+ve cell bodies in the proximal colon, and no change in nNOS+ve immunoreactivity in either tissue. The basal Isc was lower in MPTP-treated colonic mucosa while mucosal resistance was unchanged. VER Isc responses were complex, partially cholinergic-mediated, but not significantly altered in MPTP-treated colon. CCh Isc responses increased in MPTP-tissues, particularly following LNNA (P<0.05). In the isolated colonic strips, frequency but not the force of spontaneous contractions was increased in MPTP-treated colon, although, there was no difference in the CCh-induced contractions. Conclusions: MPTP treatment preferentially altered cholinergic colonic ion transport rather than contractility. In combination with the complex interaction between VIP and acetylcholine in the colonic myenteric plexus, and increase in frequency of basal contraction following MPTP, these changes might have a direct bearing on gut dysfunction in PD