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

TY - JOUR

T1 - Dysregulation of epithelial ion transport and neurochemical changes in the colon of a parkinsonian primate.

AU - Coletto, Erika

AU - Tough, Iain R.

AU - Pritchard, S

AU - Hikima, Atsuko

AU - Jackson, Michael

AU - Jenner, Peter

AU - Chaudhuri, K

AU - Cox, Helen

AU - Iravani, MM

AU - Salvage, Sarah

N1 - Funding Information: We thank Mr. Carl Hobbs and Professor Patrick Doherty for their help and assistance with the microscopy. E.C. was funded in part by Parkinson’s Disease Non Motor Group (PDNMG). PDNMG had no input into the study design, the collection, analysis and interpretation of data or in the writing of the report and the decision to submit the article for publication. Contribution of K.R.C. to this paper represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/1/23

Y1 - 2021/1/23

N2 - The pathological changes underlying gastrointestinal (GI) dysfunction in Parkinson's disease (PD) are poorly understood and the symptoms remain inadequately treated. In this study we compared the functional and neurochemical changes in the enteric nervous system in the colon of adult, L-DOPA-responsive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset, with naive controls. Measurement of mucosal vectorial ion transport, spontaneous longitudinal smooth muscle activity and immunohistochemical assessment of intrinsic innervation were each performed in discrete colonic regions of naive and MPTP-treated marmosets. The basal short circuit current (Isc) was lower in MPTP-treated colonic mucosa while mucosal resistance was unchanged. There was no difference in basal cholinergic tone, however, there was an increased excitatory cholinergic response in MPTP-treated tissues when NOS was blocked with L-Nomega-nitroarginine. The amplitude and frequency of spontaneous contractions in longitudinal smooth muscle as well as carbachol-evoked post-junctional contractile responses were unaltered, despite a decrease in choline acetyltransferase and an increase in the vasoactive intestinal polypeptide neuron numbers per ganglion in the proximal colon. There was a low-level inflammation in the proximal but not the distal colon accompanied by a change in alpha-synuclein immunoreactivity. This study suggests that MPTP treatment produces long-term alterations in colonic mucosal function associated with amplified muscarinic mucosal activity but decreased cholinergic innervation in myenteric plexi and increased nitrergic enteric neurotransmission. This suggests that long-term changes in either central or peripheral dopaminergic neurotransmission may lead to adaptive changes in colonic function resulting in alterations in ion transport across mucosal epithelia that may result in GI dysfunction in PD.

AB - The pathological changes underlying gastrointestinal (GI) dysfunction in Parkinson's disease (PD) are poorly understood and the symptoms remain inadequately treated. In this study we compared the functional and neurochemical changes in the enteric nervous system in the colon of adult, L-DOPA-responsive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset, with naive controls. Measurement of mucosal vectorial ion transport, spontaneous longitudinal smooth muscle activity and immunohistochemical assessment of intrinsic innervation were each performed in discrete colonic regions of naive and MPTP-treated marmosets. The basal short circuit current (Isc) was lower in MPTP-treated colonic mucosa while mucosal resistance was unchanged. There was no difference in basal cholinergic tone, however, there was an increased excitatory cholinergic response in MPTP-treated tissues when NOS was blocked with L-Nomega-nitroarginine. The amplitude and frequency of spontaneous contractions in longitudinal smooth muscle as well as carbachol-evoked post-junctional contractile responses were unaltered, despite a decrease in choline acetyltransferase and an increase in the vasoactive intestinal polypeptide neuron numbers per ganglion in the proximal colon. There was a low-level inflammation in the proximal but not the distal colon accompanied by a change in alpha-synuclein immunoreactivity. This study suggests that MPTP treatment produces long-term alterations in colonic mucosal function associated with amplified muscarinic mucosal activity but decreased cholinergic innervation in myenteric plexi and increased nitrergic enteric neurotransmission. This suggests that long-term changes in either central or peripheral dopaminergic neurotransmission may lead to adaptive changes in colonic function resulting in alterations in ion transport across mucosal epithelia that may result in GI dysfunction in PD.

UR - http://www.scopus.com/inward/record.url?scp=85098647216&partnerID=8YFLogxK

U2 - 10.1038/s41531-020-00149-4

DO - 10.1038/s41531-020-00149-4

M3 - Editorial

AN - SCOPUS:85098647216

SN - 2373-8057

VL - 7

JO - Nature Parkinson's Journal

JF - Nature Parkinson's Journal

IS - 1

M1 - 1

ER -