Jeanette M Shultz1, Henry Resnikoff2, Viktorya Bondarenko2, Valerie Joers2, Andres Mejia2, Heather Simmons2, Marina E Emborg3. 1. Wisconsin National Primate Research Center (WNPRC) and Cellular and Molecular Pathology (CMP) Graduate Program, University of Wisconsin-Madison, Madison, WI, USA. 2. WNPRC, University of Wisconsin-Madison, Madison, WI, USA. 3. WNPRC, CMP Graduate Program and Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA.
Abstract
OBJECTIVE: Constipation is a common non-motor symptom of Parkinson's disease (PD). Although pathology of the enteric nervous system (ENS) has been associated with constipation in PD, the contribution of catecholaminergic neurodegeneration to this symptom is currently debated. The goal of this study was to assess the effects of the neurotoxin 6-hydroxydopamine (6-OHDA) on the colonic myenteric plexus and shed light on the role of catecholaminergic innervation in gastrointestinal (GI) function. METHODS: Proximal colon tissue from 6-OHDA-treated (n=5) and age-matched control (n=5) rhesus monkeys was immunostained and quantified using ImageJ software. All animals underwent routine daily feces monitoring to assess for constipation or other GI dysfunction. RESULTS: Quantification of tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC)-immunoreactivity (-ir) revealed significant reduction in myenteric ganglia of 6-OHDA-treated animals compared to controls (TH-ir: 87.8%, P<0.0001; AADC-ir: 61.7% P=0.0034). Analysis of pan-neuronal markers (PGP9.5, HuC/D), other neurochemical phenotypes (VIP, nNOS), PD-associated pathology proteins (α-synuclein, phosphorylated α-synuclein), glial marker GFAP and neuroinflammation and oxidative stress (HLA-DR, CD45, Nitrotyrosine) did not show significant differences. Monitoring of feces revealed frequent (>30% days) soft stool or diarrhea in 2 of the 5 6-OHDA-treated animals and 0 of the 5 control animals during the 2 months prior to necropsy, with no animals exhibiting signs of constipation. CONCLUSION: Systemic administration of 6-OHDA to rhesus monkeys significantly reduced catecholaminergic expression in the colonic myenteric plexus without inducing constipation. These findings support the concept that ENS catecholaminergic loss is not responsible for constipation in PD.
OBJECTIVE:Constipation is a common non-motor symptom of Parkinson's disease (PD). Although pathology of the enteric nervous system (ENS) has been associated with constipation in PD, the contribution of catecholaminergic neurodegeneration to this symptom is currently debated. The goal of this study was to assess the effects of the neurotoxin 6-hydroxydopamine (6-OHDA) on the colonic myenteric plexus and shed light on the role of catecholaminergic innervation in gastrointestinal (GI) function. METHODS: Proximal colon tissue from 6-OHDA-treated (n=5) and age-matched control (n=5) rhesus monkeys was immunostained and quantified using ImageJ software. All animals underwent routine daily feces monitoring to assess for constipation or other GI dysfunction. RESULTS: Quantification of tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC)-immunoreactivity (-ir) revealed significant reduction in myenteric ganglia of 6-OHDA-treated animals compared to controls (TH-ir: 87.8%, P<0.0001; AADC-ir: 61.7% P=0.0034). Analysis of pan-neuronal markers (PGP9.5, HuC/D), other neurochemical phenotypes (VIP, nNOS), PD-associated pathology proteins (α-synuclein, phosphorylated α-synuclein), glial marker GFAP and neuroinflammation and oxidative stress (HLA-DR, CD45, Nitrotyrosine) did not show significant differences. Monitoring of feces revealed frequent (>30% days) soft stool or diarrhea in 2 of the 5 6-OHDA-treated animals and 0 of the 5 control animals during the 2 months prior to necropsy, with no animals exhibiting signs of constipation. CONCLUSION: Systemic administration of 6-OHDA to rhesus monkeys significantly reduced catecholaminergic expression in the colonic myenteric plexus without inducing constipation. These findings support the concept that ENS catecholaminergic loss is not responsible for constipation in PD.
Authors: Carmen Henze; Christopher Earl; Jürgen Sautter; Nicole Schmidt; Claudia Themann; Andreas Hartmann; Wolfgang H Oertel Journal: Brain Res Date: 2005-08-02 Impact factor: 3.252
Authors: Heiko Braak; Magdalena Sastre; Jürgen R E Bohl; Rob A I de Vos; Kelly Del Tredici Journal: Acta Neuropathol Date: 2007-02-09 Impact factor: 17.088
Authors: T Chaumette; T Lebouvier; P Aubert; B Lardeux; C Qin; Q Li; D Accary; E Bézard; S Bruley des Varannes; P Derkinderen; M Neunlist Journal: Neurogastroenterol Motil Date: 2008-12-05 Impact factor: 3.598
Authors: Francisco Pan-Montojo; Oleg Anichtchik; Yanina Dening; Lilla Knels; Stefan Pursche; Roland Jung; Sandra Jackson; Gabriele Gille; Maria Grazia Spillantini; Heinz Reichmann; Richard H W Funk Journal: PLoS One Date: 2010-01-19 Impact factor: 3.240
Authors: Valerie Joers; Gunasingh Masilamoni; Doty Kempf; Alison R Weiss; Travis M Rotterman; Benjamin Murray; Gul Yalcin-Cakmakli; Ronald J Voll; Mark M Goodman; Leonard Howell; Jocelyne Bachevalier; Stefan J Green; Ankur Naqib; Maliha Shaikh; Phillip A Engen; Ali Keshavarzian; Christopher J Barnum; Jonathon A Nye; Yoland Smith; Malú G Tansey Journal: Neurobiol Dis Date: 2020-07-24 Impact factor: 5.996
Authors: Alexandra D Zinnen; Jonathan Vichich; Jeanette M Metzger; Julia C Gambardella; Viktoriya Bondarenko; Heather A Simmons; Marina E Emborg Journal: PLoS One Date: 2022-06-10 Impact factor: 3.752
Authors: Henry Resnikoff; Jeanette M Metzger; Mary Lopez; Viktoriya Bondarenko; Andres Mejia; Heather A Simmons; Marina E Emborg Journal: J Inflamm Res Date: 2019-05-07
Authors: Anthony M Mancinelli; Jonathan M Vichich; Alexandra D Zinnen; Anna Marie Hugon; Viktoriya Bondarenko; Jeanette M Metzger; Heather A Simmons; Thaddeus G Golos; Marina E Emborg Journal: J Inflamm Res Date: 2021-12-22