Pathological Remodelling of Colonic Wall Following Dopaminergic Nigrostriatal Neurodegeneration

Background and aim:Patients with Parkinson's disease (PD) are often characterized by functional gastrointestinaldisorders. Such disturbances can occur at all stages of PD and precede the typical motor symptoms of the diseaseby many years. However, the morphological alterations associated with intestinal disturbances in PD are un-determined. This study examined the remodelling of colonic wall in 6-hydroxydopamine (6-OHDA)-induced PDrats.Methods:8 weeks after 6-OHDA injection animals were sacrificed. Inflammatory infiltrates, collagen depositionand remodelling of intestinal epithelial barrier andtunica muscularisin the colonic wall were assessed by his-tochemistry, immunohistochemistry, immunofluorescence and western blot analysis.Results:6-OHDA rats displayed significant alterations of colonic tissues as compared with controls. Signs of mildinflammation (eosinophil infiltration) and a transmural deposition of collagenfibres were observed. Superficialcolonic layers were characterized by severe morphological alterations. In particular, lining epithelial cells dis-played a reduced claudin-1 and transmembrane 16A/Anoctamin 1 (TMEM16A/ANO1) expression; goblet cellsincreased their mucin expression; colonic crypts were characterized by an increase in proliferating epithelialcells; the density of S100-positive glial cells and vimentin-positivefibroblast-like cells was increased as well.Several changes were found in thetunica muscularis: downregulation ofα-smooth muscle actin/desmin ex-pression and increased proliferation of smooth muscle cells; increased vimentin expression and proliferativephenotype in myenteric ganglia; reduction of interstitial cells of Cajal (ICCs) density.Conclusions:A pathological remodelling occurs in the colon of 6-OHDA rats. The main changes include: en-hancedfibrotic deposition; alterations of the epithelial barrier; activation of mucosal defense; reduction of ICCs.These results indicate that central nigrostriatal denervation is associated with histological changes in the largebowel at mucosal, submucosal and muscular level. These alterations might represent morphological correlates ofdigestive symptoms in PD.https://doi.org/10.1016/j.nbd.2020.104821Received 26 August 2019; Received in revised form 30 January 2020; Accepted 19 February 2020Abbreviations:GI, gastrointestinal;ICCs, interstitial cells of Cajal;6-OHDA, 6-hydroxydopamine;PCNA, proliferating cellular nuclear antigen;PD, Parkinson'sdisease;PPP, percentage of positive pixels;S100, glial cell marker;α-SMA, alpha-smooth muscle actin;SMC, smooth muscle cell;SR/FG, Sirius red/Fast green;TMEM16A/ANO1, transmembrane 16A/Anoctamin 1⁎Corresponding author at: Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126Pisa, Italy.E-mail address:nunzia.bernardini@med.unipi.it(N. Bernardini).Neurobiology of Disease 139 (2020) 104821Available online 21 February 20200969-9961/ © 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).T