ABSTRACT
BACKGROUND: The systemic rotenone model of Parkinson's disease (PD) accurately replicates many aspects of the pathology of human PD, especially neurodegeneration of the substantia nigra and lesions in the enteric nervous system (ENS). Nevertheless, the precise effects of oral rotenone on the ENS have not been addressed yet. This study was therefore designed to assess the effects of a chronic oral treatment by rotenone on enteric neurochemical phenotype, gastrointestinal (GI) motility, and intestinal epithelial barrier permeability. METHODS: Male C57BL6N mice received once daily oral rotenone administration for 28 days. GI functions were analyzed 4 weeks after rotenone treatment. Gastrointestinal motility was assessed by measuring gastric emptying, total transit time, fecal pellet output, and bead latency. Intestinal barrier permeability was evaluated both in vivo and ex vivo. The number of enteric neurons and the enteric neurochemical phenotype were analyzed by immunohistochemistry. Tyrosine hydroxylase (TH) immunostaining of dopaminergic neurons of the substantia nigra was performed in a subset of animals. KEY RESULTS: Mice treated orally with rotenone had a decrease in fecal pellet output and in jejunal alpha-synuclein expression as compared with control animals. This was associated with a significant decrease in TH-immunoreactive neurons in the substantia nigra. No change in gastric emptying, total transit time, intestinal epithelial barrier permeability, and enteric neurochemical phenotype was observed. CONCLUSIONS & INFERENCES: Chronic oral treatment with rotenone only induced minor changes in the ENS and did not recapitulate the GI abnormalities seen in PD, while it replicates neurodegeneration of the substantia nigra.
Subject(s)
Gastrointestinal Motility/drug effects , Intestinal Mucosa/drug effects , Myenteric Plexus/drug effects , Rotenone/toxicity , Uncoupling Agents/toxicity , Administration, Oral , Animals , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Neurons/drug effects , Rotenone/administration & dosage , Substantia Nigra/drug effects , Uncoupling Agents/administration & dosageABSTRACT
It has become increasingly evident over the last years that Parkinson's disease is a multicentric neurodegenerative disease that affects several neuronal structures outside the substantia nigra, among which is the enteric nervous system. The aims of the present article are to discuss the role of the enteric nervous system lesions in pathology spreading (Braak's hypothesis) and in the gastrointestinal dysfunction encountered in Parkinson's disease. Owing to its accessibility to biopsies, we further discuss the use of the enteric nervous system as an original source of biomarker in Parkinson's disease.
Subject(s)
Enteric Nervous System/physiology , Parkinson Disease/physiopathology , Animals , Biomarkers/analysis , Brain/physiology , Enteric Nervous System/anatomy & histology , Enteric Nervous System/pathology , Humans , Models, Biological , Parkinson Disease/diagnosis , Parkinson Disease/pathology , Terminology as TopicABSTRACT
Better characterization of enteric neuropathies during the course of gastrointestinal diseases could be of great diagnostic and/or therapeutic interest. However, studies using whole mounts of the enteric nervous system (ENS) are restricted to specific diseases requiring surgery and are also limited by the small number of specimens available. Therefore, we here describe a novel method to obtain whole mounts of submucosal plexus in routine colonic biopsies. We show that a single biopsy displays a substantial number of submucosal ganglia and neurons and that it can be reliably used to perform morphometric and neurochemical analysis and Western Blots quantification of neuronal or glial markers. This method of analysis of the human ENS will enable us to gain better insight into the characterization of enteric neuropathies in living patients.
