title: MPTP-induced parkinsonism extends to a subclass of TH-positive neurons in the gut.
abstract: Gastrointestinal (GI) dysfunction occurs frequently in early Parkinson's disease (PD) and it is supposed to anticipate motor symptoms. About 80% of PD patients suffer from constipation before the onset of movement disorders. Despite such a high prevalence of gut impairment in PD, the molecular mechanisms remain poorly investigated. This is also due to the scarcity of experimental studies. In the present work, we tried to reproduce digestive abnormalities observed in PD patients by administering the parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) to C57BL mice. We show that in these mice, MPTP (20mg/kg × 3) while producing the classic striatal dopamine (DA) denervation, persistently delays colonic motility, produces constipation, and reduces the number of enteric TH-positive neurons. The loss of TH-positive cells in the gut is selectively due to the disappearance of DA neurons within both myenteric and mostly submucosal plexus in the intestine, while no change is detected in the esophagus and stomach. In contrast, norepinephrine (NE) neurons are not affected. These data were confirmed by immunohistochemistry and by HPLC showing the significant loss of DA levels while NE and 5-HT content was not affected. Dopamine cell loss was associated with increased α-synuclein levels. These functional, biochemical, and morphological findings extend the PD-mimicking effects of MPTP to GI dysfunctions and provide a useful experimental model to understand gut dysfunction in PD and to find effective treatments for digestive symptoms.
authors.affiliation: Department of Human Morphology and Applied Biology, University of Pisa, Pisa, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Natale
authors.forename: Olga
authors.initials: O
authors.lastname: Kastsiushenka
authors.forename: Federica
authors.initials: F
authors.lastname: Fulceri
authors.forename: Stefano
authors.initials: S
authors.lastname: Ruggieri
authors.forename: Antonio
authors.initials: A
authors.lastname: Paparelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Fornai
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D017615:Enteric Nervous System / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D005767:Gastrointestinal Diseases / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000145:classification / Q000201:enzymology* / Q000473:pathology; D020734:Parkinsonian Disorders / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D011897:Random Allocation; D013378:Substantia Nigra / Q000201:enzymology / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis*; D051844:alpha-Synuclein / Q000096:biosynthesis
chemical_list: D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase