Chronic rotenone exposure reproduces Parkinson's disease gastrointestinal neuropathology.
Gastrointestinal disorders, particularly severe constipation and delayed gastric emptying, are core symptoms of Parkinson's disease that affect most patients. However, the neuropathological substrate and physiological basis for this dysfunction are poorly defined. To begin to explore these phenomena in laboratory models of PD, rats were treated with either vehicle or rotenone (2.0 mg/kg, i.p.; 5 days/week) for 6-weeks. Myenteric plexus alpha-synuclein aggregate pathology and neuron loss were assessed 3-days and 6-months after the last rotenone injection. Gastrointestinal motility was assessed at 3-days, 1-month and 6-months after the last rotenone injection. Rotenone treatment caused an acute reduction in alpha-synuclein-immunoreactivity, but this was followed 6 months later by a robust increase in aggregate pathology and cytoplasmic inclusions that were similar in appearance to enteric Lewy-bodies in idiopathic PD. Rotenone-treated rats also had a moderate but permanent loss of small intestine myenteric neurons and an associated modest slowing of gastrointestinal motility 6-months after treatment. Our results suggest that a circumscribed exposure to an environmental toxicant can cause the delayed appearance of parkinsonian alpha-synuclein pathology in the enteric nervous system and an associated functional deficit in gastrointestinal motility. The rotenone model may therefore, provide a means to investigate pathogenic mechanisms and to test new therapeutic interventions into gastrointestinal dysfunction in PD.
Drolet
Robert E
RE
Pittsburgh Institute for Neurodegenerative Disease, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 1526, USA. droletre@upmc.edu
Cannon
Jason R
JR
Montero
Laura
L
Greenamyre
J Timothy
JT
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051959:ELAV Proteins / Q000378:metabolism; D000067778:ELAV-Like Protein 3; D004435:Eating / Q000187:drug effects; D005561:Formates / Q000494:pharmacology; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D005769:Gastrointestinal Motility / Q000187:drug effects; D007306:Insecticides / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D012402:Rotenone / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D051844:alpha-Synuclein / Q000187:drug effects / Q000378:metabolism
D051959:ELAV Proteins; D000067778:ELAV-Like Protein 3; C490263:Elavl3 protein, mouse; D005561:Formates; D007306:Insecticides; D051844:alpha-Synuclein; D012402:Rotenone; C030544:formic acid