Progression of Parkinson's disease pathology is reproduced by intragastric administration of rotenone in mice

• Published in: PloS one Vol. 5; no. 1; p. e8762
• Main Authors: Pan-Montojo, Francisco, Anichtchik, Oleg, Dening, Yanina, Knels, Lilla, Pursche, Stefan, Jung, Roland, Jackson, Sandra, Gille, Gabriele, Spillantini, Maria Grazia, Reichmann, Heinz, Funk, Richard H W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.01.2010; Public Library of Science (PLoS)
• Subjects: Agrochemicals; Analysis; Anatomy; Animals; Brain research; Central nervous system; Chromatography, High Pressure Liquid; Disease Models, Animal; Electron transport; Electron transport chain; Enteric nervous system; Enteric Nervous System - drug effects; Environmental factors; High-performance liquid chromatography; Inflammation; Liquid chromatography; Methods; Mice; Mice, Inbred BALB C; Mitochondria; Motor nuclei; Motor vehicle registration; Movement disorders; Musculoskeletal system; Mutation; NADH-ubiquinone oxidoreductase; Nervous system; Neurodegenerative diseases; Neurological Disorders/Disorders of Neurogastroenterology and Motility; Neurological Disorders/Movement Disorders; Neurology; Neurons; Neuropathology; Neuroscience/Neurobiology of Disease and Regeneration; Nuclei; Parkinson Disease - pathology; Parkinson's disease; Pathology; Patients; Pesticides; Phosphorylation; Rodents; Rotenone; Rotenone - administration & dosage; Rotenone - pharmacology; Spinal cord; Stomach; Substantia nigra; Synuclein; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0008762

In patients with Parkinson's disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alpha-synuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]<20 nM) and mitochondrial Complex I measurements showed no systemic Complex I inhibition after 1.5 months of treatment. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment time-dependent and accompanied by inflammatory signs and motor dysfunctions. These results strongly suggest that the local effect of pesticides on the ENS might be sufficient to induce PD-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging. It provides new insight into how environmental factors could trigger PD and suggests a transsynaptic mechanism by which PD might spread throughout the central nervous system.