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Chronic systemic exposure reproduces features of Parkinson's disease Rats chronically exposed to the pesticide rotenone develop most of the cellular pathophysiologic features of Parkinson's disease, according to this report. E-MOVE's initial report on this study from the Annual Meeting of the American Association of Neurology is archived at: http://www.wemove.org/emove/article.asp?ID=194. 25 rats were infused for 7 days or more with 2-3 mg/kg/day of rotenone, a highly specific inhibitor of mitochondrial complex I. (The dose was below that needed to inhibit brain mitochondrial respiration rates, ruling out ATP depletion as a cause of pathology.) Histochemical analysis showed: - 12 of the 25 rats had brain lesions, versus no vehicle-treated rats. - while complex I inhibition was found throughout the brain, lesions were restricted to nigrostriatal dopaminergic pathways. - "Lesions typically began focally in the central or dorsolateral portion of the anterior striatum ... and spread to involve most of the striatum." - the pattern of areas that were most severely affected versus those that were relatively spared matched the pattern seen in PD. - Cytoplasmic inclusions were detected that contained ubiquitin and alpha-synuclein. "Ultrastructural features included a homogenous dense core surrounded by fibrillar elements similar to those seen in Lewy bodies. Some of the inclusions had a more granular appearance, like those described in alpha-synuclein transgenic mice." - Preliminary observations of behavior showed that animals with dopaminergic lesions had hypokinesia, unsteady movement, and hunched posture. 7 animals had severe rigidity, and 3 had shaking of one or more paws. The authors conclude, "Our results indicate that a systemic partial defect in complex I is enough to reproduce the behavioral, anatomical, neurochemical, and neuropathological features of PD." In a News and Views article accompanying the report, Benoit Giasson and Virginia Lee note, "The question remains as to why rotenone, which inhibits complex I throughout the brain, should preferentially target dopaminergic neurons. "The likely answer is that these neurons are particularly sensitive to oxidative stress [known to result from mitochondrial inhibition] because of the permanently elevated level of free radicals generated by dopamine metabolism and auto-oxidation." R Betarbet, TB Sherer, G MacKenzie, M Garcia-Osuna, AV Panov, JT Greenamyre Nature Neuroscience 2000;3:1301-1306 Copyright 2000 WE MOVE http://www.wemove.org janet paterson, an akinetic rigid subtype parkie 53 now /44 dx cd / 43 onset cd /41 dx pd / 37 onset pd TEL: 613 256 8340 SMAIL: POBox 171 Almonte Ontario K0A 1A0 Canada EMAIL: [log in to unmask] URL: http://www.geocities.com/janet313/