Rotenone Rat and Other Neurotoxin Models of Parkinson Disease

TODD B. SHERER, RANJITA BETARBET, and J. TIMOTHY GREENAMYRE

Parkinson disease (PD) is a progressive neurodegenerative disease marked by motor and non-motor abnormalities. The hallmark pathological features of PD are selective nigrostriatal dopaminergic degeneration and formation of filamentous, cytoplasmic inclusions called Lewy bodies, containing a-synuclein and ubiquitin. Brains of PD patients show evidence of extensive oxidative damage and microglial activation. Additionally, PD patients are characterized by systemic mitochondrial dysfunction, marked by inhibition of complex I of the mitochondrial electron transport chain. The pathogenesis of idiopathic PD is believed to involve an interaction between genetic and environmental factors. Specifically, PD has been associated with pesticide exposure and rural living. Two recently developed animal models of PD investigate the involvement of environmental exposures in PD pathogenesis. In the rotenone model of PD, rats are exposed, chronically and systemically, to low doses of rotenone, a commonly used pesticide and specific mito-chondrial complex I inhibitor. Because of its lipophilic nature, rotenone crosses biological membranes easily, independent of transporters. Despite causing uniform mitochondrial inhibition throughout the brain, rotenone treatment reproduces many features of PD including motor abnormalities, selective nigrostriatal dopaminergic degeneration, and formation of a-synuclein, ubiquitin-positive aggregates in nigral neurons. In the paraquat model of PD, mice exposed to paraquat, an environmental toxin, demonstrate selective nigrostriatal dopaminergic degeneration accompanied by aggregation of a-synuclein in nigral neurons. Thus, the rotenone and paraquat models of PD provide useful systems to understand PD pathogenesis and screen potential therapeutic strategies.

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