articlesParkinson's disease is a late-onset, progressive motor disease marked by selective degeneration of dopaminergic neurons of the substantia nigra and formation of fibrillar cytoplasmic inclusions, known as Lewy bodies, which contain ubiquitin and α-synuclein 1 . Rare cases of familial PD have been linked to mutations in α-synuclein or parkin [2][3][4] , but the cause of the more commonly encountered sporadic disease is unknown, and the role of genetics in these cases is uncertain 5 . Post mortem studies strongly implicate oxidative damage and mitochondrial impairment in the pathogenesis of PD 6 . Epidemiological studies have suggested that pesticide exposure is associated with an increased risk of developing PD 7-9 .After the pro-toxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was reported to produce in humans an acute parkinsonian syndrome that is virtually indistinguishable from idiopathic PD 10 , its metabolite, 1-methyl-4-pyridinium (MPP + ), was found to be a mitochondrial poison that inhibits mitochondrial respiration at complex I of the electron transport chain 11,12 . The selectivity of MPP + for dopaminergic neurons is due to the fact that it is an excellent substrate for the dopamine transporter, and is thereby accumulated preferentially in cells that transport dopamine 13 . Following recognition of MPTP's toxicity and its mechanism of action, several laboratories reported a selective defect in complex I of the electron transport chain in PD [14][15][16][17][18][19][20][21][22] . This defect seems to be systemic, affecting not only the brain, but also peripheral tissues such as platelets.An accurate in vivo experimental model of PD should reproduce the progressive, selective nigrostriatal dopaminergic degeneration and Lewy body formation seen in PD, test the relevance of the systemic complex I defect, and explain the potential involvement of pesticide exposure in development of parkinsonism. Unfortunately, no current animal model incorporates all of these features. The MPTP model causes selective nigrostriatal degeneration by inhibiting complex I, but, unlike PD, MPTP does not cause a systemic complex I defect. Instead, the inhibition is highly selective for dopaminergic neurons. Moreover, MPTP does not typically produce cytoplasmic inclusions that closely resemble Lewy bodies 23 . Transgenic mice expressing the pathogenic human α-synuclein mutation develop modest dopaminergic pathology (although the specificity of this degeneration is not detailed), and many neurons contain small cytoplasmic inclusions that are granular rather than fibrillar 24 .To develop a more accurate in vivo model of PD, we exposed rats chronically, continuously and systemically to the common pesticide, rotenone. A naturally occurring compound derived from the roots of certain plant species, rotenone is commonly used as an insecticide in vegetable gardens, and is also used to kill or sample fish populations in lakes and reservoirs. It is widely believed to be a safe, natural alternative to synthetic pesticides. Ro...
