Role of oxidative stress in paraquat-induced dopaminergic cell degeneration.
Systemic treatment of mice with the herbicide paraquat causes the selective loss of nigrostriatal dopaminergic neurons, reproducing the primary neurodegenerative feature of Parkinson's disease. To elucidate the role of oxidative damage in paraquat neurotoxicity, the time-course of neurodegeneration was correlated to changes in 4-hydroxy-2-nonenal (4-HNE), a lipid peroxidation marker. When mice were exposed to three weekly injections of paraquat, no nigral dopaminergic cell loss was observed after the first administration, whereas a significant reduction of neurons followed the second exposure. Changes in the number of nigral 4-HNE-positive neurons suggest a relationship between lipid peroxidation and neuronal death, since a dramatic increase in this number coincided with the onset and development of neurodegeneration after the second toxicant injection. Interestingly, the third paraquat administration did not cause any increase in 4-HNE-immunoreactive cells, nor did it produce any additional dopaminergic cell loss. Further evidence of paraquat-induced oxidative injury derives from the observation of nitrotyrosine immunoreactivity in the substantia nigra of paraquat-treated animals and from experiments with ferritin transgenic mice. These mice, which are characterized by a decreased susceptibility to oxidative stress, were completely resistant to the increase in 4-HNE-positive neurons and the cell death caused by paraquat. Thus, paraquat exposure yields a model that emphasizes the susceptibility of dopaminergic neurons to oxidative damage.
McCormack
Alison L
AL
The Parkinson's Institute, Sunnyvale, CA 94089, USA.
Atienza
Jennifer G
JG
Johnston
Louisa C
LC
Andersen
Julie K
JK
Vu
Susan
S
Di Monte
Donato A
DA
D000447:Aldehydes / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002452:Cell Count / Q000379:methods; D004298:Dopamine / Q000378:metabolism*; D004334:Drug Administration Schedule; D005293:Ferritins / Q000235:genetics; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010269:Paraquat / Q000633:toxicity*; D011401:Promoter Regions, Genetic / Q000502:physiology; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
D000447:Aldehydes; D006540:Herbicides; C002744:3-nitrotyrosine; D014443:Tyrosine; D005293:Ferritins; D014446:Tyrosine 3-Monooxygenase; C027576:4-hydroxy-2-nonenal; D010269:Paraquat; D004298:Dopamine