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The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

Mechanism of Toxicity in Rotenone Models of Parkinson's Disease

Open access
Sherer, Todd B., Betarbet, Ranjita, Testa, Claudia M., Seo, Byoung Boo, Richardson, Jason R., Kim, Jin Ho, Miller, Gary W., Yagi, Takao, Matsuno-Yagi, Akemi, Greenamyre, J. Timothy·2003·The Journal of Neuroscience
DOI 10.1523/jneurosci.23-34-10756.2003
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Abstract

Exposure of rats to the pesticide and complex I inhibitor rotenone reproduces features of Parkinson's disease, including selective nigrostriatal dopaminergic degeneration and α-synuclein-positive cytoplasmic inclusions (Betarbet et al., 2000; Sherer et al., 2003). Here, we examined mechanisms of rotenone toxicity using three model systems. In SK-N-MC human neuroblastoma cells, rotenone (10 n m to 1 μ m) caused dose-dependent ATP depletion, oxidative damage, and death. To determine the molecular site of action of rotenone, cells were transfected with the rotenone-insensitive single-subunit NADH dehydrogenase of Saccharomyces cerevisiae(NDI1), which incorporates into the mammalian ETC and acts as a “replacement” for endogenous complex I. In response to rotenone, NDI1-transfected cells did not show mitochondrial impairment, oxidative damage, or death, demonstrating that these effects of rotenone were caused by specific interactions at complex I. Although rotenone caused modest ATP depletion, equivalent ATP loss induced by 2-deoxyglucose was without toxicity, arguing that bioenergetic defects were not responsible for cell death. In contrast, reducing oxidative damage with antioxidants, or by NDI1 transfection, blocked cell death. To determine the relevance of rotenone-induced oxidative damage to dopaminergic neuronal death, we used a chronic midbrain slice culture model. In this system, rotenone caused oxidative damage and dopaminergic neuronal loss, effects blocked by α-tocopherol. Finally, brains from rotenone-treated animals demonstrated oxidative damage, most notably in midbrain and olfactory bulb, dopaminergic regions affected by Parkinson's disease. These results, using three models of increasing complexity, demonstrate the involvement of oxidative damage in rotenone toxicity and support the evaluation of antioxidant therapies for Parkinson's disease.

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Metadata

Authors
Sherer, T. B., Betarbet, R., Testa, C. M., Seo, B. B., Richardson, J. R., Kim, J. H., Miller, G. W., Yagi, T., Matsuno-Yagi, A., & Greenamyre, J. T.
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2003-11-26
Volume
23
Issue
34
Pages
10756-10764
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.23-34-10756.2003
OpenAlex
W1954514489
Cited by
1,072
References
4
FWCI
19.67
Type
journal article
Language
en
Open access
hybrid

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