Mechanism of Toxicity in Rotenone Models of Parkinson's Disease

By Todd B. Sherer, R. Betarbet, Claudia M. Testa, B. Seo, J. Richardson, Jin Hoo Kim, Gary W. Miller, T. Yagi, A. Matsuno‐Yagi, J. Greenamyre. Journal of Neuroscience, 2003

1,040 citations recorded by the source corpus.

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 nm to 1 μm) 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.

Subfields: Biotechnology, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/d916b6a33a7f1df587093bc1b16b3002f796ad39

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In Molecular Biology

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In Neurology

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Citations in the corpus

• Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease (2011, background): “The extensive microglial activation seen in both the SNpc and striatum following rotenone infusion (Sherer et al., 2003b) is consistent with the inflammatory features found in idiopathic PD (Gerhard et al., 2006; Whitton, 2007; Tansey and Goldberg, 2010), lending support to the construct validity…”
• Mitochondrial Glutathione, a Key Survival Antioxidant (2009, background): “For instance, Parkinson’s disease (PD) is characterized by a mitochondrial dysfunction, and established animal models of PD are based on prolonged infusion of inhibitors of complex I of the mitochondrial electrontransport chain, such as rotenone (131) or MPTP (40).”
• Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention (2009, background): “Several environmental triggers known to promote neuroinflammatory responses have been implicated in idiopathic PD and include traumatic head injury, viral inflammation, exposure to heavy metals, organophosphate compounds, neurotoxins like MPTP, and certain pesticides such as paraquat and rotenone (C”
• Mitochondria take center stage in aging and neurodegeneration (2005, background): “The mechanism of neurotoxicity appears to involve oxidative damage, rather than ATP depletion, because a similar degree of ATP depletion produced by 2-deoxyglucose did not have toxic effects.(37) Several studies provide genetic evidence that mtDNA abnormalities may contribute to PD pathogenesis.”
• Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences (2012, positive): “…ectopic expression of Ndi1p, a yeast single-subunit NADH dehydrogenase that is insensitive to MPTP and rotenone, has been shown to protect DA neurons from MPTP and rotenone toxicity in vitro and in vivo (Sherer et al , 2003; Seo et al , 2006; Richardson et al , 2007; Marella et al , 2008).”
• Mitochondria in health and disease: perspectives on a new mitochondrial biology. (2004, background): “The specific site of action of rotenone seems unambiguously defined as mitochondrial complex I––the drug is relatively selective, and the same group remarkably also managed to transfect into cells a yeast subunit of complex I which lacks the rotenone binding site, and cells became resistant to roten”
• Oxidative Stress in Parkinson's Disease: A Mechanism of Pathogenic and Therapeutic Significance (2008, background): “Rotenone, a complex I inhibitor induces dopaminergic cell loss in cell culture [32] and can cause PD type neuropathology and movement abnormalities [33-35].”