Mechanism of Toxicity in Rotenone Models of Parkinson's Disease

Abstract

Exposure of rats to the pesticide and complex I inhibitor rotenone reproduces features of Parkinson's disease, including selective nigrostriatal dopaminergic degeneration and alpha-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 microm) 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 alpha-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.

Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's disease-related insults

“…From these data, we inferred that MsrA failed to inhibit dopaminergic cell death or aggresome formation induced by MG132. The suppression of rotenone-induced neurodegeneration and aggresome formation by MsrA suggests that the enzyme interferes with oxidative stress triggered by complex I inhibition [43]. This result agrees with previous data showing that MsrA protects against cell death elicited by other oxidative insults [20][21][22][23].…”

“…Because rotenone triggers dopaminergic cell death by causing a buildup of ROS [43], MsrA could protect against rotenone-induced neurodegeneration by (i) suppressing intracellular oxidative stress via a ROS scavenging mechanism, and/or (ii) repairing methionine-oxidized proteins. To address these mechanisms, we tested the effect of MsrA on indices of oxidative stress in rotenone-treated, primary midbrain cultures.…”

Reactive oxygen species generation by the ethylene-bis-dithiocarbamate (EBDC) fungicide mancozeb and its contribution to neuronal toxicity in mesencephalic cells

“…Pesticide exposure in experimental rodent and cell culture models has been linked to ROS generation and/or an inflammatory response that potentiates ROS production. Dopaminergic toxicity by rotenone, a naturally occurring complex I inhibitor and a common herbicide, is caused by oxidative stress and is mediated, in part, by the activation of microglia (Gao et al, 2002(Gao et al, , 2003bSherer et al, 2002;Sherer et al, 2003;Zeevalk and Bernard, 2005). The neurotoxicity of paraquat (PQ), a bipyridial herbicide, mimics PD in experimental models and results in microglia activation and redox cycling via microglial NADPH oxidase (McCormack et al, 2002;Bonneh-Barkay et al, 2005).…”

Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Betarbet and co-workers [31,32] showed that chronic treatment with rotenone was sufficient to cause typical features of PD, including loss of dopaminergic neurons and appearance of a-syn-positive inclusions in rodents. The involvement of oxidative damage caused by mitochondrial dysfunction after rotenone treatment was also demonstrated in in vitro models, suggesting specific neuronal death by rotenone [33]. In this regard, a large number of environmental situations and agents have been identified, including farming and rural life, industrial chemicals, metals, and pesticide exposure; however, no conclusive relationships between individual studies have been found [26,34,35].…”