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ToxSci Advance Access published online on February 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh089
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received September 20, 2003; accepted January 23, 2003
© 2004 Society of Toxicology

Neurotoxicology

Rotenone-Induced Apoptosis Is Mediated by p38 and JNK MAP Kinases in Human Dopaminergic SH-SY5Y Cells

Kathleen Newhouse 1, Shih-Ling Hsuan 1, Sandra H. Chang 1, Beibei Cai 1, Yupeng Wang 1, and Zhengui Xia 2*

1 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195-7234
2 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195-7234; Department of Pharmacology, University of Washington, Seattle, Washington 98195-7234

* To whom correspondence should be addressed. E-mail: zxia{at}u.washington.edu.


  Abstract

Rotenone is a naturally derived pesticide that has recently been shown to evoke the behavioral and pathological symptoms of Parkinson's disease in animal models. Though rotenone is known to be an inhibitor of the mitochondrial complex I electron transport chain, little is known about downstream pathways leading to its toxicity. We used human dopaminergic SH-SY5Y cells to study mechanisms of rotenone-induced neuronal cell death. Our results suggest that rotenone, at nanomolar concentrations, induces apoptosis in SH-SY5Y cells that is caspase-dependent. Furthermore, rotenone treatment induces phosphorylation of c-Jun, the c-Jun N- terminal protein kinase (JNK), and the p38 mitogen activated protein (MAP) kinase, indicative of activation of the p38 and JNK pathways. Importantly, expression of dominant interfering constructs of the JNK or p38 pathways attenuated rotenone-induced apoptosis. These data suggest that rotenone induces apoptosis in the dopaminergic SH-SY5Y cells that requires activation of the JNK and p38 MAP kinases, and caspases. These studies provide insights concerning the molecular mechanisms of rotenone-induced apoptosis in neuronal cells.

Key Words: rotenone, MAP kinase, p38, JNK, c-Jun, SH-SY5Y, apoptosis, pesticide, Parkinson's Disease .


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