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Dopamine Selectively Sensitizes Dopaminergic Neurons to Rotenone-Induced Apoptosis

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Abstract

Among various types of neurons affected in Parkinson’s disease, dopamine (DA) neurons of the substantia nigra undergo the most pronounced degeneration. Products of DA oxidation and consequent cellular damage have been hypothesized to contribute to neuronal death. To examine whether elevated intracellular DA will selectively predispose the dopaminergic subpopulation of nigral neurons to damage by an oxidative insult, we first cultured rat primary mesencephalic cells in the presence of rotenone to elevate reactive oxygen species. Although MAP2+ neurons were more sensitive to rotenone-induced toxicity than type 1 astrocytes, rotenone affected equally both DA (TH+) neurons and MAP2+ neurons. In contrast, when intracellular DA concentration was elevated, DA neurons became selectively sensitized to rotenone. Raising intracellular DA levels in primary DA neurons resulted in dopaminergic neuron death in the presence of subtoxic concentrations of rotenone. Furthermore, mitochondrial superoxide dismutase mimetic, manganese (III) meso-tetrakis (4-benzoic acid) porphyrin, blocked activation of caspase-3, and consequent cell death. Our results demonstrate that an inhibitor of mitochondrial complex I and increased cytosolic DA may cooperatively lead to conditions of elevated oxidative stress and thereby promote selective demise of dopaminergic neurons.

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Acknowledgments

This research was supported by National Institutes of Health grants NINDS NS 38619 and NIAAA U01 AA13473 (Integrated Neuroscience Initiative on Alcoholism, INIA West Consortium). The authors thank Dr Curt Freed for scientific suggestions, Dr Kimberly Bjugstad for help with the statistical analysis, Dr Nancy Zahniser and Dr Susane Doolen for dopamine uptake analysis, Cindy Hutt for technical assistance, and Peggy Borgese from Hoffman-La Roche Inc. for providing tetrabenazine.

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Authors and Affiliations

  1. Division of Clinical Pharmacology and Toxicology, Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, CO, 80262, USA

    Ferogh A. Ahmadi, Tom N. Grammatopoulos, Andy M. Poczobutt, Susan M. Jones, Mita Das & W. Michael Zawada

  2. Neuroscience Program, University of Colorado at Denver and Health Sciences Center, Denver, CO, USA

    Ferogh A. Ahmadi & W. Michael Zawada

  3. Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Denver, CO, USA

    Tom N. Grammatopoulos & Laurence D. Snell

  4. Division of Clinical Pharmacology, C-237, University of Colorado at Denver and Health Sciences Center, 4200 East 9th Avenue, Denver, CO, 80262, USA

    W. Michael Zawada

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  1. Ferogh A. Ahmadi
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Correspondence to W. Michael Zawada.

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Ahmadi, F.A., Grammatopoulos, T.N., Poczobutt, A.M. et al. Dopamine Selectively Sensitizes Dopaminergic Neurons to Rotenone-Induced Apoptosis. Neurochem Res 33, 886–901 (2008). https://doi.org/10.1007/s11064-007-9532-5

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