Effects of GDNF on 6-OHDA-induced death in a dopaminergic cell line: Modulation by inhibitors of PI3 kinase and MEK

Authors

  • Susana D. Ugarte,

    1. Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania
    Current affiliation:
    1. Children's Memorial Hospital, CMIER, 2300 Children's Plaza, Box #209, Chicago, IL 60614
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    • The first two authors contributed equally to this work.

  • Eva Lin,

    1. Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania
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    • The first two authors contributed equally to this work.

  • Eric Klann,

    1. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas
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  • Michael J. Zigmond,

    1. Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Ruth G. Perez

    Corresponding author
    1. Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania
    • University of Pittsburgh, Department of Neurology, 3500 Terrace St., BST S510, Pittsburgh, PA 15213
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Abstract

Parkinson's disease is a neurodegenerative disorder associated with the selective death of dopaminergic neurons. Glial cell line-derived neurotrophic factor (GDNF) can protect dopaminergic neurons in several parkinsonian models. We used the dopaminergic cell line MN9D to explore the mechanisms underlying GDNF-mediated protection against the neurotoxin 6-hydroxydopamine (6-OHDA). MN9D cell viability was decreased 24 hr after a 15-min exposure to 6-OHDA (50–1,000 μM) as revealed by staining with Hoechst reagent and Trypan blue. The addition of GDNF (10 ng/ml) before, during, and after exposure to 6-OHDA significantly increased the number of viable cells as assessed by Hoechst staining. In contrast, 6-OHDA-induced cell membrane damage was unaffected as measured by Trypan blue exclusion. The PI3K specific inhibitor LY294002 (10–50 μM) blocked GDNF-mediated protection against nuclear condensation, as did the MAPK kinase (MEK) inhibitor U0126 (5– 20 μM). These studies suggest that GDNF can protect dopaminergic cells against some but not all aspects of 6-OHDA-induced toxicity by acting through both PI3K and MAPK signaling pathways. © 2003 Wiley-Liss, Inc.

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