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 (50-1000 microM) 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 microM) blocked GDNF-mediated protection against nuclear condensation, as did the MAPK kinase (MEK) inhibitor U0126 (5- 20 microM). 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.
Copyright 2003 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Butadienes / pharmacology
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Cell Death / drug effects*
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Cell Line
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Cell Survival / drug effects
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Chromones / pharmacology
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Dopamine / physiology
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Enzyme Inhibitors / pharmacology
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Glial Cell Line-Derived Neurotrophic Factor
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology
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Mitogen-Activated Protein Kinases / metabolism
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Morpholines / pharmacology
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Nerve Growth Factors / pharmacology*
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Neurons / cytology
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Neurons / drug effects*
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Neurons / enzymology
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Neuroprotective Agents / pharmacology*
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Nitriles / pharmacology
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Oxidative Stress / physiology
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Oxidopamine
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Parkinson Disease / metabolism
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Parkinson Disease / pathology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Sympatholytics
Substances
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Butadienes
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Chromones
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Enzyme Inhibitors
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Glial Cell Line-Derived Neurotrophic Factor
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Morpholines
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Nerve Growth Factors
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Neuroprotective Agents
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Nitriles
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Phosphoinositide-3 Kinase Inhibitors
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Sympatholytics
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U 0126
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Oxidopamine
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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Dopamine