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

J Neurosci Res. 2003 Jul 1;73(1):105-12. doi: 10.1002/jnr.10632.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Butadienes / pharmacology
  • Cell Death / drug effects*
  • Cell Line
  • Cell Survival / drug effects
  • Chromones / pharmacology
  • Dopamine / physiology
  • Enzyme Inhibitors / pharmacology
  • Glial Cell Line-Derived Neurotrophic Factor
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Mitogen-Activated Protein Kinases / metabolism
  • Morpholines / pharmacology
  • Nerve Growth Factors / pharmacology*
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / enzymology
  • Neuroprotective Agents / pharmacology*
  • Nitriles / pharmacology
  • Oxidative Stress / physiology
  • Oxidopamine
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Sympatholytics

Substances

  • Butadienes
  • Chromones
  • Enzyme Inhibitors
  • Glial Cell Line-Derived Neurotrophic Factor
  • Morpholines
  • Nerve Growth Factors
  • Neuroprotective Agents
  • Nitriles
  • Phosphoinositide-3 Kinase Inhibitors
  • Sympatholytics
  • U 0126
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Oxidopamine
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • Dopamine