Glial-derived neurotrophic factor (GDNF) prevents ethanol (EtOH) induced B92 glial cell death by both PI3K/AKT and MEK/ERK signaling pathways

Brain Res Bull. 2006 Dec 11;71(1-3):116-26. doi: 10.1016/j.brainresbull.2006.08.014. Epub 2006 Sep 15.


We investigated the neuroprotective effect of glial-derived neurotrophic factor (GDNF) upon alcohol-exposed B92 cultures, as well as the role of the cytoskeleton and mitogen-activated protein kinase (MAPK) pathways in this effect. Ethanol (EtOH) was added to cultures, either alone or in combination with 30 ng/ml GDNF. Exposure to EtOH (86 and 172 mM; 60 and 120 min) increased the frequency of apoptotic cells identified by nuclear DNA staining with 4,6-diamidino-2-phenylindole (DAPI). Cultures treated with GDNF showed a decrease in ethanol-induced apoptosis. A jun N-terminal kinase (JNK) pathway is activated by EtOH and their pharmacological inhibition (by SP600125) neutralized ethanol-induced apoptosis, suggesting a role for JNK in EtOH neurotoxicity. Immunocytochemically detected phospho-JNK (p-JNK) showed an unusual filamental expression, and localized together with actin stress fibers. Examination of the cytoskeleton showed that EtOH depolymerized actin filaments, inducing p-JNK dissociation and translocation to the nucleus, which suggests that released p-JNK may contribute to glial cell death after EtOH exposure. Treatment with GDNF, in turn, may neutralize the ethanol-induced cell death pathway. Either a phosphatidylinositol 3-kinase (PI3K)/AKT pathway inhibitor (LY294002) or an inhibitor of the extracellular signal-regulated kinase (ERK) 1, 2 pathways (UO126) failed to neutralize GDNF protective effects. However, the simultaneous use of both inhibitors blocked the protective effect of GDNF, suggesting a role for both signaling cascades in the GDNF protection. These findings provide further insight into the mechanism involved in ethanol-induced apoptosis and the neurotrophic protection of glial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / drug effects
  • Actin Cytoskeleton / metabolism
  • Alcohol-Induced Disorders, Nervous System / drug therapy
  • Alcohol-Induced Disorders, Nervous System / metabolism
  • Alcohol-Induced Disorders, Nervous System / physiopathology
  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / physiopathology
  • Cell Line, Tumor
  • Central Nervous System Depressants / antagonists & inhibitors
  • Central Nervous System Depressants / toxicity
  • Cytoprotection / drug effects
  • Cytoprotection / physiology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Ethanol / antagonists & inhibitors*
  • Ethanol / toxicity
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism
  • Glial Cell Line-Derived Neurotrophic Factor / pharmacology*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / physiology
  • Neuroglia / drug effects*
  • Neuroglia / metabolism
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Rats


  • Central Nervous System Depressants
  • Enzyme Inhibitors
  • Glial Cell Line-Derived Neurotrophic Factor
  • Neuroprotective Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • Ethanol
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1