Specific regulation of rat glial cell line-derived neurotrophic factor gene expression by riluzole in C6 glioma cells

J Neurochem. 2006 Apr;97(1):128-39. doi: 10.1111/j.1471-4159.2006.03711.x. Epub 2006 Mar 8.

Abstract

Contrasting with its robust expression during embryogenesis, the glial cell line-derived neurotrophic factor (GDNF) is repressed in the adult organism. However, rapid induction of this neuronal growth factor is observed following diverse neuronal insults and it is now widely accepted that the control of its expression could constitute a powerful target in neuropharmacology. We investigated the effects of the neuroprotective drug, riluzole, on the GDNF gene expression in glial cells. Exposure of C6 glioma cells to riluzole (1 microM) significantly increased GDNF protein and mRNA levels. Using luciferase reporter gene constructs encoding fragments of the 5' untranslated region of the rat GDNF gene, we demonstrated that riluzole mediates its effect at the transcription level. Furthermore, luciferase assays revealed the presence of a negative regulatory region within the +343/+587 region of exon 1. This region was shown to contribute to the high sensitivity and specificity of the induction mediated by riluzole in the C6 glioma cell line at pharmacologically relevant concentrations. The effects of riluzole were inhibited by the mitogen-activated protein kinase extracellular signal-related kinase (MEK) inhibitor PD 98059. Together, these results indicated that the induction of GDNF release by riluzole in the C6 glioma cells results from the activation of its corresponding gene promoter through a signalling pathway involving MEK activity. This study suggests that the regulation of GDNF gene transcription in glial cells could contribute to the pharmacological properties of riluzole and possibly other neuroprotective drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Glial Cell Line-Derived Neurotrophic Factor / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / 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 / pharmacology
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Rats
  • Riluzole / pharmacology*
  • Silencer Elements, Transcriptional / drug effects
  • Silencer Elements, Transcriptional / physiology
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / physiology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology

Substances

  • Enzyme Inhibitors
  • Glial Cell Line-Derived Neurotrophic Factor
  • Neuroprotective Agents
  • RNA, Messenger
  • Riluzole
  • MAP Kinase Kinase 1