MAP kinase activation by fluoxetine and its relation to gene expression in cultured rat astrocytes

J Mol Neurosci. 2004;24(2):207-16. doi: 10.1385/JMN:24:2:207.

Abstract

Chronic treatments with antidepressants active on major depressive disorders influence pathways involved in cell survival and plasticity. As astrocytes seem to play a key role in the protection of brain cells, we investigated in these cells the rapid effects of the antidepressant fluoxetine (Prozac) on signaling cascades and gene induction, which probably play a role in neuroprotection. We show here that fluoxetine alone activates the extracellular signal-regulated-protein kinase (Erk) and p38 mitogen-associated protein (MAP) kinase cascades. RT-PCR revealed that genes, modulated in brain by long-term fluoxetine treatment, are rapidly induced by fluoxetine in cultured astrocytes: brain-derived nerve factor (BDNF) and its receptors, glial-derived nerve factor (GDNF) and deiodinase 3 (D3). Induction of D3 by fluoxetine is inhibited by U0126 and SB203580, suggesting that Erk and p38 MAP kinases are involved. Glial-derived nerve factor (GDNF) induction by fluoxetine is prevented by U0126, suggesting that Erk is implicated. Brain-derived nerve factor (BDNF) induction seems mediated by other signaling pathways. In conclusion, we show that fluoxetine alone rapidly activates mitogen activated protein (MAP) kinase cascades in rat astrocytes and that genes involved in neuroprotection are induced in a few hours in a MAP kinase-dependent or -independent manner.

MeSH terms

  • Animals
  • Antidepressive Agents, Second-Generation / pharmacology
  • Astrocytes / cytology
  • Astrocytes / physiology*
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cells, Cultured
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fluoxetine / pharmacology*
  • Gene Expression Regulation / drug effects*
  • Glial Cell Line-Derived Neurotrophic Factor
  • Mitogen-Activated Protein Kinases / metabolism*
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, trkB / genetics
  • Receptor, trkB / metabolism
  • Signal Transduction / physiology
  • Transcriptional Activation
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antidepressive Agents, Second-Generation
  • Brain-Derived Neurotrophic Factor
  • Gdnf protein, rat
  • Glial Cell Line-Derived Neurotrophic Factor
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • nervous tissue specific protein D3
  • Fluoxetine
  • Receptor, trkB
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases