Ethanol exposure enhances cell death in the developing cerebral cortex: role of brain-derived neurotrophic factor and its signaling pathways

J Neurosci Res. 2002 Apr 15;68(2):213-25. doi: 10.1002/jnr.10208.


Exposure to ethanol during fetal development induces brain damage, causing cell loss in several brain areas and affecting synaptic connections. Because neurotrophin signaling plays an important role in neuronal survival and differentiation, we have investigated the effect of ethanol exposure on cell death in the developing cerebral cortex and whether this effect correlates with alterations in brain-derived neurotrophic factor (BDNF) levels, expression of its receptors, TrkB, and its signaling. We report that chronic ethanol intake during gestation and lactation enhances natural cell death and induces cell necrosis, decreases BDNF levels, and increases the ratio of the truncated to full-length TrkB mRNA receptors during postnatal developing cerebral cortex. Furthermore, we provide evidence that during brain development BDNF activates the extracellular signal-regulated kinases (ERK1 and ERK2) and the phosphoinoside-3-kinase (PI-3-K/Akt) pathways. However, BDNF-induced cell signaling throughout the above-mentioned survival pathways is significantly reduced by ethanol exposure. These findings suggest that ethanol-induced alterations in BDNF availability and in its receptor function might impair intracellular signaling pathways involved in cell survival, growth, and differentiation, leading to enhanced natural cell death during cerebral cortex development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology*
  • Animals
  • Animals, Newborn / growth & development*
  • Apoptosis / drug effects
  • Brain / growth & development
  • Brain-Derived Neurotrophic Factor / antagonists & inhibitors
  • Brain-Derived Neurotrophic Factor / physiology
  • Caspase 3
  • Caspases / metabolism
  • Cell Death / drug effects
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / pathology
  • Cerebral Cortex / physiology*
  • Enzyme Activation
  • Ethanol / pharmacology*
  • Female
  • Mitogen-Activated Protein Kinases / metabolism
  • Necrosis
  • Peptide Fragments / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Poly(ADP-ribose) Polymerases / metabolism
  • Rats
  • Rats, Wistar
  • Receptor, trkB / chemistry
  • Receptor, trkB / metabolism
  • Signal Transduction / physiology


  • Brain-Derived Neurotrophic Factor
  • Peptide Fragments
  • Ethanol
  • Poly(ADP-ribose) Polymerases
  • Phosphatidylinositol 3-Kinases
  • Receptor, trkB
  • Mitogen-Activated Protein Kinases
  • Casp3 protein, rat
  • Caspase 3
  • Caspases