Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways

Cell Death Differ. 2005 Oct;12(10):1329-43. doi: 10.1038/sj.cdd.4401662.


Neurotrophins protect neurons against glutamate excitotoxicity, but the signaling mechanisms have not been fully elucidated. We studied the role of the phosphatidylinositol 3-kinase (PI3-K) and Ras/mitogen-activated protein kinase (MAPK) pathways in the protection of cultured hippocampal neurons from glutamate induced apoptotic cell death, characterized by nuclear condensation and activation of caspase-3-like enzymes. Pre-incubation with the neurotrophin brain-derived neurotrophic factor (BDNF), for 24 h, reduced glutamate-evoked apoptotic morphology and caspase-3-like activity, and transiently increased the activity of the PI3-K and of the Ras/MAPK pathways. Inhibition of the PI3-K and of the Ras/MAPK signaling pathways abrogated the protective effect of BDNF against glutamate-induced neuronal death and similar effects were observed upon inhibition of protein synthesis. Moreover, incubation of hippocampal neurons with BDNF, for 24 h, increased Bcl-2 protein levels. The results indicate that the protective effect of BDNF in hippocampal neurons against glutamate toxicity is mediated by the PI3-K and the Ras/MAPK signaling pathways, and involves a long-term change in protein synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Brain-Derived Neurotrophic Factor / pharmacology*
  • Caspase 3
  • Caspases / biosynthesis
  • Cell Survival
  • Down-Regulation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Glutamic Acid / toxicity*
  • Hippocampus / cytology
  • Hippocampus / drug effects*
  • Hippocampus / enzymology
  • Hippocampus / metabolism
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / enzymology
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Rats, Wistar
  • Transfection
  • ras Proteins / metabolism


  • Brain-Derived Neurotrophic Factor
  • Neuroprotective Agents
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Glutamic Acid
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • ras Proteins