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

R D Almeida; B J Manadas; C V Melo; J R Gomes; C S Mendes; M M Grãos; R F Carvalho; A P Carvalho; C B Duarte

doi:10.1038/sj.cdd.4401662

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.

Authors

R D Almeida¹, B J Manadas, C V Melo, J R Gomes, C S Mendes, M M Grãos, R F Carvalho, A P Carvalho, C B Duarte

Affiliation

¹ Center for Neuroscience and Cell Biology and Department of Zoology, University of Coimbra, 3004-517 Coimbra, Portugal.

PMID: 15905876
DOI: 10.1038/sj.cdd.4401662

Abstract

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

Substances

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