title: Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways.
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.
authors.affiliation: Center for Neuroscience and Cell Biology and Department of Zoology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: R D
authors.initials: RD
authors.lastname: Almeida
authors.forename: B J
authors.initials: BJ
authors.lastname: Manadas
authors.forename: C V
authors.initials: CV
authors.lastname: Melo
authors.forename: J R
authors.initials: JR
authors.lastname: Gomes
authors.forename: C S
authors.initials: CS
authors.lastname: Mendes
authors.forename: M M
authors.initials: MM
authors.lastname: Grãos
authors.forename: R F
authors.initials: RF
authors.lastname: Carvalho
authors.forename: A P
authors.initials: AP
authors.lastname: Carvalho
authors.forename: C B
authors.initials: CB
authors.lastname: Duarte
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D002470:Cell Survival; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D053148:Caspase 3; D020169:Caspases; D048049:Extracellular Signal-Regulated MAP Kinases; D018698:Glutamic Acid; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D018631:ras Proteins; C505410:Casp3 protein, rat