Brain-derived neurotrophic factor inhibits cell cycle reentry but not endoplasmic reticulum stress in cultured neurons following oxidative or excitotoxic stress.
Neurotrophins protect neurons against glutamate and oxidative stress, but the underlying mechanism remains unclear. We investigated the neuroprotective role of the neurotrophin brain-derived neurotrophic factor (BDNF) in neuronal cultures subjected to NMDA or H(2)O(2) toxicity and analyzed the molecular mechanisms involved, particularly those related to regulation of cell cycle or endoplasmic reticulum (ER) stress. Preincubation with BDNF of cortical neuron cultures prevented NMDA- or H(2)O(2)-induced neuronal death as well as MAPK-ERK1/2 activation. Inhibition of phosphatidylinositol 3-kinase (PI3-K) abolished the protective effect of BDNF. NMDA and H(2)O(2) induced activation of cell cycle reentry regulators such as retinoblastoma (Rb) protein and E2F1 transcription factor. However, BDNF abolished the activation of both factors. NMDA-induced expression of chaperone encoding gene BIP was slightly inhibited by BDNF, but it did not affect expression of ER stress protein CHOP. Our results suggest that BDNF neuroprotection may be mediated through inhibition of Ras-MAPK pathway and cell cycle reentry during oxidative or excitotoxic stress responses. However, BDNF did not modify expression of ER stress signal induced by NMDA.
Boutahar
Nadia
N
Faculté de Médecine, Laboratoire de Neurobiochimie, Saint-Etienne, France.
Reynaud
Evelyne
E
Lassabliere
François
F
Borg
Jacques
J
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002540:Cerebral Cortex / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D016202:N-Methylaspartate; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt