title: Brain-derived neurotrophic factor prevents phencyclidine-induced apoptosis in developing brain by parallel activation of both the ERK and PI-3K/Akt pathways.
abstract: Phencyclidine is an N-methyl d-aspartate receptor (NMDAR) blocker that has been reported to induce neuronal apoptosis during development and schizophrenia-like behaviors in rats later in life. Brain-derived neurotrophic factor (BDNF) has been shown to prevent neuronal death caused by NMDAR blockade, but the precise mechanism is unknown. This study examined the role of the phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways in BDNF protection of PCP-induced apoptosis in corticostriatal organotypic cultures. It was observed that BDNF inhibited PCP-induced apoptosis in a concentration-dependent fashion. BDNF effectively prevented PCP-induced inhibition of the ERK and PI-3K/Akt pathways and suppressed GSK-3beta activation. Blockade of either PI-3K/Akt or ERK activation abolished BDNF protection. Western blot analysis revealed that the PI-3K inhibitor LY294002 prevented the stimulating effect of BDNF on the PI-3K/Akt pathway, but had no effect on the ERK pathway. Similarly, the ERK inhibitor PD98059 prevented the stimulating effect of BDNF on the ERK pathway, but not the PI-3K/Akt pathway. Co-application of LY294002 and PD98059 had no additional effect on BDNF-evoked activation of Akt or ERK. However, concurrent exposure to PD98059 and LY294002 caused much greater inhibition of BDNF-evoked phosphorylation of GSK-3beta at serine 9 than did LY294002 alone. Finally, either BDNF or GSK-3beta inhibition prevented PCP-induced suppression of cyclic-AMP response element binding protein (CREB) phosphorylation. These data demonstrate that the protective effect of BDNF against PCP-induced apoptosis is mediated by parallel activation of the PI-3K/Akt and ERK pathways, most likely involves inhibition of GSK-3beta and activation of CREB.
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-1031, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Cheng Z
authors.initials: CZ
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Noelle C
authors.initials: NC
authors.lastname: Anastasio
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Johnson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D010622:Phencyclidine / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D010622:Phencyclidine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C000605508:Gsk3b protein, rat