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BDNF protects against phencyclidine neurotoxicity in neonatal brain via activation of the PI‐3K/Ak/GSK‐3β and MEK/ERK pathways
Author(s) -
Xia Yan,
Wang Cheng Z,
Anastasio Noelle C,
Johnson Kenneth M.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.716.2
Subject(s) - phencyclidine , tropomyosin receptor kinase b , trk receptor , ly294002 , protein kinase b , mapk/erk pathway , neuroprotection , pharmacology , signal transduction , neurotoxicity , chemistry , tropomyosin receptor kinase a , nmda receptor , neurotrophin , neuroscience , receptor , neurotrophic factors , medicine , biology , toxicity , biochemistry
NMDA receptor blockade by phencyclidine (PCP) in neonatal rats causes wide‐spread apoptosis and certain schizophrenia‐like behavioral abnormalities later in life. Disruption of BDNF signaling may play a role in the development of schizophrenia and mediate the neurotoxic effects of NMDAR blockers. Therefore, this study was designed to test the potential protective effects of BDNF on PCP‐induced apoptosis in corticostriatal slice culture and to explore the possible mechanisms. We observed that BDNF prevented PCP‐induced capase‐3 activation and DNA fragmentation dose‐dependently. The Trk B receptor inhibitor, K252a, abolished the protective effects of BDNF, indicating that BDNF acts through TrkB receptors. Further investigation of the downstream signaling transduction of TrkB activation revealed that BDNF prevented the dephosphorylation of Akt, GSK‐3β and ERK induced by PCP. In addition, pharmacological blockade of these pathways with either the MEK inhibitor PD98059 or the PI‐3K/Akt pathway inhibitors, LY294002 and Akt inhibitor V, completely abolished the protective effects of BDNF. Finally, the observation that the inhibitors of either the PI‐3K/Akt or the MEK/ERK pathway selectively prevented the stimulating effects of BDNF on the two pathways suggests that the two pathways are independently involved in the neuroprotection against PCP toxicity afforded by BDNF. Supported by DA‐02073.