title: The role of Akt/FoxO3a in the protective effect of venlafaxine against corticosterone-induced cell death in PC12 cells.
abstract: BACKGROUND
  Antidepressants could exert neuroprotective effects against various insults and the antidepressant-like effect may result from its neuroprotective effects. The phosphatidylinositol-3-kinase/protein kinase B/Forkhead box O3 (PI3K/Akt/FoxO3a) pathway is a key signaling pathway in mediating cell survival. However, no information is available regarding the interaction of FoxO3a and antidepressants.
  
  
  OBJECTIVE
  PC12 cells treated with corticosterone were used as a model to study the protective effect of venlafaxine and underlying mechanisms.
  
  
  METHODS
  Methyl thiazolyl tetrazolium (MTT) assay, Hoechst staining, and the observation of FoxO3a subcellular location were used to study the protective effect of venlafaxine against cell damage caused by corticosterone. Pretreatments with various pathway inhibitors were used to investigate the possible pathways involved in the protection of venlafaxine. The phosphorylation of Akt and FoxO3a was analyzed by Western blot.
  
  
  RESULTS
  Corticosterone decreased the phosphorylation of Akt and FoxO3a and led to the nuclear localization of FoxO3a and the apoptosis of PC12 cells. Venlafaxine concentration-dependently protected PC12 cells against corticosterone. The protective effect of venlafaxine was reversed by LY294002 and wortmannin, two PI3K inhibitors, and Akt inhibitor VIII, whereas mitogen-activated protein kinase kinase (MAPK kinase) inhibitor PD98059 and the p38 MAPK inhibitor PD160316 had no effect. Western blot analyses showed that venlafaxine induced the phosphorylation of Akt and FoxO3a by the PI3K/Akt pathway and reversed the reduction of the phosphorylated Akt and FoxO3a, and the nuclear translocation of Foxo3a induced by corticosterone.
  
  
  CONCLUSIONS
  Venlafaxine protects PC12 cells against corticosterone-induced cell death by modulating the activity of the PI3K/Akt/FoxO3a pathway.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wang
authors.forename: Xuanhe
authors.initials: X
authors.lastname: Zhou
authors.forename: Jianchu
authors.initials: J
authors.lastname: Huang
authors.forename: Nan
authors.initials: N
authors.lastname: Mu
authors.forename: Zeli
authors.initials: Z
authors.lastname: Guo
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wen
authors.forename: Rikang
authors.initials: R
authors.lastname: Wang
authors.forename: Shaorui
authors.initials: S
authors.lastname: Chen
authors.forename: Zhong-Ping
authors.initials: ZP
authors.lastname: Feng
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects*; D003345:Corticosterone / Q000633:toxicity; D003511:Cyclohexanols / Q000494:pharmacology*; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D000069470:Venlafaxine Hydrochloride
chemical_list: D018687:Antidepressive Agents, Second-Generation; D003345:Corticosterone; D003511:Cyclohexanols; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000069470:Venlafaxine Hydrochloride; C499515:FOXO3 protein, rat