The role of Akt/FoxO3a in the protective effect of venlafaxine against corticosterone-induced cell death in PC12 cells
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ORIGINAL INVESTIGATION
The role of Akt/FoxO3a in the protective effect of venlafaxine against corticosterone-induced cell death in PC12 cells Haitao Wang & Xuanhe Zhou & Jianchu Huang & Nan Mu & Zeli Guo & Qiang Wen & Rikang Wang & Shaorui Chen & Zhong-Ping Feng & Wenhua Zheng
Received: 2 September 2012 / Accepted: 1 February 2013 / Published online: 15 March 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Rationale 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. Objectives 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 concentrationdependently 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. Keywords Venlafaxine . Corticosterone . PI3K/Akt/ FoxO3a . Neuroprotection
Haitao Wang and Xuanhe Zhou contributed equally to this work. H. Wang : X. Zhou : Z. Guo : Q. Wen : Z.-P. Feng : W. Zheng (*) State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China e-mail: [email protected] J. Huang Family Planning Service Center of Dongguan, Dongguan 523079, China N. Mu Guangzhou Brain Hospital, 36 Mingxin Road, Liwan District, Guangzhou 510370, China R. Wang : S. Chen Neuropharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
Introduction Depression is a serious psychiatric disorder affecting a person’s thoughts, behavior, feelings, and physical well-being. Despite years of study, many critically i
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