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Journal of Molecular Neuroscience

, Volume 59, Issue 4, pp 567–578 | Cite as

Involvement of PI3K/Akt/FoxO3a and PKA/CREB Signaling Pathways in the Protective Effect of Fluoxetine Against Corticosterone-Induced Cytotoxicity in PC12 Cells

  • Bingqing Zeng
  • Yiwen Li
  • Bo Niu
  • Xinyi Wang
  • Yufang Cheng
  • Zhongzhen Zhou
  • Tingting You
  • Yonggang Liu
  • Haitao WangEmail author
  • Jiangping XuEmail author
Article

Abstract

The selective serotonin reuptake inhibitor fluoxetine is neuroprotective in several brain injury models. It is commonly used to treat major depressive disorder and related conditions, but its mechanism of action remains incompletely understood. Activation of the phosphatidylinositol-3-kinase/protein kinase B/forkhead box O3a (PI3K/Akt/FoxO3a) and protein kinase A/cAMP-response element binding protein (PKA/CREB) signaling pathways has been strongly implicated in the pathogenesis of depression and might be the downstream target of fluoxetine. Here, we used PC12 cells exposed to corticosterone (CORT) to study the neuroprotective effects of fluoxetine and the involvement of the PI3K/Akt/FoxO3a and PKA/CREB signaling pathways. Our results show that CORT reduced PC12 cells viability by 70 %, and that fluoxetine showed a concentration-dependent neuroprotective effect. Neuroprotective effects of fluoxetine were abolished by inhibition of PI3K, Akt, and PKA using LY294002, KRX-0401, and H89, respectively. Treatment of PC12 cells with fluoxetine resulted in increased phosphorylation of Akt, FoxO3a, and CREB. Fluoxetine also dose-dependently rescued the phosphorylation levels of Akt, FoxO3a, and CREB, following administration of CORT (from 99 to 110, 56 to 170, 80 to 170 %, respectively). In addition, inhibition of PKA and PI3K/Akt resulted in decreased levels of p-CREB, p-Akt, and p-FoxO3a in the presence of fluoxetine. Furthermore, fluoxetine reversed CORT-induced upregulation of p53-upregulated modulator of apoptosis (Puma) and Bcl-2-interacting mediator of cell death (Bim) via the PI3K/Akt/FoxO3a signaling pathway. H89 treatment reversed the effect of fluoxetine on the mRNA level of brain-derived neurotrophic factor, which was decreased in the presence of CORT. Our data indicate that fluoxetine elicited neuroprotection toward CORT-induced cell death that involves dual regulation from PI3K/Akt/FoxO3a and PKA/CREB pathways.

Keywords

Fluoxetine Corticosterone PI3K/Akt/FoxO3a PKA/CREB Neuroprotection 

Abbreviations

Akt

Protein kinase B

BDNF

Brain-derived neurotrophic factor

Bim

Bcl-2-interacting mediator of cell death

CORT

Corticosterone

CREB

cAMP-response element binding protein

DMSO

Dimethyl sulfoxide

FoxO3a

Forkhead box O3a

HPA

Hypothalamic-pituitary-adrenal

MTT

Methyl thiazolyl tetrazolium

PI3K

Phosphatidylinositol-3-kinase

PKA

Protein kinase A

Puma

p53 upregulated modulator of apoptosis

RPL19

Ribosomal protein L19

RT-PCR

Reverse transcription-polymerase chain reaction

Notes

Acknowledgments

This research was supported by National Natural Science Foundation of China (Nos. 81301099 and 81373384), Natural Science Foundation of Guangdong Province (No. S2013040014202), China Postdoctoral Science Foundation (No. 2013M542192), and National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (No. 2012ZX09J1211003C).

Compliance with Ethical Standards

Conflict of Interest Disclosures

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Bingqing Zeng
    • 1
  • Yiwen Li
    • 1
  • Bo Niu
    • 1
  • Xinyi Wang
    • 1
  • Yufang Cheng
    • 1
  • Zhongzhen Zhou
    • 1
  • Tingting You
    • 1
  • Yonggang Liu
    • 2
  • Haitao Wang
    • 1
    Email author
  • Jiangping Xu
    • 1
    Email author
  1. 1.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhouChina
  2. 2.Department of PharmacyGuangdong Provincial Corps Hospital of Chinese People’s Armed Police ForcesGuangzhouChina

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