Lithium ions attenuate serum-deprivation-induced apoptosis in PC12 cells through regulation of the Akt/FoxO1 signaling pathways

Zeng, Zhiwen, Wang, Haitao, Shang, Fu, Zhou, Lihua, Little, Peter J., Quirion, Remi and Zheng, Wenhua (2015) Lithium ions attenuate serum-deprivation-induced apoptosis in PC12 cells through regulation of the Akt/FoxO1 signaling pathways. Psychopharmacology, 233 5: 785-794. doi:10.1007/s00213-015-4168-7


Author Zeng, Zhiwen
Wang, Haitao
Shang, Fu
Zhou, Lihua
Little, Peter J.
Quirion, Remi
Zheng, Wenhua
Title Lithium ions attenuate serum-deprivation-induced apoptosis in PC12 cells through regulation of the Akt/FoxO1 signaling pathways
Journal name Psychopharmacology   Check publisher's open access policy
ISSN 1432-2072
0033-3158
Publication date 2015-12-02
Sub-type Article (original research)
DOI 10.1007/s00213-015-4168-7
Open Access Status Not Open Access
Volume 233
Issue 5
Start page 785
End page 794
Total pages 10
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Formatted abstract
Rationale:  Lithium is currently used in the treatment of mental illness. We have previously reported that lithium stimulated the protein kinase B/Forkhead box O1 (Akt/FoxO1) pathway in rats. However, little information is available regarding its neuroprotective role of this pathway and underlying mechanisms.

Objectives:  PC12 cells treated with serum deprivation were used as a toxicity model to study the protective effect of lithium and its underlying mechanisms.

Methods:  
Cell viability was determined by methyl thiazolyl tetrazolium assay and Hoechst staining. FoxO1 subcellular location and its overexpression were used to study the underlying mechanisms. Various pathway inhibitors were used to investigate the possible pathways, while the phosphorylation of Akt and FoxO1 was analyzed by Western blot.

Results:  Lithium pretreatment dose-dependently reduced PC12 cell apoptosis induced by serum starvation. The protective effect of lithium was abolished by LY294002, a PI3K-specific inhibitor, and Akt inhibitor Akt inhibitor VIII, whereas mitogen-activated protein kinase kinase (MEK kinase) inhibitor U0126 had no effect. Lithium induced the phosphorylation of Akt and FoxO1 in a time- and concentration-dependent manner. Lithium-induced phosphorylation of Akt and FoxO1 is mediated by the PI3K/Akt pathway. Serum deprivation caused nuclear translocation of FoxO1 while application of lithium reversed the effect of serum deprivation. Moreover, overexpression of FoxO1 enhanced cell apoptosis induced by serum withdrawal. Finally, lithium was found to reduce the exogenous and endogenous FoxO1 protein levels in PC12 cells in a concentration-dependent fashion.

Conclusions:  The protective effect of lithium against serum starvation cell death is mediated by the PI3K/Akt/FoxO1 pathway.
Keyword Apoptosis
Lithium
Neuroprotection
PI3K/Akt/FoxO1
Serum deprivation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Pharmacy Publications
 
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