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

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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.

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Abbreviations

Akt:

Protein kinase B

BSA:

Bovine serum albumin

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethyl sulfoxide

ERK1/2:

Extracellular regulated protein kinases 1/2

FBS:

Fetal bovine serum

FoxO3a:

Forkhead box O3a

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GSK-3β:

Glycogen synthase kinase-3β

HBSS:

Hanks’ balanced salt solution

HPA:

Hypothalamic–pituitary–adrenal

IGF-1:

Insulin-like growth factor 1

MAPK:

Mitogen-activated protein kinase

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

OD:

Optical density

PBS:

Phosphate-buffered saline

PC12:

Pheochromocytoma cells

PI3K:

Phosphatidylinositol 3-kinase

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Acknowledgments

This work was supported by National Natural Science Fund of China (No 31371088); Guangdong Provincial Project of Science and Technology (2011B050200005) and the Science and Technology Development Fund (FDCT) of Macao (FDCT 021/2015/A1).

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Authors and Affiliations

  1. Faculty of Health Science, University of Macau, Room 4021, Building E12, Avenida de Universidade Taipa, Macau, People’s Republic of China

    Zhiwen Zeng & Wenhua Zheng

  2. Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China

    Zhiwen Zeng

  3. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center and Neurophamacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510060, People’s Republic of China

    Haitao Wang & Fu Shang

  4. Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, 510060, People’s Republic of China

    Lihua Zhou

  5. School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, 20 Cornwall St, Woolloongabba, QLD, 4102, Australia

    Peter J. Little

  6. Douglas Hospital Research Center, McGill University, Montreal, Canada

    Remi Quirion

Authors
  1. Zhiwen Zeng
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  2. Haitao Wang
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  3. Fu Shang
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  4. Lihua Zhou
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Correspondence to Wenhua Zheng.

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Zeng, Z., Wang, H., Shang, F. et al. Lithium ions attenuate serum-deprivation-induced apoptosis in PC12 cells through regulation of the Akt/FoxO1 signaling pathways. Psychopharmacology 233, 785–794 (2016). https://doi.org/10.1007/s00213-015-4168-7

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  • DOI: https://doi.org/10.1007/s00213-015-4168-7

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