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Protracted lithium treatment protects against the ER stress elicited by thapsigargin in rat PC12 cells: roles of intracellular calcium, GRP78 and Bcl-2

The Pharmacogenomics Journal volume 5, pages 102–111 (2005)Cite this article

Abstract

We investigated the cytoprotective effects of lithium, the mood-stabilizer, on thapsigargin-induced stress on the endoplasmic reticulum (ER) in rat PC12 cells. Protracted lithium pretreatment of PC12 cells elicited cytoprotection against thapsigargin-induced cytotoxicity. Lithium protection was concurrent with inhibition of thapsigargin-induced intracellular calcium increase and with elevated expression of the molecular chaperone GRP78. Moreover, lithium pretreatment upregulated the antiapoptotic protein Bcl-2, and blocked Bcl-2 downregulation elicited by thapsigargin. Prior to the induction of GRP78, lithium treatment alone increased the expression of c-Fos whose induction by ER stress is necessary for GRP78 induction. Curcumin, an inhibitor of transcription factor AP-1, blocked lithium cytoprotection against thapsigargin cytotoxicity. Thus, the induction of GRP78 and Bcl-2, and activation of AP-1 likely contribute to lithium-induced protection against cytotoxicity resulting from ER stress. Additionally, thapsigargin-induced cytotoxicity was suppressed by pretreatment with another mood-stabilizer, valproate, indicating that cytoprotection against ER stress is a common action of mood-stabilizing drugs.

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Abbreviations

AP-1:

activator protein-1

ER:

endoplasmic reticulum

GRP78:

78 kDa glucose-regulated protein

GSK-3β:

glycogen synthase kinase-3β

LDH:

lactate dehydrogenase

NMDA:

N-methyl-D-aspartate

PC12:

rat pheochromocytoma cells

VPA:

valproate

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Acknowledgements

We thank Dr Wenlin Wei for his expertise and assistance with experimental procedures, and Drs Yan Leng and Yanning Qian for their stimulating discussions.

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Authors and Affiliations

  1. Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    T Hiroi, H Wei, P Leeds & D-M Chuang

  2. Department of Psychiatry, Uniformed Services University of Health Sciences, Bethesda, MD, USA

    C Hough

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Correspondence to D-M Chuang.

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Hiroi, T., Wei, H., Hough, C. et al. Protracted lithium treatment protects against the ER stress elicited by thapsigargin in rat PC12 cells: roles of intracellular calcium, GRP78 and Bcl-2. Pharmacogenomics J 5, 102–111 (2005). https://doi.org/10.1038/sj.tpj.6500296

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