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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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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DOI: https://doi.org/10.1038/sj.tpj.6500296
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