1. ¹Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
2. ²Department of Psychiatry, Uniformed Services University of Health Sciences, Bethesda, MD, USA

Correspondence: Dr D-M Chuang, Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bldg. 10, Rm. 4C-206, 10 Center Dr MSC 1363, Bethesda, MD 20892-1363, USA. Tel: +1 301 496 4915; Fax: +1 301 480 9290; E-mail: chuang@mail.nih.gov

Received 3 September 2004; Revised 4 October 2004; Accepted 19 October 2004; Published online 25 January 2005.

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.