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

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.

Lithium protects against toxic effects of cadmium in the rat testes

“…Several investigations have shown that lithium has antiapoptotic properties in low concentrations while it is proapoptotic at higher concentrations [12,[21][22][23][24][25]. Previous studies on the effect of chronic administration of lithium on the male reproductive system have used high doses of lithium even though these doses are therapeutically relevant.…”

“…Glutamateinduced cytochrome c and caspase-3 release were also blocked by lithium [11]. Long term treatment with lithium has also been shown to protect against thapsigargin-induced cytotoxicity in rat PC 12 cells [12]. This was associated with an enhanced expression of Bcl-2, an anti-apoptotic protein.…”

Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes

“…1 In cellular models, VPA protects rat cerebral cortical neurons and cerebellar granule cells from glutamate-induced excitotoxicity, 3,4 and apoptotic death from stress on the endoplasmic reticulum in C6 glioma cells and PC 12 cells. 5,6 In a rat model of stroke, post-insult VPA treatment reduces ischemia-induced brain damage, caspase-3 activation and neurological deficits. 7 A number of studies reported that VPA activates cell survival factors such as Akt, 8 extracellular signalregulated protein kinase 9 and cyclic AMP response element binding protein.…”

Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines

“…Estrogen has been an important factor in reducing several diseases and regulating the menstrual cycle of women; however, artificial supplementation leaves the patient with unwanted side effects. It was suggested that natural supplementation of estrogen such as soy phytoestrogen (SPE) could benefit female patients since it does not have either agonist or antagonist activity [26].…”

“…The serotonin (5-HT) is one of the main neurotransmitters for mood stabilization, and several environmental factors as well as genetics can affect its level in the human body. 5-HT is controlled by several neurotransmitters and regulatory proteins, mainly tryptophan hydroxylase (TPH), the committal enzyme in 5-HT synthesis, and the 5-HT reuptake transporter (SERT), which has been a target for several antidepressant medications such as the selective serotonin reuptake inhibitors (SSRIs) [26].…”