Valproate, a Mood Stabilizer, Induces WFS1 Expression and Modulates Its Interaction with ER Stress Protein GRP94

Kakiuchi, Chihiro; Ishigaki, Shinsuke; Oslowski, Christine M.; Fonseca, Sonya G.; Kato, Takeshi; Urano, Fumihiko

doi:10.1371/journal.pone.0004134

Cited by 54 publications

(49 citation statements)

References 24 publications

(32 reference statements)

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“…Valproic acid has a multitude of targets, including inhibition of protein kinase C, inhibition of myoinositol transport, inhibition of GSK3, activation of extracellular regulated kinase (Erk), potentiation of GABA signaling, and alleviation of endoplasmic reticulum stress response [9,22]. Many targets of VPA are also regulated by Li; nevertheless, Li failed to mimic the VPA effects described in this study.…”

Section: Discussionmentioning

confidence: 59%

“…VPA has been shown to inhibit the activity of glycogen synthase kinase-3 (GSK3) in vivo, an enzyme related to cell survival and regulation of cellular architecture and motility [21]. VPA induces wolframin (WFS1) expression and modulates the ER stress response [22]. Expression of the WFS1 gene is elevated in response to ER stress via the X-box binding protein (XBP1), a transcription factor of ER stress response pathway [23].…”

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confidence: 99%

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Wfs1 mutation makes mice sensitive to insulin-like effect of acute valproic acid and resistant to streptozocin

et al. 2011

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Valproic acid (VLP) is a widely used anticonvulsant and mood-stabilizing drug that relieves the endoplasmic reticulum (ER) stress response, a pathogenetic process related to diabetes. The aim of the present study was to evaluate whether acute valproic acid is able to interfere with glucose intolerance in two different diabetes models: The first model was a Wfs1 mutant mouse with an elevated ER stress response and the second model a streptozocin-induced diabetic mouse. VLP (300 mg/kg, i.p.) was administered to Wfs1 knockout (KO) mice and glucose tolerance test was performed 15 min later. VLP did not have an effect on the course of the glucose tolerance test in wild-type mice, while it did normalize the glucose intolerance in Wfs1 knockout mice. Acute valproic acid also lowered the blood glucose levels in streptozocin-treated mice and potentiated the effect of insulin in these mice. Thus, acute valproic acid is effective in lowering blood glucose levels possibly by potentiating insulin action in both Wfs1 KO mice and in streptozocin-induced type 1 diabetic mice.

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Section: Discussionmentioning

confidence: 59%

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confidence: 99%

Wfs1 mutation makes mice sensitive to insulin-like effect of acute valproic acid and resistant to streptozocin

et al. 2011

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“…Recently, the involvement of GRP94 in the treatment for bipolar disorder had been reported. 34) These findings indicate that the antidepressant-like effects of luteolin could be due to the inhibition of the endoplasmic reticulum stress in the pre-induction of GRP78 and GRP94. However, further experiments will be needed to clarify the detailed mechanism.…”

Section: Discussionmentioning

confidence: 91%

Luteolin Shows an Antidepressant-Like Effect via Suppressing Endoplasmic Reticulum Stress

Ishisaka

Kakefuda

Yamauchi

et al. 2011

Biological & Pharmaceutical Bulletin

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In terms of mental illnesses, depression has an enormous influence in society. Major symptoms of depression are a "depressed mood" and "loss of interest and joy." Despite recent advances in the knowledge related to brain development and function, the mechanisms underlying the pathogenesis of depression remain unclear.The endoplasmic reticulum is a principal site for protein synthesis, folding, and calcium signaling.1) It is highly sensitive to alterations in calcium homeostasis and perturbations in its environment. A condition that impaired the function of the endoplasmic reticulum, collectively designated "endoplasmic reticulum stress," can lead to an accumulation of unfolded proteins in the endoplasmic reticulum lumen.2) In response to endoplasmic reticulum stress, cells have developed a self-protective signal pathway termed the unfolded protein response (UPR), leading to induction of molecular chaperones such as 78 kDa glucose-regulated protein (GRP78) and 94 kDa glucose-regulated protein (GRP94), translational attenuation, and endoplasmic reticulum associated degradation.3) However, if the damage is excessive, the UPR ultimately activates an apoptotic pathway such as CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) activation. 4)Recently, GRP78 and GRP94 have been found in the temporal cortex of subjects with major depressive disorder who died by suicide.5) Furthermore, in a rodent depression model, endoplasmic reticulum stress-related proteins were increased and these were attenuated by an antidepressant.6) Recently, we have reported that restraint stress increases in the expression of endoplasmic reticulum stress-related genes in the mouse brain.7) These findings indicate that endoplasmic reticulum stress may have some roles in the pathogenesis of depression.Luteolin is a common flavonoid that exists in many types of plants such as Apium graveolens L. var. dulce, 8)Petroselium crispum, 9) and Capsicum annuum L. var.'grossum.' 10) It has various pharmacological activities such as antioxidant, 11) anticancer action, 12) memory-improving, 13) and anxiolytic 14) activities, suggesting that luteolin could penetrate easily into the brain. 15) In this study, we investigated the antidepressant effects of luteolin from the green pepper leaf, as well as its mechanism, using cell death assay induced by endoplasmic reticulum stress in human neuroblastoma (SH-SY5Y) cells and animal models of depression. MATERIALS AND METHODS Purification of LuteolinLuteolin aglycon (luteolin) was provided by Theravalues (Tokyo, Japan). The purity of luteolin was 80%. In the experiments, it was dissolved in phosphate buffered saline contained 1% dimethyl sulfoxide (DMSO) or suspended in the 0.5% carboxymethylcellulose (Wako, Osaka, Japan).Cell Culture SH-SY5Y cells were purchased from the European Collection of Cell Culture (Wiltshire, U.K.) and maintained in Dulbecco's modified Eagle's medium (SigmaAldrich, St. Louis, MO, U.S.A.) containing 10% fetal bovine serum (VALEANT, Costa Mesa, CA, U.S.A.), 100 units/ml of penici...

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“…Moreover, b-cell death and neuronal cell dysfunction in WS are attributed to high levels of ER stress (Rigoli et al 2011) and are consequences of the loss of function of WFS1. Interestingly, the impaired ER stress response has been proposed as a pathway involved in BD (Kato 2008). Both lithium and valproate facilitate the ER stress response (Chuang 2005), but unlike lithium, valproate specifically increases the expression of WFS1; therefore, it increases the production of the protein, Wolframin (Kakiuchi et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Bipolar Disorder Type 1 in a 17-Year-Old Girl with Wolfram Syndrome

Xavier

Bourvis

Tanet

et al. 2016

Journal of Child and Adolescent Psychopharmacology

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Valproate, a Mood Stabilizer, Induces WFS1 Expression and Modulates Its Interaction with ER Stress Protein GRP94

Cited by 54 publications

References 24 publications

Wfs1 mutation makes mice sensitive to insulin-like effect of acute valproic acid and resistant to streptozocin

Wfs1 mutation makes mice sensitive to insulin-like effect of acute valproic acid and resistant to streptozocin

Luteolin Shows an Antidepressant-Like Effect via Suppressing Endoplasmic Reticulum Stress

Bipolar Disorder Type 1 in a 17-Year-Old Girl with Wolfram Syndrome

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