Valproate Attenuates Endoplasmic Reticulum Stress-Induced Apoptosis in SH-SY5Y Cells via the AKT/GSK3β Signaling Pathway

Abstract

Endoplasmic reticulum (ER) stress-induced apoptosis plays an important role in a range of neurological disorders, such as neurodegenerative diseases, spinal cord injury, and diabetic neuropathy. Valproate (VPA), a typical antiepileptic drug, is commonly used in the treatment of bipolar disorder and epilepsy. Recently, VPA has been reported to exert neurotrophic effects and promote neurite outgrowth, but its molecular mechanism is still unclear. In the present study, we investigated whether VPA inhibited ER stress and promoted neuroprotection and neuronal restoration in SH-SY5Y cells and in primary rat cortical neurons, respectively, upon exposure to thapsigargin (TG). In SH-SY5Y cells, cell viability was detected by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and the expression of ER stress-related apoptotic proteins such as glucose‑regulated protein (GRP78), C/EBP homologous protein (CHOP), and cleaved caspase-12/-3 were analyzed with Western blot analyses and immunofluorescence assays. To explore the pathway involved in VPA-induced cell proliferation, we also examined p-AKT, GSK3β, p-JNK and MMP-9. Moreover, to detect the effect of VPA in primary cortical neurons, immunofluorescence staining of β-III tubulin and Anti-NeuN was analyzed in primary cultured neurons exposed to TG. Our results demonstrated that VPA administration improved cell viability in cells exposed to TG. In addition, VPA increased the levels of GRP78 and p-AKT and decreased the levels of ATF6, XBP-1, GSK3β, p-JNK and MMP-9. Furthermore, the levels of the ER stress-induced apoptosis response proteins CHOP, cleaved caspase-12 and cleaved caspase-3 were inhibited by VPA treatment. Meanwhile, VPA administration also increased the ratio of Bcl-2/Bax. Moreover, VPA can maintain neurite outgrowth of primary cortical neurons. Collectively, the neurotrophic effect of VPA is related to the inhibition of ER stress-induced apoptosis in SH-SY5Y cells and the maintenance of neuronal growth. Collectively, our results suggested a new approach for the therapeutic function of VPA in neurological disorders and neuroprotection.

Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives

“…A research project, currently in progress at Birmingham University, has the aim of studying valproate acid (VPA) as a novel, repurposed drug treatment for neurodegeneration and diabetes in WS. Several studies reported that VPA is indeed neuroprotective, by exerting neurotrophic effects and promoting neurite outgrowth via the inhibition of ER stress-induced apoptosis [89, 90]. VPA promotes the expression of both WFS1 and ER chaperones and attenuates ER-induced apoptosis after both ischemia/reperfusion (I/R) injury in retina and in a model of diabetic nephropathy [91–93].…”

Investigating the synergic effects of valproic acid and crocin on BDNF and GDNF expression in epidermal neural crest stem cells

“…Because VPA can also inhibit GSK-3, VPA can enhance neuroprotective effects either directly or indirectly, through the Wnt/β-catenin, PI3K/Akt, and MAPK/ERK (MEK) pathway, during psychiatric and neurodegenerative disorder, such as bipolar disorder and Alzheimer's disease. In addition, VPA can trigger a cascade of events that neutralize and compensate for the events associated with secondary damage during SCI, through neuroprotective effects and neurogenesis, via HDAC and GSK-3 inhibition (Chu et al, 2015;Li et al, 2017). During a neural condition, such as SCI, cell damage occurs due to microglial activation, the production of various inflammatory cytokines, and the activation of the nuclear factor (NF)-kB signaling pathway, which produces NF-kB proteins that bind to gene promoters in response to neuroinflammation.…”

Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure

“…[16][17][18][19][20] Furthermore, VPA has been shown to inhibit HDAC and GSK3 signaling events, 21,22 and although reported to induce endoplasmic reticulum stress (ER stress), 23,24 there are studies showing that VPA protects cells against ER stressmediated apoptosis and atherosclerosis. 25,26 As VPA has been shown to deplete glutathione levels and stimulate steroidogenesis by increasing mitochondrial cholesterol trafficking, 27,28 we hypothesized that VPA can sensitize to APAP-mediated ALF independently of fasting by inducing steroidogenic acute regulatory protein 1 (STARD1), a mitochondrial protein that mediates the transport of cholesterol to the mitochondrial inner membrane, 29 which results in impaired transport of glutathione into mitochondria. 30,31 Our data reveal that VPA pretreatment in nonfasted mice results in APAP-induced ALF by a mechanism that requires the complimentary action of STARD1 and Sab-JNK1/2.…”