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Valproate Attenuates Endoplasmic Reticulum Stress-Induced Apoptosis in SH-SY5Y Cells via the AKT/GSK3β Signaling Pathway
- Source :
- International Journal of Molecular Sciences, International Journal of Molecular Sciences, Vol 18, Iss 2, p 315 (2017), International Journal of Molecular Sciences; Volume 18; Issue 2; Pages: 315
- Publication Year :
- 2017
- Publisher :
- MDPI AG, 2017.
-
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.
- Subjects :
- 0301 basic medicine
SH-SY5Y
ER stress
valproate
apoptosis
neurological disorders
neurite outgrowth
Pharmacology
lcsh:Chemistry
0302 clinical medicine
Phosphorylation
lcsh:QH301-705.5
Endoplasmic Reticulum Chaperone BiP
Spectroscopy
bcl-2-Associated X Protein
Neurons
General Medicine
Endoplasmic Reticulum Stress
Computer Science Applications
Matrix Metalloproteinase 9
Proto-Oncogene Proteins c-bcl-2
Biochemistry
Thapsigargin
lipids (amino acids, peptides, and proteins)
Signal Transduction
Neurite
Cell Survival
Biology
Neuroprotection
Article
Catalysis
Inorganic Chemistry
03 medical and health sciences
Cell Line, Tumor
Humans
Viability assay
Physical and Theoretical Chemistry
Molecular Biology
Glycogen Synthase Kinase 3 beta
ATF6
Valproic Acid
Endoplasmic reticulum
Organic Chemistry
JNK Mitogen-Activated Protein Kinases
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
Apoptosis
Unfolded protein response
Proto-Oncogene Proteins c-akt
Transcription Factor CHOP
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 14220067
- Volume :
- 18
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....6b51eea78fbaa0fba6ff87263e796136
- Full Text :
- https://doi.org/10.3390/ijms18020315