PMID- 28208696 OWN - NLM STAT- MEDLINE DCOM- 20170428 LR - 20220330 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 18 IP - 2 DP - 2017 Feb 8 TI - Valproate Attenuates Endoplasmic Reticulum Stress-Induced Apoptosis in SH-SY5Y Cells via the AKT/GSK3beta Signaling Pathway. LID - 10.3390/ijms18020315 [doi] LID - 315 AB - 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, GSK3beta, p-JNK and MMP-9. Moreover, to detect the effect of VPA in primary cortical neurons, immunofluorescence staining of beta-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, GSK3beta, 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. FAU - Li, Zhengmao AU - Li Z AD - Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. LiZM_YX@163.com. FAU - Wu, Fenzan AU - Wu F AD - Science and Education division, Cixi People's Hospital, Wenzhou Medical University, Ningbo 315300, China. wufenzan@163.com. FAU - Zhang, Xie AU - Zhang X AD - Ningbo Medical Treatment Center, Li Huili Hospital, Ningbo 315000, China. rennie22@126.com. FAU - Chai, Yi AU - Chai Y AD - Department of neurosurgery, The second Affiliated Hospital, Nanchang University, Nanchang 330006, China. lulpls@126.com. FAU - Chen, Daqing AU - Chen D AD - Emergency Department, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China. cdq1965@126.com. FAU - Yang, Yuetao AU - Yang Y AD - Emergency Department, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China. yangyuetao1234@163.com. FAU - Xu, Kebin AU - Xu K AD - Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. xukebin827@163.com. FAU - Yin, Jiayu AU - Yin J AD - Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. pashayin@hotmail.com. FAU - Li, Rui AU - Li R AD - Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. xiaoerrui1989@163.com. FAU - Shi, Hongxue AU - Shi H AD - Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. xue.henwuji@163.com. FAU - Wang, Zhouguang AU - Wang Z AD - Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. huaikongwang@126.com. FAU - Li, Xiaokun AU - Li X AD - Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. xiaokunli@163.com. AD - Institute of Life Sciences, Wenzhou University, Wenzhou 325035, China. xiaokunli@163.com. FAU - Xiao, Jian AU - Xiao J AD - Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. xfxj2000@126.com. FAU - Zhang, Hongyu AU - Zhang H AD - Key Laboratory of Biotechnology and Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. hyzhang@wmu.edu.cn. LA - eng PT - Journal Article DEP - 20170208 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Endoplasmic Reticulum Chaperone BiP) RN - 0 (HSPA5 protein, human) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 0 (bcl-2-Associated X Protein) RN - 147336-12-7 (Transcription Factor CHOP) RN - 614OI1Z5WI (Valproic Acid) RN - 67526-95-8 (Thapsigargin) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - Apoptosis/*drug effects MH - Cell Line, Tumor MH - Cell Survival/drug effects MH - Endoplasmic Reticulum Chaperone BiP MH - Endoplasmic Reticulum Stress/*drug effects MH - Glycogen Synthase Kinase 3 beta/*metabolism MH - Humans MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - Matrix Metalloproteinase 9/metabolism MH - Neurons/drug effects/metabolism MH - Phosphorylation MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Proto-Oncogene Proteins c-bcl-2/metabolism MH - Signal Transduction/*drug effects MH - Thapsigargin/pharmacology MH - Transcription Factor CHOP/metabolism MH - Valproic Acid/*pharmacology MH - bcl-2-Associated X Protein/metabolism PMC - PMC5343851 OTO - NOTNLM OT - ER stress OT - apoptosis OT - neurite outgrowth OT - neurological disorders OT - valproate COIS- The authors declare no conflict of interest. EDAT- 2017/02/18 06:00 MHDA- 2017/04/30 06:00 PMCR- 2017/02/01 CRDT- 2017/02/18 06:00 PHST- 2016/09/27 00:00 [received] PHST- 2017/01/12 00:00 [revised] PHST- 2017/01/27 00:00 [accepted] PHST- 2017/02/18 06:00 [entrez] PHST- 2017/02/18 06:00 [pubmed] PHST- 2017/04/30 06:00 [medline] PHST- 2017/02/01 00:00 [pmc-release] AID - ijms18020315 [pii] AID - ijms-18-00315 [pii] AID - 10.3390/ijms18020315 [doi] PST - epublish SO - Int J Mol Sci. 2017 Feb 8;18(2):315. doi: 10.3390/ijms18020315.