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Valproic Acid Protects Primary Dopamine Neurons from MPP(+)-Induced Neurotoxicity: Involvement of GSK3β Phosphorylation by Akt and ERK through the Mitochondrial Intrinsic Apoptotic Pathway.

Abstract Valproic acid (VPA), a drug widely used to treat manic disorder and epilepsy, has recently shown neuroprotective effects in several neurological diseases, particularly in Parkinson's disease (PD). The goal of the present study was to confirm VPA's dose-dependent neuroprotective propensities in the MPP(+) model of PD in primary dopamine (DA) neurons and to investigate the underlying molecular mechanisms using specific mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase- (PI3K-) Akt signaling inhibitors. VPA reversed MPP(+)-induced mitochondrial apoptosis and counteracted MPP(+)-induced extracellular signal-regulated kinase (ERK) and Akt repression and inhibited glycogen synthase kinase 3β (GSK3β) activation through induction of GSK3β phosphorylation. Moreover, inhibitors of the PI3K and MAPK pathways abolished GSK3β phosphorylation and diminished the VPA-induced neuroprotective effect. These findings indicated that VPA's neuroprotective effect in the MPP(+)-model of PD is associated with GSK3β phosphorylation via Akt and ERK activation in the mitochondrial intrinsic apoptotic pathway. Thus, VPA may be a promising therapeutic candidate for clinical treatment of PD.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title biomed research international
Publication Year Start




PMID- 28421199
OWN - NLM
STAT- In-Process
DA  - 20170419
LR  - 20170423
IS  - 2314-6141 (Electronic)
VI  - 2017
DP  - 2017
TI  - Valproic Acid Protects Primary Dopamine Neurons from MPP+-Induced Neurotoxicity: 
      Involvement of GSK3beta Phosphorylation by Akt and ERK through the Mitochondrial 
      Intrinsic Apoptotic Pathway.
PG  - 8124501
LID - 10.1155/2017/8124501 [doi]
AB  - Valproic acid (VPA), a drug widely used to treat manic disorder and epilepsy, has
      recently shown neuroprotective effects in several neurological diseases,
      particularly in Parkinson's disease (PD). The goal of the present study was to
      confirm VPA's dose-dependent neuroprotective propensities in the MPP+ model of PD
      in primary dopamine (DA) neurons and to investigate the underlying molecular
      mechanisms using specific mitogen-activated protein kinases (MAPKs) and
      phosphatidylinositol 3-kinase- (PI3K-) Akt signaling inhibitors. VPA reversed
      MPP+-induced mitochondrial apoptosis and counteracted MPP+-induced extracellular 
      signal-regulated kinase (ERK) and Akt repression and inhibited glycogen synthase 
      kinase 3beta (GSK3beta) activation through induction of GSK3beta phosphorylation.
      Moreover, inhibitors of the PI3K and MAPK pathways abolished GSK3beta
      phosphorylation and diminished the VPA-induced neuroprotective effect. These
      findings indicated that VPA's neuroprotective effect in the MPP+-model of PD is
      associated with GSK3beta phosphorylation via Akt and ERK activation in the
      mitochondrial intrinsic apoptotic pathway. Thus, VPA may be a promising
      therapeutic candidate for clinical treatment of PD.
FAU - Zhang, Chi
AU  - Zhang C
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha,
      Hunan 410008, China.
FAU - Yuan, Xianrui
AU  - Yuan X
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha,
      Hunan 410008, China.
FAU - Hu, Zhongliang
AU  - Hu Z
AD  - Department of Pathology, Xiangya Hospital, Central South University, Changsha,
      Hunan 410008, China.
FAU - Liu, Songlin
AU  - Liu S
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha,
      Hunan 410008, China.
FAU - Li, Haoyu
AU  - Li H
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha,
      Hunan 410008, China.
FAU - Wu, Ming
AU  - Wu M
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha,
      Hunan 410008, China.
FAU - Yuan, Jian
AU  - Yuan J
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha,
      Hunan 410008, China.
FAU - Zhao, Zijin
AU  - Zhao Z
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha,
      Hunan 410008, China.
FAU - Su, Jun
AU  - Su J
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha,
      Hunan 410008, China.
FAU - Wang, Xiangyu
AU  - Wang X
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha,
      Hunan 410008, China.
FAU - Liao, Yiwei
AU  - Liao Y
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha,
      Hunan 410008, China.
FAU - Liu, Qing
AU  - Liu Q
AUID- ORCID: 0000-0001-8374-9882
AD  - Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha,
      Hunan 410008, China.
LA  - eng
PT  - Journal Article
DEP - 20170322
PL  - United States
TA  - Biomed Res Int
JT  - BioMed research international
JID - 101600173
PMC - PMC5380829
EDAT- 2017/04/20 06:00
MHDA- 2017/04/20 06:00
CRDT- 2017/04/20 06:00
PHST- 2017/01/24 [received]
PHST- 2017/03/06 [accepted]
AID - 10.1155/2017/8124501 [doi]
PST - ppublish
SO  - Biomed Res Int. 2017;2017:8124501. doi: 10.1155/2017/8124501. Epub 2017 Mar 22.

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