PMID- 25661849
OWN - NLM
STAT- MEDLINE
DCOM- 20160122
LR  - 20181202
IS  - 1878-4216 (Electronic)
IS  - 0278-5846 (Linking)
VI  - 60
DP  - 2015 Jul 3
TI  - Topiramate protects against glutamate excitotoxicity via activating 
      BDNF/TrkB-dependent ERK pathway in rodent hippocampal neurons.
PG  - 11-7
LID - S0278-5846(15)00016-0 [pii]
LID - 10.1016/j.pnpbp.2015.01.015 [doi]
AB  - Topiramate (TPM) was previously found to have neuroprotection against neuronal 
      injury in epileptic and ischemic models. However, whether TPM protects against 
      glutamate-induced excitotoxicity in hippocampal neurons is elusive. Our present 
      work aimed to evaluate the protective effect of TPM against glutamate toxicity in 
      hippocampal neurons and further figure out the potential molecular mechanisms. 
      The in vitro glutamate excitotoxic model was prepared with 125muM glutamate for 
      20min. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) 
      analysis and Hoechst 33342 staining were conducted to detect neuronal survival. 
      The protein expressions of brain-derived neurotrophic factor (BDNF), TrkB, 
      mitogen-activated protein kinase (MAPK) cascade (including extracellular 
      signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK), 
      cyclic AMP response element binding protein (CREB), Bcl-2, Bax and beta-actin were 
      detected via Western blot assay. Our results demonstrated that TPM protected 
      hippocampal neurons from glutamate toxicity. Meanwhile, the pretreatment of TPM 
      for 10min significantly prevented the down-regulation of BDNF and the 
      phosphorylation of TrkB. Furthermore, the elevation of phosphorylated EKR 
      expression was significantly inhibited after blockade of TrkB by TrkB IgG, while 
      no alterations of phosphorylated JNK and p38 MAPK were found in the cultured 
      hippocampal neurons. Besides, it was also found that the enhanced phosphorylation 
      of CREB was evidently reversed under excitotoxic conditions after treating with 
      U0126 (the selective inhibitor of ERK). The protein level of Bcl-2 was also 
      observed to be remarkably increased after TPM treatment. In conclusion, these 
      findings implicate that TPM exerts neuroprotective effects against glutamate 
      excitotoxicity in hippocampal neurons and its protection may be modulated through 
      BDNF/TrkB-dependent ERK pathway.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Mao, Xiao-Yuan
AU  - Mao XY
AD  - Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      Changsha 410008, China; Institute of Clinical Pharmacology, Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, Changsha 410078, China; Hunan 
      Province Cooperation Innovation Center for Molecular Target New Drug Study, 
      Hengyang 421001, China.
FAU - Cao, Yong-Gang
AU  - Cao YG
AD  - Department of Pharmacology, Daqing Campus of Harbin Medical University, Daqing 
      163319, China. Electronic address: yonggangcaodr2014@163.com.
FAU - Ji, Zhong
AU  - Ji Z
AD  - Department of Physiology, Daqing Campus of Harbin Medical University, Daqing 
      163319, China.
FAU - Zhou, Hong-Hao
AU  - Zhou HH
AD  - Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      Changsha 410008, China; Institute of Clinical Pharmacology, Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, Changsha 410078, China; Hunan 
      Province Cooperation Innovation Center for Molecular Target New Drug Study, 
      Hengyang 421001, China.
FAU - Liu, Zhao-Qian
AU  - Liu ZQ
AD  - Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, 
      Changsha 410008, China; Institute of Clinical Pharmacology, Hunan Key Laboratory 
      of Pharmacogenetics, Central South University, Changsha 410078, China; Hunan 
      Province Cooperation Innovation Center for Molecular Target New Drug Study, 
      Hengyang 421001, China. Electronic address: liuzhaoqian63@126.com.
FAU - Sun, Hong-Li
AU  - Sun HL
AD  - Department of Pharmacology, Daqing Campus of Harbin Medical University, Daqing 
      163319, China. Electronic address: honglisundr2014@126.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150207
PL  - England
TA  - Prog Neuropsychopharmacol Biol Psychiatry
JT  - Progress in neuro-psychopharmacology & biological psychiatry
JID - 8211617
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Excitatory Amino Acid Agonists)
RN  - 0 (Neuroprotective Agents)
RN  - 0H73WJJ391 (Topiramate)
RN  - 30237-26-4 (Fructose)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Inhibitors/pharmacology
MH  - Excitatory Amino Acid Agonists/toxicity
MH  - Fructose/*analogs & derivatives/pharmacology
MH  - Glutamic Acid/toxicity
MH  - Hippocampus/*cytology
MH  - MAP Kinase Signaling System/*drug effects
MH  - Neurons/*drug effects
MH  - Neuroprotective Agents/*pharmacology
MH  - Rats
MH  - Rats, Wistar
MH  - Receptor, trkB/metabolism
MH  - Time Factors
MH  - Topiramate
OTO - NOTNLM
OT  - BDNF
OT  - Glutamate excitotoxicity
OT  - Hippocampal neurons
OT  - MAPKs
OT  - Topiramate
EDAT- 2015/02/11 06:00
MHDA- 2016/01/23 06:00
CRDT- 2015/02/10 06:00
PHST- 2014/11/03 00:00 [received]
PHST- 2015/01/15 00:00 [revised]
PHST- 2015/01/29 00:00 [accepted]
PHST- 2015/02/10 06:00 [entrez]
PHST- 2015/02/11 06:00 [pubmed]
PHST- 2016/01/23 06:00 [medline]
AID - S0278-5846(15)00016-0 [pii]
AID - 10.1016/j.pnpbp.2015.01.015 [doi]
PST - ppublish
SO  - Prog Neuropsychopharmacol Biol Psychiatry. 2015 Jul 3;60:11-7. doi: 
      10.1016/j.pnpbp.2015.01.015. Epub 2015 Feb 7.