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Topiramate protects against glutamate excitotoxicity via activating BDNF/TrkB-dependent ERK pathway in rodent hippocampal neurons.

Abstract

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 125μM 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 β-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.

Authors+Show Affiliations

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.Department of Pharmacology, Daqing Campus of Harbin Medical University, Daqing 163319, China. Electronic address: yonggangcaodr2014@163.com.Department of Physiology, Daqing Campus of Harbin Medical University, Daqing 163319, China.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.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.Department of Pharmacology, Daqing Campus of Harbin Medical University, Daqing 163319, China. Electronic address: honglisundr2014@126.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25661849

Citation

Mao, Xiao-Yuan, et al. "Topiramate Protects Against Glutamate Excitotoxicity Via Activating BDNF/TrkB-dependent ERK Pathway in Rodent Hippocampal Neurons." Progress in Neuro-psychopharmacology & Biological Psychiatry, vol. 60, 2015, pp. 11-7.
Mao XY, Cao YG, Ji Z, et al. Topiramate protects against glutamate excitotoxicity via activating BDNF/TrkB-dependent ERK pathway in rodent hippocampal neurons. Prog Neuropsychopharmacol Biol Psychiatry. 2015;60:11-7.
Mao, X. Y., Cao, Y. G., Ji, Z., Zhou, H. H., Liu, Z. Q., & Sun, H. L. (2015). Topiramate protects against glutamate excitotoxicity via activating BDNF/TrkB-dependent ERK pathway in rodent hippocampal neurons. Progress in Neuro-psychopharmacology & Biological Psychiatry, 60, 11-7. https://doi.org/10.1016/j.pnpbp.2015.01.015
Mao XY, et al. Topiramate Protects Against Glutamate Excitotoxicity Via Activating BDNF/TrkB-dependent ERK Pathway in Rodent Hippocampal Neurons. Prog Neuropsychopharmacol Biol Psychiatry. 2015 Jul 3;60:11-7. PubMed PMID: 25661849.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Topiramate protects against glutamate excitotoxicity via activating BDNF/TrkB-dependent ERK pathway in rodent hippocampal neurons. AU - Mao,Xiao-Yuan, AU - Cao,Yong-Gang, AU - Ji,Zhong, AU - Zhou,Hong-Hao, AU - Liu,Zhao-Qian, AU - Sun,Hong-Li, Y1 - 2015/02/07/ PY - 2014/11/03/received PY - 2015/01/15/revised PY - 2015/01/29/accepted PY - 2015/2/10/entrez PY - 2015/2/11/pubmed PY - 2016/1/23/medline KW - BDNF KW - Glutamate excitotoxicity KW - Hippocampal neurons KW - MAPKs KW - Topiramate SP - 11 EP - 7 JF - Progress in neuro-psychopharmacology & biological psychiatry JO - Prog. Neuropsychopharmacol. Biol. Psychiatry VL - 60 N2 - 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 125μM 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 β-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. SN - 1878-4216 UR - https://www.unboundmedicine.com/medline/citation/25661849/Topiramate_protects_against_glutamate_excitotoxicity_via_activating_BDNF/TrkB_dependent_ERK_pathway_in_rodent_hippocampal_neurons_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0278-5846(15)00016-0 DB - PRIME DP - Unbound Medicine ER -