Activation of Transient Receptor Potential Vanilloid 4 is Involved in Neuronal Injury in Middle Cerebral Artery Occlusion in Mice

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• 作者：Pinghui Jie ; Zihong Lu ; Zhiwen Hong ; Lin Li ; Libin Zhou…
• 关键词：Transient receptor potential vanilloid 4 ; Neurotoxicity ; Cerebral ischemia ; NR2B subunit ; Akt signaling pathway
• 刊名：Molecular Neurobiology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：53
• 期：1
• 页码：8-17
• 全文大小：1,652 KB
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• 作者单位：Pinghui Jie (1)
  Zihong Lu (1)
  Zhiwen Hong (1)
  Lin Li (1)
  Libin Zhou (1)
  Yingchun Li (1)
  Rong Zhou (1)
  Yebo Zhou (1)
  Yimei Du (2)
  Lei Chen (1)
  Ling Chen (1)
  
  1. Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, People’s Republic of China
  2. Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
  
• 刊物主题：Neurosciences; Neurobiology; Cell Biology; Neurology;
• 出版者：Springer US
• ISSN：1559-1182

文摘

Transient receptor potential vanilloid 4 (TRPV4) is widely expressed in the central nervous system and can be activated by multiple stimuli during cerebral ischemia. Recently, we reported that intracerebroventricular (icv.) injection of HC-067047, a specific TRPV4 antagonist, reduced brain infarction following 60-min of middle cerebral artery occlusion (MCAO). This study was undertaken to investigate the molecular mechanisms underlying TRPV4-mediated neuronal injury in cerebral ischemia. We demonstrated that TRPV4 expression was upregulated in the ipsilateral hippocampus at 4 to 48 h post-MCAO, peaking at 18 h post-MCAO. Treatment with TRPV4 antagonists (HC-067047 and ruthenium red) dose-dependently reduced brain infarction at 24 h post-MCAO. Phosphorylation of protein kinase B (p-Akt) was downregulated and that of extracellular signal-related kinase (p-ERK) was upregulated at 8 to 24 h post-MCAO, which was markedly blocked by treatment with HC-067047. Icv. injection of GSK1016790A (a TRPV4 agonist), dose-dependently induced hippocampal neuronal death, accompanied by an increase in phosphorylation of the NR2B subunit of the N-methyl-d-aspartate receptor (NMDAR). In addition, the level of p-Akt was decreased and that of p-ERK was increased by GSK1016790A-injection, which was sensitive to an NR2B antagonist. The neuronal toxicity of GSK1016790A was blocked by treatment with an NR2B antagonist and a phosphatidylinositol-3-kinase (PI3K) agonist but not by administration of a MAPK/ERK kinase antagonist. We conclude that the activation of TRPV4 is upregulated and involved in neuronal injury during cerebral ischemia and that the neurotoxicity associated with TRPV4-activation is mediated through NR2B-NMDAR and the related downregulation of the Akt signaling pathway.