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

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Abstract

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.

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Acknowledgments

This work was supported by National Natural Science Foundation of China (31271206), Research Award Fund for Outstanding Young Teachers in Nanjing Medical University (JX2161015033), and Fonds de recherche Santé-National Natural Science Foundation of China Collaboration (812111370).

Conflict of Interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, China

    Pinghui Jie, Zihong Lu, Zhiwen Hong, Lin Li, Libin Zhou, Yingchun Li, Rong Zhou, Yebo Zhou, Lei Chen & Ling Chen

  2. Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Yimei Du

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  1. Pinghui Jie
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  2. Zihong Lu
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Correspondence to Lei Chen.

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Pinghui Jie and Zihong Lu contributed equally to this work.

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Jie, P., Lu, Z., Hong, Z. et al. Activation of Transient Receptor Potential Vanilloid 4 is Involved in Neuronal Injury in Middle Cerebral Artery Occlusion in Mice. Mol Neurobiol 53, 8–17 (2016). https://doi.org/10.1007/s12035-014-8992-2

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