Activation of Transient Receptor Potential Vanilloid 4 is Involved in Neuronal Injury in Middle Cerebral Artery Occlusion in Mice.
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.
Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, China.
Pinghui
P
Jie
Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, China.
Zihong
Z
Lu
Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, China.
Zhiwen
Z
Hong
Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, China.
Lin
L
Li
Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, China.
Libin
L
Zhou
Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, China.
Yingchun
Y
Li
Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, China.
Rong
R
Zhou
Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, China.
Yebo
Y
Zhou
Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yimei
Y
Du
Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, China. chenl@njmu.edu.cn.
Lei
L
Chen
Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, China.
Ling
L
Chen
D000818:Animals; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000293:injuries; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism*
C573308:HC-067047; D009025:Morpholines; D011758:Pyrroles; D016194:Receptors, N-Methyl-D-Aspartate; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D019869:Phosphatidylinositol 3-Kinases
Akt signaling pathway; Cerebral ischemia; NR2B subunit; Neurotoxicity; Transient receptor potential vanilloid 4