Activation of Transient Receptor Potential Vanilloid 4 is Involved in Neuronal Injury in Middle Cerebral Artery Occlusion in Mice
| Autor: | Lin Li, Libin Zhou, Ling Chen, Rong Zhou, Pinghui Jie, Zhiwen Hong, Yebo Zhou, Yimei Du, Yingchun Li, Lei Chen, Zi-Hong Lu |
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| Rok vydání: | 2014 |
| Předmět: |
Male
0301 basic medicine MAPK/ERK pathway Agonist medicine.drug_class Morpholines Neuroscience (miscellaneous) Ischemia TRPV Cation Channels Pharmacology Biology Hippocampus Receptors N-Methyl-D-Aspartate Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine medicine Animals Pyrroles Protein kinase B Akt/PKB signaling pathway Neurotoxicity Antagonist Infarction Middle Cerebral Artery medicine.disease Disease Models Animal 030104 developmental biology nervous system Neurology Reperfusion Injury NMDA receptor Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Molecular Neurobiology. 53:8-17 |
| ISSN: | 1559-1182 0893-7648 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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