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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References
Nilius B, Szallasi A (2014) Transient receptor potential channels as drug targets: from the science of basic research to the art of medicine. Pharmacol Rev 66(3):676–814. doi:10.1124/pr.113.008268
Nilius B, Voets T (2013) The puzzle of TRPV4 channelopathies. EMBO Rep 14(2):152–163. doi:10.1038/embor.2012.219
Vincent F, Duncton MA (2011) TRPV4 agonists and antagonists. Curr Top Med Chem 11(17):2216–2226
Moran MM, McAlexander MA, Bíró T, Szallasi A (2011) Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov 10(8):601–620. doi:10.1038/nrd3456
Simard JM, Kent TA, Chen M, Tarasov KV, Gerzanich V (2007) Brain edema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 6(3):258–268
Lipski J, Park TI, Li D, Lee SC, Trevarton AJ, Chung KK, Freestone PS, Bai JZ (2006) Involvement of TRP-like channels in the acute ischemic response of hippocampal CA1 neurons in brain slices. Brain Res 1077(1):187–199
Bai JZ, Lipski J (2010) Differential expression of TRPM2 and TRPV4 channels and their potential role in oxidative stress-induced cell death in organotypic hippocampal culture. Neurotoxicology 31(2):204–214. doi:10.1016/j.neuro.2010.01.001
Li L, Qu W, Zhou L, Lu Z, Jie P, Chen L, Chen L (2013) Activation of transient receptor potential vanilloid 4 increases NMDA-activated current in hippocampal pyramidal neurons. Front Cell Neurosci 7:17–26. doi:10.3389/fncel.2013.00017
Butenko O, Dzamba D, Benesova J, Honsa P, Benfenati V, Rusnakova V, Ferroni S, Anderova M (2012) The increased activity of TRPV4 channel in the astrocytes of the adult rat hippocampus after cerebral hypoxia/ischemia. PLoS One 7(6):e39959. doi:10.1371/journal.pone.0039959
Ryskamp DA, Witkovsky P, Barabas P, Huang W, Koehler C, Akimov NP, Lee SH, Chauhan S, Xing W, Rentería RC, Liedtke W, Krizaj D (2011) The polymodal ion channel transient receptor potential vanilloid 4 modulates calcium flux, spiking rate, and apoptosis of mouse retinal ganglion cells. J Neurosci 31(19):7089–7101. doi:10.1523/JNEUROSCI. 0359-11.2011
Paschen W (1996) Glutamate excitotoxicity in transient global cerebral ischemia. Acta Neurobiol Exp (Wars) 56(1):313–322
Hetman M, Kharebava G (2006) Survival signaling pathways activated by NMDA receptors. Curr Top Med Chem 6(8):787–799
Ivanov A, Pellegrino C, Rama S, Dumalska I, Salyha Y, Ben-Ari Y, Medina I (2006) Opposing role of synaptic and extrasynaptic NMDA receptors in regulation of the extracellular signal-regulated kinases (ERK) activity in cultured rat hippocampal neurons. J Physiol 572(Pt3):789–798
Waxman EA, Lynch DR (2005) N-methyl-D-aspartate receptor subtypes: multiple roles in excitotoxicity and neurological disease. Neuroscientist 11(1):37–49
Ye L, Kleiner S, Wu J, Sah R, Gupta RK, Banks AS, Cohen P, Khandekar MJ, Boström P, Mepani RJ, Laznik D, Kamenecka TM, Song X, Liedtke W, Mootha VK, Puigserver P, Griffin PR, Clapham DE, Spiegelman BM (2012) TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell 151(1):96–110. doi:10.1016/j.cell.2012.08.034
Thodeti CK, Matthews B, Ravi A, Mammoto A, Ghosh K, Bracha AL, Ingber DE (2009) TRPV4 channels mediate cyclic strain-induced endothelial cell reorientation through integrin-to-integrin signaling. Circ Res 104(9):1123–1130. doi:10.1161/CIRCRESAHA.108.192930
Gradilone SA, Masyuk TV, Huang BQ, Banales JM, Lehmann GL, Radtke BN, Stroope A, Masyuk AI, Splinter PL, LaRusso NF (2010) Activation of Trpv4 reduces the hyperproliferative phenotype of cystic cholangiocytes from an animal model of ARPKD. Gastroenterology 139(1):304–314.e2. doi:10.1053/j.gastro.2010.04.010
Yang R, Chen L, Wang H, Xu B, Tomimoto H, Chen L (2012) Anti-amnesic effect of neurosteroid PREGS in Aβ25–35-injected mice through σ1 receptor- anda7nAChR-mediated neuroprotection. Neuropharmacology 63(6):1042–1050. doi:10.1016/j.neuropharm.2012.07.035
Williams EJ, Doherty P (1999) Evidence for and against a pivotal role of PI3-kinase in a neuronal cell survival pathway. Mol Cell Neurosci 13(4):272–280
Howland JG, Cazakoff BN (2010) Effects of acute stress and GluN2B-containing NMDA receptor antagonism on object and object-place recognition memory. Neurobiol Learn Mem 93(2):261–267. doi:10.1016/j.nlm.2009.10.006
Mulcahy NJ, Ross J, Rothwell NJ, Loddick SA (2003) Delayed administration of interleukin-1 receptor antagonist protects against transient cerebral ischemia in the rat. Br J Pharmacol 140(3):471–476
Cai W, Zhu Y, Furuya K, Li Z, Sokabe M, Chen L (2008) Two different molecular mechanisms underlying progesterone neuroprotection against ischemic brain damage. Neuropharmacology 55(2):127–138. doi:10.1016/j.neuropharm.2008.04.023
Shibasaki K, Suzuki M, Mizuno A, Tominaga M (2007) Effects of body temperature on neural activity in the hippocampus: regulation of resting membrane potentials by transient receptor potential vanilloid 4. J Neurosci 27(7):1566–1575
Zhao H, Sapolsky RM, Steinberg GK (2006) Phosphoinositide-3-kinase/Akt survival signal pathways are implicated in neuronal survival after stroke. Mol Neurobiol 34(3):249–270
Sawe N, Steinberg G, Zhao H (2008) Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. J Neurosci Res 86(8):1659–1669. doi:10.1002/jnr.21604
Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J, Tymianski M, Craig AM, Wang YT (2007) NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci 27(11):2846–2857
Cao DS, Yu SQ, Premkumar LS (2009) Modulation of transient receptor potential vanilloid 4-mediated membrane currents and synaptic transmission by protein kinase C. Mol Pain 5:5–17. doi:10.1186/1744-8069-5-5
Li L, Yin J, Jie PH, Lu ZH, Zhou LB, Chen L, Chen L (2013) Transient receptor potential vanilloid 4 mediates hypotonicity-induced enhancement of synaptic transmission in hippocampal slices. CNS Neurosci Ther 19(11):854–862. doi:10.1111/cns.12143
Noshita N, Lewen A, Sugawara T, Chan PH (2001) Evidence of phosphorylation of Akt and neuronal survival after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 21(12):1442–1450
Luo HR, Hattori H, Hossain MA, Hester L, Huang Y, Lee-Kwon W, Donowitz M, Nagata E, Snyder SH (2003) Akt as a mediator of cell death. Proc Natl Acad Sci U S A. 100(20):11712–11717
Li F, Omori N, Jin G, Wang SJ, Sato K, Nagano I, Shoji M, Abe K (2003) Cooperative expression of survival p-ERK and p-Akt signals in rat brain neurons after transient MCAO. Brain Res 962(1–2):21–26
Shi M, Du F, Liu Y, Li L, Cai J, Zhang GF, Xu XF, Lin T, Cheng HR, Liu XD, Xiong LZ, Zhao G (2013) Glial cell-expressed mechanosensitive channel TRPV4 mediates infrasound-induced neuronal impairment. Acta Neuropathol 126(5):725–739. doi:10.1007/s00401-013-1166-x
Bai JZ, Lipski J (2014) Involvement of TRPV4 channels in Aβ(40)-induced hippocampal cell death and astrocytic Ca(2+) signaling. Neurotoxicology 41:64–72. doi:10.1016/j.neuro.2014.01.001
Sonkusare SK, Bonev AD, Ledoux J, Liedtke W, Kotlikoff MI, Heppner TJ, Hill-Eubanks DC, Nelson MT (2012) Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function. Science 336(6081):597–5601. doi:10.1126/science.1216283
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).
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The authors declare that they have no conflicts of interest.
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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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DOI: https://doi.org/10.1007/s12035-014-8992-2