Generic placeholder image

Current Molecular Medicine

Author(s): Panpan Chang, Yuzi Tian, Aaron M. Williams, Umar F. Bhatti, Baoling Liu, Yongqing Li* and Hasan B. Alam*

DOI: 10.2174/1566524019666190724102755

DownloadDownload PDF Flyer Cite As
Inhibition of Histone Deacetylase 6 Protects Hippocampal Cells Against Mitochondria-mediated Apoptosis in a Model of Severe Oxygen-glucose Deprivation

Page: [673 - 682] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Background: Histone deacetylase (HDAC) 6 inhibitors have demonstrated significant protective effects in traumatic injuries. However, their roles in neuroprotection and underlying mechanisms are poorly understood. This study sought to investigate the neuroprotective effects of Tubastatin A (Tub-A), an HDAC6 inhibitor, during oxygenglucose deprivation (OGD) in HT22 hippocampal cells.

Methods: HT22 hippocampal cells were exposed to OGD. Cell viability and cytotoxicity were assessed by cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assay. Cellular apoptosis was assessed by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Mitochondria membrane potential was detected using JC-1 dye. Expressions of acetylated α-tubulin, α-tubulin, cytochrome c, VDAC, Bax, Bcl- 2, cleaved caspase 3, phosphorylated Akt, Akt, phosphorylated GSK3β and GSK3β were analyzed by Western blot analysis.

Results: Tub-A induced acetylation of α-tubulin, demonstrating appropriate efficacy. Tub-A significantly increased cell viability and attenuated LDH release after exposure to OGD. Furthermore, Tub-A treatment blunted the increase in TUNEL-positive cells following OGD and preserved the mitochondrial membrane potential. Tub-A also attenuated the release of cytochrome c from the mitochondria into the cytoplasm and suppressed the ratio of Bax/Bcl-2 and cleaved caspase 3. This was mediated, in part, by the increased phosphorylation of Akt and GSK3β signaling pathways.

Conclusion: HDAC 6 inhibition, using Tub-A, protects against OGD-induced injury in HT22 cells by modulating Akt/GSK3β signaling and inhibiting mitochondria-mediated apoptosis.

Keywords: Histone deacetylase 6, oxygen-glucose deprivation, neurons, mitochondria membrane potential, apoptosis, HT22 cells.

[1]
Sheriff FG, Hinson HE. Pathophysiology and clinical management of moderate and severe traumatic brain injury in the ICU. Semin Neurol 2015; 35(1): 42-9.
[http://dx.doi.org/10.1055/s-0035-1544238] [PMID: 25714866]
[2]
Prentice H, Modi JP, Wu JY. Mechanisms of neuronal protection against excitotoxicity, endoplasmic reticulum stress, and mitochondrial dysfunction in stroke and neurodegenerative diseases. Oxid Med Cell Longev 2015; 2015964518
[http://dx.doi.org/10.1155/2015/964518] [PMID: 26576229]
[3]
Hertz L. Bioenergetics of cerebral ischemia: a cellular perspective. Neuropharmacology 2008; 55(3): 289-309.
[http://dx.doi.org/10.1016/j.neuropharm.2008.05.023] [PMID: 18639906]
[4]
Guo JM, Liu AJ, Zang P, et al. ALDH2 protects against stroke by clearing 4-HNE. Cell Res 2013; 23(7): 915-30.
[http://dx.doi.org/10.1038/cr.2013.69] [PMID: 23689279]
[5]
Lai TW, Zhang S, Wang YT. Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol 115 ( 157): 88.2014.
[http://dx.doi.org/10.1016/j.pneurobio.2013.11.006]
[6]
Park JH. Park Ok, Cho JH, et al Anti-inflammatory effect of tanshinone I in neuroprotection against cerebral ischemia-reperfusion injury in the gerbil hippocampus. Neurochem Res 2014; 39(7): 1300-12.
[http://dx.doi.org/10.1007/s11064-014-1312-4] [PMID: 24760430]
[7]
Li Y, Zhang X, Polakiewicz RD, Yao TP, Comb MJ. HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization. J Biol Chem 2008; 283(19): 12686-90.
[http://dx.doi.org/10.1074/jbc.C700185200] [PMID: 18356165]
[8]
Simoes-Pires C, Zwick V, Nurisso A, Schenker E, Carrupt PA, Cuendet M. HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs? Mol Neurodegener 2013; 8: 7.
[http://dx.doi.org/10.1186/1750-1326-8-7] [PMID: 23356410]
[9]
Dompierre JP, Godin JD, Charrin BC, et al. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation. J Neurosci 2007; 27(13): 3571-83.
[http://dx.doi.org/10.1523/JNEUROSCI.0037-07.2007] [PMID: 17392473]
[10]
Rivieccio MA, Brochier C, Willis DE, et al. HDAC6 is a target for protection and regeneration following injury in the nervous system. Proc Natl Acad Sci USA 2009; 106(46): 19599-604.
[http://dx.doi.org/10.1073/pnas.0907935106] [PMID: 19884510]
[11]
Wang Z, Leng Y, Wang J, Liao HM, Bergman J, Leeds P, et al. Tubastatin A, an HDAC6 inhibitor, alleviates stroke-induced brain infarction and functional deficits: potential roles of alpha-tubulin acetylation and FGF-21 up-regulation. Sci Rep 2016; 6: 19626.
[http://dx.doi.org/10.1038/srep19626] [PMID: 26790818]
[12]
Zhang L, Liu C, Wu J, et al. Tubastatin A/ACY-1215 improves cognition in Alzheimer’s disease transgenic mice. J Alzheimers Dis 2014; 41(4): 1193-205.
[http://dx.doi.org/10.3233/JAD-140066] [PMID: 24844691]
[13]
Chang P, Weykamp M, Dennahy IS, et al. Histone deacetylase inhibitors: Isoform selectivity improves survival in a hemorrhagic shock model. J Trauma Acute Care Surg 2018; 84(5): 795-801.
[http://dx.doi.org/10.1097/TA.0000000000001824] [PMID: 29401190]
[14]
Tang J, Shi Y, Liu N, et al. Blockade of histone deacetylase 6 protects against cisplatin-induced acute kidney injury. Clin Sci (Lond) 2018; 132(3): 339-59.
[http://dx.doi.org/10.1042/CS20171417] [PMID: 29358506]
[15]
Zhang J, Li L, Peng Y, et al. Surface chemistry induces mitochondria-mediated apoptosis of breast cancer cells via PTEN/PI3K/AKT signaling pathway. Biochim Biophys Acta Mol Cell Res 2018; 1865(1): 172-85.
[http://dx.doi.org/10.1016/j.bbamcr.2017.10.007] [PMID: 29054429]
[16]
Jonassen AK, Sack MN, Mjøs OD, Yellon DM. Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circ Res 2001; 89(12): 1191-8.
[http://dx.doi.org/10.1161/hh2401.101385] [PMID: 11739285]
[17]
Embi N, Rylatt DB, Cohen P. Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem 1980; 107(2): 519-27.
[http://dx.doi.org/10.1111/j.1432-1033.1980.tb06059.x] [PMID: 6249596]
[18]
Darshit BS, Ramanathan M. Activation of AKT1/GSK-3β/β-catenin-TRIM11/survivin pathway by novel GSK-3β inhibitor promotes neuron cell survival: Study in differentiated SH-SY5Y cells in OGD model. Mol Neurobiol 2016; 53(10): 6716-29.
[http://dx.doi.org/10.1007/s12035-015-9598-z] [PMID: 26660108]
[19]
Chuang DM, Wang Z, Chiu CT. GSK-3 as a target for lithium-induced neuroprotection against excitotoxicity in neuronal cultures and animal models of ischemic stroke. Front Mol Neurosci 2011; 4: 15.
[http://dx.doi.org/ 10.3389/fnmol.2011.00015] [PMID: 21886605]
[20]
Li ZY, Li QZ, Chen L, Chen BD, Zhang C, Wang X, et al. HPOB, an HDAC6 inhibitor, attenuates corticosterone-induced injury in rat adrenal pheochromocytoma PC12 cells by inhibiting mitochondrial GR translocation and the intrinsic apoptosis pathway. Neurochem Int 2016; 99: 239-51.
[http://dx.doi.org/10.1016/j.neuint.2016.08.004]
[21]
Gerencser AA, Chinopoulos C, Birket MJ, et al. Quantitative measurement of mitochondrial membrane potential in cultured cells: calcium-induced de- and hyperpolarization of neuronal mitochondria. J Physiol 2012; 590(12): 2845-71.
[http://dx.doi.org/10.1113/jphysiol.2012.228387] [PMID: 22495585]
[22]
Yin W, Li X, Feng S, et al. Plasma membrane depolarization and Na,K-ATPase impairment induced by mitochondrial toxins augment leukemia cell apoptosis via a novel mitochondrial amplification mechanism. Biochem Pharmacol 2009; 78(2): 191-202.
[http://dx.doi.org/10.1016/j.bcp.2009.03.025] [PMID: 19442964]
[23]
Bortner CD, Gomez-Angelats M, Cidlowski JA. Plasma membrane depolarization without repolarization is an early molecular event in anti-Fas-induced apoptosis. J Biol Chem 2001; 276(6): 4304-14.
[http://dx.doi.org/10.1074/jbc.M005171200] [PMID: 11050080]
[24]
Hubbert C, Guardiola A, Shao R, et al. HDAC6 is a microtubule-associated deacetylase. Nature 2002; 417(6887): 455-8.
[http://dx.doi.org/10.1038/417455a] [PMID: 12024216]
[25]
Kroemer G, Dallaporta B, Resche-Rigon M. The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol 1998; 60: 619-42.
[http://dx.doi.org/10.1146/annurev.physiol.60.1.619] [PMID: 9558479]
[26]
Malagelada C, Xifró X, Miñano A, Sabriá J, Rodríguez-Alvarez J. Contribution of caspase-mediated apoptosis to the cell death caused by oxygen-glucose deprivation in cortical cell cultures. Neurobiol Dis 2005; 20(1): 27-37.
[http://dx.doi.org/10.1016/j.nbd.2005.01.028] [PMID: 16137564]
[27]
Mattson MP, Duan W, Pedersen WA, Culmsee C. Neurodegenerative disorders and ischemic brain diseases. Apoptosis 2001; 6(1-2): 69-81.
[http://dx.doi.org/10.1023/A:1009676112184] [PMID: 11321043]
[28]
Manzanero S, Santro T, Arumugam TV. Neuronal oxidative stress in acute ischemic stroke: sources and contribution to cell injury. Neurochem Int 2013; 62(5): 712-8.
[http://dx.doi.org/10.1016/j.neuint.2012.11.009] [PMID: 23201332]
[29]
Wu CX, Liu R, Gao M, Zhao G, Wu S, Wu CF, et al. Pinocembrin protects brain against ischemia/reperfusion injury by attenuating endoplasmic reticulum stress induced apoptosis. Neurosci Lett 546: 57-62 2013.
[30]
Kichev A, Rousset CI, Baburamani AA, et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling and cell death in the immature central nervous system after hypoxia-ischemia and inflammation. J Biol Chem 2014; 289(13): 9430-9.
[http://dx.doi.org/10.1074/jbc.M113.512350] [PMID: 24509861]
[31]
Jordan J, de Groot PW, Galindo MF. Mitochondria: the headquarters in ischemia-induced neuronal death. Cent Nerv Syst Agents Med Chem 2011; 11(2): 98-106.
[http://dx.doi.org/10.2174/187152411796011358] [PMID: 21521170]
[32]
Liang J, Yu Y, Wang B, et al. Ginsenoside Rb1 attenuates oxygen-glucose deprivation-induced apoptosis in SH-SY5Y cells via protection of mitochondria and inhibition of AIF and cytochrome c release. Molecules 2013; 18(10): 12777-92.
[http://dx.doi.org/10.3390/molecules181012777] [PMID: 24135936]
[33]
Liu L, Huang W, Wang J, Song H, Cen J, Ji B. Anthraquinone derivative exerted hormetic effect on the apoptosis in oxygen-glucose deprivation-induced PC12 cells via ERK and Akt activated Nrf2/HO-1 signaling pathway. Chem Biol Interact 2017; 262: 1-11.
[http://dx.doi.org/10.1016/j.cbi.2016.12.001] [PMID: 27923643]
[34]
Krajewski S, Krajewska M, Ellerby LM, et al. Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci USA 1999; 96(10): 5752-7.
[http://dx.doi.org/10.1073/pnas.96.10.5752] [PMID: 10318956]
[35]
Hasegawa Y, Suzuki H, Sozen T, Altay O, Zhang JH. Apoptotic mechanisms for neuronal cells in early brain injury after subarachnoid hemorrhage. Acta Neurochir Suppl (Wien) 2011; 110(Pt 1): 43-8.
[http://dx.doi.org/10.1007/978-3-7091-0353-1_8] [PMID: 21116913]
[36]
Li Z, Cui G, Wang J, Yu Z, Zhao L, Lv Z. Nemo-like kinase (NLK) involves in neuronal apoptosis after traumatic brain injury. Cell Mol Neurobiol 2012; 32(3): 381-9.
[http://dx.doi.org/10.1007/s10571-011-9766-2] [PMID: 22127415]
[37]
Shi Y, Xu L, Tang J, et al. Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury. Am J Physiol Renal Physiol 2017; 312(3): F502-15.
[http://dx.doi.org/10.1152/ajprenal.00546.2016] [PMID: 28052874]
[38]
Zhao T, Li Y, Bronson RT, Liu B, Velmahos GC, Alam HB. Selective histone deacetylase-6 inhibition attenuates stress responses and prevents immune organ atrophy in a lethal septic model. Surgery 2014; 156(2): 235-42.
[http://dx.doi.org/10.1016/j.surg.2014.03.033] [PMID: 24947640]
[39]
Maldonado EN, Patnaik J, Mullins MR, Lemasters JJ. Free tubulin modulates mitochondrial membrane potential in cancer cells. Cancer Res 2010; 70(24): 10192-201.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2429] [PMID: 21159641]
[40]
Gold WA, Lacina TA, Cantrill LC, Christodoulou J. MeCP2 deficiency is associated with reduced levels of tubulin acetylation and can be restored using HDAC6 inhibitors. J Mol Med (Berl) 2015; 93(1): 63-72.
[http://dx.doi.org/10.1007/s00109-014-1202-x] [PMID: 25209898]
[41]
Matsuyama A, Shimazu T, Sumida Y, et al. In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation. EMBO J 2002; 21(24): 6820-31.
[http://dx.doi.org/10.1093/emboj/cdf682] [PMID: 12486003]
[42]
Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993; 74(4): 609-19.
[http://dx.doi.org/10.1016/0092-8674(93)90509-O] [PMID: 8358790]
[43]
Scheid MP, Woodgett JR. Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett 2003; 546(1): 108-12.
[http://dx.doi.org/10.1016/S0014-5793(03)00562-3] [PMID: 12829245]
[44]
Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 2002; 14(5): 381-95.
[http://dx.doi.org/10.1016/S0898-6568(01)00271-6] [PMID: 11882383]
[45]
Dudek H, Datta SR, Franke TF, et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 1997; 275(5300): 661-5.
[http://dx.doi.org/10.1126/science.275.5300.661] [PMID: 9005851]
[46]
Uchiyama T, Engelman RM, Maulik N, Das DK. Role of Akt signaling in mitochondrial survival pathway triggered by hypoxic preconditioning. Circulation 2004; 109(24): 3042-9.
[http://dx.doi.org/10.1161/01.CIR.0000130647.29030.90] [PMID: 15184284]
[47]
Zhang QG, Wang XT, Han D, Yin XH, Zhang GY, Xu TL. Akt inhibits MLK3/JNK3 signaling by inactivating Rac1: a protective mechanism against ischemic brain injury. J Neurochem 2006; 98(6): 1886-98.
[http://dx.doi.org/10.1111/j.1471-4159.2006.04020.x] [PMID: 16831194]
[48]
Hetman M, Cavanaugh JE, Kimelman D, Xia Z. Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal. J Neurosci 2000; 20(7): 2567-74.
[http://dx.doi.org/10.1523/JNEUROSCI.20-07-02567.2000] [PMID: 10729337]
[49]
Jiang W, Luo T, Li S, et al. Quercetin Protects against Okadaic Acid-Induced Injury via MAPK and PI3K/Akt/GSK3β Signaling Pathways in HT22 Hippocampal Neurons. PLoS One 2016; 11(4)e0152371
[http://dx.doi.org/10.1371/journal.pone.0152371] [PMID: 27050422]
[50]
Zhou C, Tu J, Zhang Q, et al. Delayed ischemic postconditioning protects hippocampal CA1 neurons by preserving mitochondrial integrity via Akt/GSK3β signaling. Neurochem Int 2011; 59(6): 749-58.
[http://dx.doi.org/10.1016/j.neuint.2011.08.008] [PMID: 21867737]
[51]
Chen S, Owens GC, Makarenkova H, Edelman DB. HDAC6 regulates mitochondrial transport in hippocampal neurons. PLoS One 2010; 5(5)e10848
[http://dx.doi.org/10.1371/journal.pone.0010848] [PMID: 20520769]
[52]
Kaliszczak M, Trousil S, Ali T, Aboagye EO. AKT activation controls cell survival in response to HDAC6 inhibition. Cell Death Dis 2016; 7(6)e2286
[http://dx.doi.org/10.1038/cddis.2016.180] [PMID: 27362804]