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Role of Metallothionein-1 and Metallothionein-2 in the Neuroprotective Mechanism of Sevoflurane Preconditioning in Mice

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Abstract

This study investigated the protective effects and mechanisms of sevoflurane preconditioning (SPC) on neurons in ischemic mice. After SPC, mice were subjected to middle cerebral artery occlusion (MCAO). Cerebral infarction area, cell apoptosis, and metallothionein-1 (MT-1) and metallothionein-2 (MT-2) expressions in MCAO mice were analyzed. Mouse primary neurons were isolated and cultured to determine the location of metallothioneins (MTs) using immunofluorescence. Neurons transfected with MT-siRNA, exogenous MTs, or sh-MTF-1 were subjected to SPC and/or oxygen-glucose deprivation (OGD), and MT-1/MT-2 expression and neurotoxin release were assayed. Meanwhile, neurons were treated with the nitric oxide donor SNAP, degraded SNAP, or the peroxide initiator paraquat, and alterations in MT-1/MT-2 expression and neurotoxicity release were observed. SPC attenuated neuronal injury and apoptosis in MCAO mice. SPC could protect neurons against OGD injury and resulted in upregulated MT-1/MT-2 expression. MT-siRNA transfection led to the downregulated expression of MT-1/MT-2 and increased neurotoxicity, and the expression patterns of these neurons were different from those of neurons transfected with exogenous MTs. The knockdown of MTs could hinder the protective effect of SPC against OGD. Pretreatment with SNAP or paraquat could increase MTF-1 expression in the nucleus of neurons, protecting against OGD injury. The inhibition of nitric oxide and peroxide inhibited the protective role of SPC in OGD by downregulating MTF-1 expression. sh-MTF-1 transfection downregulated MT-1/MT-2 expression and enhanced neurotoxicity in neurons. SPC confers neuroprotection in focal cerebral ischemia mouse models by upregulating the expression of MT-1 and MT-2 by activating NO and peroxide and increasing MTF-1 expression in the nucleus.

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References

  • Agarwal B, Stowe DF, Dash RK, Bosnjak ZJ, Camara AK (2014) Mitochondrial targets for volatile anesthetics against cardiac ischemia-reperfusion injury. Front Physiol 5:341

    Article  Google Scholar 

  • Andrews GK (2000) Regulation of metallothionein gene expression by oxidative stress and metal ions. Biochem Pharmacol 59:95–104

    Article  CAS  Google Scholar 

  • Bellanti F, Mirabella L, Mitarotonda D, Blonda M, Tamborra R, Cinnella G, Fersini A, Ambrosi A, Dambrosio M, Vendemiale G, Serviddio G (2016) Propofol but not sevoflurane prevents mitochondrial dysfunction and oxidative stress by limiting HIF-1alpha activation in hepatic ischemia/reperfusion injury. Free Radic Biol Med 96:323–333

    Article  CAS  Google Scholar 

  • Bi M, Gladbach A, van Eersel J, Ittner A, Przybyla M, van Hummel A, Chua SW, van der Hoven J, Lee WS, Muller J, Parmar J, Jonquieres GV, Stefen H, Guccione E, Fath T, Housley GD, Klugmann M, Ke YD, Ittner LM (2017) Tau exacerbates excitotoxic brain damage in an animal model of stroke. Nat Commun 8:473

    Article  Google Scholar 

  • Caraci F, Sultana J, Drago F, Spina E (2017) Clinically relevant drug interactions with anti-Alzheimer’s drugs. CNS Neurol Disord Drug Targets 16:501–513

    CAS  PubMed  Google Scholar 

  • Carmel JB, Kakinohana O, Mestril R, Young W, Marsala M, Hart RP (2004) Mediators of ischemic preconditioning identified by microarray analysis of rat spinal cord. Exp Neurol 185:81–96

    Article  CAS  Google Scholar 

  • Catalin B, Rogoveanu OC, Pirici I, Balseanu TA, Stan A, Tudorica V, Balea M, Mindrila I, Albu CV, Mohamed G, Pirici D, Muresanu DF (2018) Cerebrolysin and aquaporin 4 inhibition improve pathological and motor recovery after ischemic stroke. CNS Neurol Disord Drug Targets 17:299–308

    Article  CAS  Google Scholar 

  • Crowley MG, Liska MG, Lippert T, Corey S, Borlongan CV (2017) Utilizing delta opioid receptors and peptides for cytoprotection: implications in stroke and other neurological disorders. CNS Neurol Disord Drug Targets 16:414–424

    Article  CAS  Google Scholar 

  • Duerr GD, Dewald D, Schmitz EJ, Verfuerth L, Keppel K, Peigney C, Ghanem A, Welz A, Dewald O (2016) Metallothioneins 1 and 2 modulate inflammation and support remodeling in ischemic cardiomyopathy in mice. Mediat Inflamm 2016:7174127

    Article  Google Scholar 

  • Edmands SD, Hall AC (2009) Role for metallothioneins-I/II in isoflurane preconditioning of primary murine neuronal cultures. Anesthesiology 110:538–547

    Article  CAS  Google Scholar 

  • Eidizadeh A, Trendelenburg G (2016) Focusing on the protective effects of metallothionein-I/II in cerebral ischemia. Neural Regen Res 11:721–722

    Article  Google Scholar 

  • Feigin VL, Norrving B, George MG, Foltz JL, Roth GA, Mensah GA (2016) Prevention of stroke: a strategic global imperative. Nat Rev Neurol 12:501–512

    Article  Google Scholar 

  • Feng D, Wang B, Wang L, Abraham N, Tao K, Huang L, Shi W, Dong Y, Qu Y (2017) Pre-ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress-dependent autophagy via PERK and IRE1 signalings. J Pineal Res 62:1–5

  • Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, Roy D, Jovin TG, Willinsky RA, Sapkota BL, Dowlatshahi D, Frei DF, Kamal NR, Montanera WJ, Poppe AY, Ryckborst KJ, Silver FL, Shuaib A, Tampieri D, Williams D, Bang OY, Baxter BW, Burns PA, Choe H, Heo JH, Holmstedt CA, Jankowitz B, Kelly M, Linares G, Mandzia JL, Shankar J, Sohn SI, Swartz RH, Barber PA, Coutts SB, Smith EE, Morrish WF, Weill A, Subramaniam S, Mitha AP, Wong JH, Lowerison MW, Sajobi TT, Hill MD, Investigators ET (2015) Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 372:1019–1030

    Article  CAS  Google Scholar 

  • Juarez-Rebollar D, Rios C, Nava-Ruiz C, Mendez-Armenta M (2017) Metallothionein in brain disorders. Oxidative Med Cell Longev 2017:5828056

    Article  Google Scholar 

  • Kitano H, Kirsch JR, Hurn PD, Murphy SJ (2007) Inhalational anesthetics as neuroprotectants or chemical preconditioning agents in ischemic brain. J Cereb Blood Flow Metab 27:1108–1128

    Article  CAS  Google Scholar 

  • Kowalska K, Bizon A, Zalewska M, Milnerowicz H (2015) The influence of biological and environmental factors on metallothionein concentration in the blood. J Trace Elem Med Biol 29:99–103

    Article  CAS  Google Scholar 

  • Li H H TK, Kaynar M, et al (2015) Comparative biology of the normal lung. Zinc Homeostasis in Lung 45:479-88

  • Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79:1431–1568

    Article  CAS  Google Scholar 

  • Liu JH, Feng D, Zhang YF, Shang Y, Wu Y, Li XF, Pei L (2015) Chloral hydrate preconditioning protects against ischemic stroke via upregulating annexin A1. CNS Neurosci Ther 21:718–726

    Article  CAS  Google Scholar 

  • Liu Z, Chopp M (2016) Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog Neurobiol 144:103–120

    Article  CAS  Google Scholar 

  • Mohammadi F, Nezafat N, Negahdaripour M, Dabbagh F, Haghghi AB, Kianpour S, Banihashemi M, Ghasemi Y (2018) Neuroprotective effects of heat shock protein70. CNS Neurol Disord Drug Targets 17:736–742

    Article  CAS  Google Scholar 

  • Mondragon PBA (2018) Metallothionein expression in slow-vs. fast-twitch muscle fibers following 4 weeks of streptozotocin-induced type 1 diabetes. FACETS 3:315–325

    Article  Google Scholar 

  • Narayanan SV, Dave KR, Saul I, Perez-Pinzon MA (2015) Resveratrol preconditioning protects against cerebral ischemic injury via nuclear erythroid 2-related factor 2. Stroke 46:1626–1632

    Article  CAS  Google Scholar 

  • Ohsumi AMK, Slinger P et al (2017) Protective effect of anesthetic preconditioning during ex vivo lung perfusion in a rat lung transplantation model. J Heart Lung Transplant 36:S375–SS76

    Article  Google Scholar 

  • Qu YZ, Li M, Zhao YL, Zhao ZW, Wei XY, Liu JP, Gao L, Gao GD (2009) Astragaloside IV attenuates cerebral ischemia-reperfusion-induced increase in permeability of the blood-brain barrier in rats. Eur J Pharmacol 606:137–141

    Article  CAS  Google Scholar 

  • Radyuk SN, Michalak K, Rebrin I, Sohal RS, Orr WC (2006) Effects of ectopic expression of Drosophila DNA glycosylases dOgg1 and RpS3 in mitochondria. Free Radic Biol Med 41:757–764

    Article  CAS  Google Scholar 

  • Rodriguez-Menendez S, Garcia M, Fernandez B, Alvarez L, Fernandez-Vega-Cueto A, Coca-Prados M, Pereiro R, Gonzalez-Iglesias H (2018) The zinc-metallothionein redox system reduces oxidative stress in retinal pigment epithelial cells. Nutrients 10:1874

    Article  Google Scholar 

  • Sadana P, Coughlin L, Burke J, Woods R, Mdzinarishvili A (2015) Anti-edema action of thyroid hormone in MCAO model of ischemic brain stroke: possible association with AQP4 modulation. J Neurol Sci 354:37–45

    Article  CAS  Google Scholar 

  • Sun J, Chen XL, Zheng JY, Zhou JW, Ma ZL (2016) Astragaloside IV protects new born rats from anesthesia-induced apoptosis in the developing brain. Exp Ther Med 12:1829–1835

    Article  CAS  Google Scholar 

  • Wang C, Hu SM, Xie H, Qiao SG, Liu H, Liu CF (2015) Role of mitochondrial ATP-sensitive potassium channel-mediated PKC-epsilon in delayed protection against myocardial ischemia/reperfusion injury in isolated hearts of sevoflurane-preconditioned rats. Braz J Med Biol Res 48:528–536

    Article  CAS  Google Scholar 

  • Wang H, Li P, Xu N, Zhu L, Cai M, Yu W, Gao Y (2016a) Paradigms and mechanisms of inhalational anesthetics mediated neuroprotection against cerebral ischemic stroke. Med Gas Res 6:194–205

    Article  CAS  Google Scholar 

  • Wang H, Shi H, Yu Q, Chen J, Zhang F, Gao Y (2016b) Sevoflurane preconditioning confers neuroprotection via anti-apoptosis effects. Acta Neurochir Suppl 121:55–61

    Article  Google Scholar 

  • Wang S, Ma F, Huang L, Zhang Y, Peng Y, Xing C, Feng Y, Wang X, Peng Y (2018) Dl-3-n-Butylphthalide (NBP): a promising therapeutic agent for ischemic stroke. CNS Neurol Disord Drug Targets 17:338–347

    Article  CAS  Google Scholar 

  • Wen XR, Fu YY, Liu HZ, Wu J, Shao XP, Zhang XB, Tang M, Shi Y, Ma K, Zhang F, Wang YW, Tang H, Han D, Zhang P, Wang SL, Xu Z, Song YJ (2016) Neuroprotection of sevoflurane against ischemia/reperfusion-induced brain injury through inhibiting JNK3/caspase-3 by enhancing Akt signaling pathway. Mol Neurobiol 53:1661–1671

    Article  CAS  Google Scholar 

  • Wu H, Zhou S, Kong L, Chen J, Feng W, Cai J, Miao L, Tan Y (2015) Metallothionein deletion exacerbates intermittent hypoxia-induced renal injury in mice. Toxicol Lett 232:340–348

    Article  CAS  Google Scholar 

  • Yang Q, Dong H, Deng J, Wang Q, Ye R, Li X, Hu S, Dong H, Xiong L (2011) Sevoflurane preconditioning induces neuroprotection through reactive oxygen species-mediated up-regulation of antioxidant enzymes in rats. Anesth Analg 112:931–937

    Article  CAS  Google Scholar 

  • Zhang CC, Volkmann M, Tuma S, Stremmel W, Merle U (2018) Metallothionein is elevated in liver and duodenum of Atp7b((-/-)) mice. Biometals 31:617–625

    Article  CAS  Google Scholar 

  • Zhao WJ, Song Q, Wang YH, Li KJ, Mao L, Hu X, Lian HZ, Zheng WJ, Hua ZC (2014) Zn-responsive proteome profiling and time-dependent expression of proteins regulated by MTF-1 in A549 cells. PLoS One 9:e105797

    Article  Google Scholar 

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Acknowledgments

We would like to thank the participants for all the support and contributions.

Funding

This work was supported by the Clinical Research Center for Anesthesiology of ERAS in Hunan Province (2018SK7001).

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Authors and Affiliations

  1. Department of Anesthesiology, Clinical Research Center for Anesthesiology of ERAS in Hunan Province, Hunan Provincial People’s Hospital, Changsha, 410005, Hunan, People’s Republic of China

    Jitong Liu, Suhong Tan, Yongsheng Wang, Jia Luo, Yi Long, Xiping Mei & Yixun Tang

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  1. Jitong Liu
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  2. Suhong Tan
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  3. Yongsheng Wang
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  4. Jia Luo
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  5. Yi Long
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  6. Xiping Mei
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  7. Yixun Tang
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Contributions

LJT conceived the ideas. TSH and WTS designed the experiments. LJT, LJ, and LY performed the experiments. TSH analyzed the data. MXP and LJT provided critical materials. LJT and TSH wrote the manuscript. TYX supervised the study. All the authors have read and approved the final version for publication.

Corresponding author

Correspondence to Yixun Tang.

Ethics declarations

All experimental procedures were approved by the Ethical Committee at Hunan Provincial People’s Hospital. Animals were treated in accordance with the Guide for the Care and Use of Laboratory Animals.

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The authors declare that there are no conflicts of interest.

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Liu, J., Tan, S., Wang, Y. et al. Role of Metallothionein-1 and Metallothionein-2 in the Neuroprotective Mechanism of Sevoflurane Preconditioning in Mice. J Mol Neurosci 70, 713–723 (2020). https://doi.org/10.1007/s12031-020-01481-3

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  • DOI: https://doi.org/10.1007/s12031-020-01481-3

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