Zinc in the Brain: Friend or Foe?

Seunghyuk Choi, Dae Ki Hong, Bo Young Choi, Sang Won Suh, Seunghyuk Choi, Dae Ki Hong, Bo Young Choi, Sang Won Suh

Abstract

Zinc is a trace metal ion in the central nervous system that plays important biological roles, such as in catalysis, structure, and regulation. It contributes to antioxidant function and the proper functioning of the immune system. In view of these characteristics of zinc, it plays an important role in neurophysiology, which leads to cell growth and cell proliferation. However, after brain disease, excessively released and accumulated zinc ions cause neurotoxic damage to postsynaptic neurons. On the other hand, zinc deficiency induces degeneration and cognitive decline disorders, such as increased neuronal death and decreased learning and memory. Given the importance of balance in this context, zinc is a biological component that plays an important physiological role in the central nervous system, but a pathophysiological role in major neurological disorders. In this review, we focus on the multiple roles of zinc in the brain.

Keywords: brain; pathophysiology; physiology; zinc.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Zinc metabolic processes associated with cell growth. IGF-1: insulin-like growth factor 1. GHR: growth hormone receptor.
Figure 2
Figure 2
Role of zinc in neurogenesis. MMP: matrix metalloproteinase. ERK: extracellular signal-regulated kinase. NFAT: nuclear factor of activated T-cells. AP-1: activator protein-1.
Figure 3
Figure 3
Schematic illustration of zinc-induced immune responses. IL: interleukin; TNF-α: tumor necrosis factor alpha. Cox2: cyclooxygenase2. iNOS: inducible nitric oxide synthase. ICAM-1: intercellular adhesion molecule 1. VCAM-1: vascular cell adhesion protein 1.
Figure 4
Figure 4
Schematic illustration of zinc-induced reactive oxygen species (ROS) generation. PKC: protein kinase C. NADPH: nicotinamide-adenine dinucleotide phosphate.
Figure 5
Figure 5
Hypoglycemia-induced neuronal death caused by zinc translocation.
Figure 6
Figure 6
Zinc and ROS interaction in ischemic stroke.
Figure 7
Figure 7
Schematic illustration of zinc-induced Alzheimer’s disease (AD). ZnT: zinc transporter. NMDAR: N-methyl-D-aspartate receptor.

References

    1. Adamo A.M., Zago M.P., Mackenzie G.G., Aimo L., Keen C.L., Keenan A., Oteiza P.I. The role of zinc in the modulation of neuronal proliferation and apoptosis. Neurotox. Res. 2010;17:1–14. doi: 10.1007/s12640-009-9067-4.
    1. Corniola R.S., Tassabehji N.M., Hare J., Sharma G., Levenson C.W. Zinc deficiency impairs neuronal precursor cell proliferation and induces apoptosis via p53-mediated mechanisms. Brain Res. 2008;1237:52–61. doi: 10.1016/j.brainres.2008.08.040.
    1. Gao H.L., Zheng W., Xin N., Chi Z.H., Wang Z.Y., Chen J., Wang Z.Y. Zinc deficiency reduces neurogenesis accompanied by neuronal apoptosis through caspase-dependent and -independent signaling pathways. Neurotox. Res. 2009;16:416–425. doi: 10.1007/s12640-009-9072-7.
    1. Suh S.W., Won S.J., Hamby A.M., Yoo B.H., Fan Y., Sheline C.T., Tamano H., Takeda A., Liu J. Decreased brain zinc availability reduces hippocampal neurogenesis in mice and rats. J. Cereb. Blood Flow Metab. 2009;29:1579–1588. doi: 10.1038/jcbfm.2009.80.
    1. Moon M.Y., Kim H.J., Choi B.Y., Sohn M., Chung T.N., Suh S.W. Zinc Promotes Adipose-Derived Mesenchymal Stem Cell Proliferation and Differentiation towards a Neuronal Fate. Stem Cells Int. 2018;2018:5736535. doi: 10.1155/2018/5736535.
    1. Jan H.H., Chen I.T., Tsai Y.Y., Chang Y.C. Structural role of zinc ions bound to postsynaptic densities. J. Neurochem. 2002;83:525–534. doi: 10.1046/j.1471-4159.2002.01093.x.
    1. Grabrucker A.M., Knight M.J., Proepper C., Bockmann J., Joubert M., Rowan M., Nienhaus G.U., Garner C.C., Bowie J.U., Kreutz M.R., et al. Concerted action of zinc and ProSAP/Shank in synaptogenesis and synapse maturation. EMBO J. 2011;30:569–581. doi: 10.1038/emboj.2010.336.
    1. Tabata T., Ishida A.T. A zinc-dependent Cl- current in neuronal somata. J. Neurosci. 1999;19:5195–5204. doi: 10.1523/JNEUROSCI.19-13-05195.1999.
    1. Draguhn A., Verdorn T.A., Ewert M., Seeburg P.H., Sakmann B. Functional and molecular distinction between recombinant rat GABAA receptor subtypes by Zn2+ Neuron. 1990;5:781–788. doi: 10.1016/0896-6273(90)90337-F.
    1. Westbrook G.L., Mayer M.L. Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons. Nature. 1987;328:640–643. doi: 10.1038/328640a0.
    1. Koh J.Y., Suh S.W., Gwag B.J., He Y.Y., Hsu C.Y., Choi D.W. The role of zinc in selective neuronal death after transient global cerebral ischemia. Science. 1996;272:1013–1016. doi: 10.1126/science.272.5264.1013.
    1. Weiss J.H., Hartley D.M., Koh J.Y., Choi D.W. AMPA receptor activation potentiates zinc neurotoxicity. Neuron. 1993;10:43–49. doi: 10.1016/0896-6273(93)90240-R.
    1. Sensi S.L., Yin H.Z., Carriedo S.G., Rao S.S., Weiss J.H. Preferential Zn2+ influx through Ca2+-permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production. Proc. Natl. Acad. Sci. USA. 1999;96:2414–2419. doi: 10.1073/pnas.96.5.2414.
    1. Jarosz M., Olbert M., Wyszogrodzka G., Mlyniec K., Librowski T. Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-kappaB signaling. Inflammopharmacology. 2017;25:11–24. doi: 10.1007/s10787-017-0309-4.
    1. MacDonald R.S. The role of zinc in growth and cell proliferation. J. Nutr. 2000;130(Suppl. S5):1500S–1508S. doi: 10.1093/jn/130.5.1500S.
    1. Choi D.W., Koh J.Y. Zinc and brain injury. Annu. Rev. Neurosci. 1998;21:347–375. doi: 10.1146/annurev.neuro.21.1.347.
    1. Sensi S.L., Paoletti P., Bush A.I., Sekler I. Zinc in the physiology and pathology of the CNS. Nat. Rev. Neurosci. 2009;10:780–791. doi: 10.1038/nrn2734.
    1. Prasad A.S. Zinc in human health: Effect of zinc on immune cells. Mol. Med. 2008;14:353–357. doi: 10.2119/2008-00033.Prasad.
    1. Wessels I., Maywald M., Rink L. Zinc as a Gatekeeper of Immune Function. Nutrients. 2017;9:1286. doi: 10.3390/nu9121286.
    1. Todd W., Elvehjem C., Hart E. Zinc in the nutrition of the rat. Am. J. Physiol. Leg. Content. 1933;107:146–156. doi: 10.1152/ajplegacy.1933.107.1.146.
    1. Wu F.Y., Wu C.W. Zinc in DNA replication and transcription. Annu. Rev. Nutr. 1987;7:251–272. doi: 10.1146/annurev.nu.07.070187.001343.
    1. Wu F.Y., Huang W.J., Sinclair R.B., Powers L. The structure of the zinc sites of Escherichia coli DNA-dependent RNA polymerase. J. Biol. Chem. 1992;267:25560–25567.
    1. Vallee B.L., Auld D.S. Zinc metallochemistry in biochemistry. EXS. 1995;73:259–277.
    1. Henkin R.I. Trace metals in endocrinology. Med. Clin. North Am. 1976;60:779–797. doi: 10.1016/S0025-7125(16)31861-2.
    1. Root A.W., Duckett G., Sweetland M., Reiter E.O. Effects of zinc deficiency upon pituitary function in sexually mature and immature male rats. J. Nutr. 1979;109:958–964. doi: 10.1093/jn/109.6.958.
    1. Roth H., Kirchgessner M. Course of concentration changes of growth hormone, IGF-1, insulin and C-peptide in serum, pituitary and liver of zinc-deficient rats. J. Anim. Physiol. Anim. Nutr. (Ger.) 1997;77:91–101. doi: 10.1111/j.1439-0396.1997.tb00742.x.
    1. De Meyts P., Wallach B., Christoffersen C.T., Urso B., Gronskov K., Latus L.J., Yakushiji F., Ilondo M.M., Shymko R.M. The insulin-like growth factor-I receptor. Structure, ligand-binding mechanism and signal transduction. Horm. Res. 1994;42:152–169. doi: 10.1159/000184188.
    1. Cossack Z.T. Decline in somatomedin-C (insulin-like growth factor-1) with experimentally induced zinc deficiency in human subjects. Clin. Nutr. 1991;10:284–291. doi: 10.1016/0261-5614(91)90008-Z.
    1. Dorup I., Flyvbjerg A., Everts M.E., Clausen T. Role of insulin-like growth factor-1 and growth hormone in growth inhibition induced by magnesium and zinc deficiencies. Br. J. Nutr. 1991;66:505–521. doi: 10.1079/BJN19910051.
    1. Beyersmann D., Haase H. Functions of zinc in signaling, proliferation and differentiation of mammalian cells. Biometals. 2001;14:331–341. doi: 10.1023/A:1012905406548.
    1. Goto M., Iwase A., Harata T., Takigawa S., Suzuki K., Manabe S., Kikkawa F. IGF1-induced AKT phosphorylation and cell proliferation are suppressed with the increase in PTEN during luteinization in human granulosa cells. Reproduction. 2009;137:835–842. doi: 10.1530/REP-08-0315.
    1. Stewart G.R., Frederickson C.J., Howell G.A., Gage F.H. Cholinergic denervation-induced increase of chelatable zinc in mossy-fiber region of the hippocampal formation. Brain Res. 1984;290:43–51. doi: 10.1016/0006-8993(84)90734-0.
    1. Freeman R.S., Burch R.L., Crowder R.J., Lomb D.J., Schoell M.C., Straub J.A., Xie L. NGF deprivation-induced gene expression: After ten years, where do we stand? Prog. Brain Res. 2004;146:111–126.
    1. Hasan W., Pedchenko T., Krizsan-Agbas D., Baum L., Smith P.G. Sympathetic neurons synthesize and secrete pro-nerve growth factor protein. J. Neurobiol. 2003;57:38–53. doi: 10.1002/neu.10250.
    1. Kristiansen M., Ham J. Programmed cell death during neuronal development: The sympathetic neuron model. Cell Death Differ. 2014;21:1025–1035. doi: 10.1038/cdd.2014.47.
    1. Mnich K., Carleton L.A., Kavanagh E.T., Doyle K.M., Samali A., Gorman A.M. Nerve growth factor-mediated inhibition of apoptosis post-caspase activation is due to removal of active caspase-3 in a lysosome-dependent manner. Cell Death Dis. 2014;5:e1202. doi: 10.1038/cddis.2014.173.
    1. Zhu D., Su Y., Zheng Y., Fu B., Tang L., Qin Y.X. Zinc regulates vascular endothelial cell activity through zinc-sensing receptor ZnR/GPR39. Am. J. Physiol. Cell Physiol. 2018;314:C404–C414. doi: 10.1152/ajpcell.00279.2017.
    1. Sunuwar L., Gilad D., Hershfinkel M. The zinc sensing receptor, ZnR/GPR39, in health and disease. Front. Biosci. (Landmark Ed.) 2017;22:1469–1492.
    1. Reid C.A., Hildebrand M.S., Mullen S.A., Hildebrand J.M., Berkovic S.F., Petrou S. Synaptic Zn(2)(+) and febrile seizure susceptibility. Br. J. Pharmacol. 2017;174:119–125. doi: 10.1111/bph.13658.
    1. Elsas S.M., Hazany S., Gregory W.L., Mody I. Hippocampal zinc infusion delays the development of afterdischarges and seizures in a kindling model of epilepsy. Epilepsia. 2009;50:870–879. doi: 10.1111/j.1528-1167.2008.01913.x.
    1. Asraf H., Salomon S., Nevo A., Sekler I., Mayer D., Hershfinkel M. The ZnR/GPR39 interacts with the CaSR to enhance signaling in prostate and salivary epithelia. J. Cell Physiol. 2014;229:868–877. doi: 10.1002/jcp.24514.
    1. Cohen L., Asraf H., Sekler I., Hershfinkel M. Extracellular pH regulates zinc signaling via an Asp residue of the zinc-sensing receptor (ZnR/GPR39) J. Biol. Chem. 2012;287:33339–33350. doi: 10.1074/jbc.M112.372441.
    1. Ganay T., Asraf H., Aizenman E., Bogdanovic M., Sekler I., Hershfinkel M. Regulation of neuronal pH by the metabotropic Zn(2+)-sensing Gq-coupled receptor, mZnR/GPR39. J. Neurochem. 2015;135:897–907. doi: 10.1111/jnc.13367.
    1. Hershfinkel M. The Zinc Sensing Receptor, ZnR/GPR39, in Health and Disease. Int. J. Mol. Sci. 2018;19:439. doi: 10.3390/ijms19020439.
    1. Hershfinkel M., Silverman W.F., Sekler I. The zinc sensing receptor, a link between zinc and cell signaling. Mol. Med. 2007;13:331–336. doi: 10.2119/2006-00038.Hershfinkel.
    1. Mero M., Asraf H., Sekler I., Taylor K.M., Hershfinkel M. ZnR/GPR39 upregulation of K(+)/Cl(−)-cotransporter 3 in tamoxifen resistant breast cancer cells. Cell Calcium. 2019;81:12–20. doi: 10.1016/j.ceca.2019.05.005.
    1. Gower-Winter S.D., Corniola R.S., Morgan T.J., Jr., Levenson C.W. Zinc deficiency regulates hippocampal gene expression and impairs neuronal differentiation. Nutr. Neurosci. 2013;16:174–182. doi: 10.1179/1476830512Y.0000000043.
    1. Dvergsten C.L., Fosmire G.J., Ollerich D.A., Sandstead H.H. Alterations in the postnatal development of the cerebellar cortex due to zinc deficiency. II. Impaired maturation of Purkinje cells. Brain Res. 1984;318:11–20. doi: 10.1016/0165-3806(84)90057-9.
    1. Chang F., Lee J.T., Navolanic P.M., Steelman L.S., Shelton J.G., Blalock W.L., Franklin R.A., McCubrey J.A. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy. Leukemia. 2003;17:590–603. doi: 10.1038/sj.leu.2402824.
    1. Gartel A.L., Shchors K. Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes. Exp. Cell Res. 2003;283:17–21. doi: 10.1016/S0014-4827(02)00020-4.
    1. Ahmed N.N., Grimes H.L., Bellacosa A., Chan T.O., Tsichlis P.N. Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. Proc. Natl. Acad. Sci. USA. 1997;94:3627–3632. doi: 10.1073/pnas.94.8.3627.
    1. Diehl J.A., Cheng M., Roussel M.F., Sherr C.J. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 1998;12:3499–3511. doi: 10.1101/gad.12.22.3499.
    1. Alt J.R., Cleveland J.L., Hannink M., Diehl J.A. Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev. 2000;14:3102–3114. doi: 10.1101/gad.854900.
    1. Brennan P., Babbage J.W., Burgering B.M., Groner B., Reif K., Cantrell D.A. Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. Immunity. 1997;7:679–689. doi: 10.1016/S1074-7613(00)80388-X.
    1. Lopez-Pajares V., Kim M.M., Yuan Z.M. Phosphorylation of MDMX mediated by Akt leads to stabilization and induces 14-3-3 binding. J. Biol. Chem. 2008;283:13707–13713. doi: 10.1074/jbc.M710030200.
    1. Graef I.A., Chen F., Crabtree G.R. NFAT signaling in vertebrate development. Curr. Opin. Genet. Dev. 2001;11:505–512. doi: 10.1016/S0959-437X(00)00225-2.
    1. Mattson M.P., Meffert M.K. Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ. 2006;13:852–860. doi: 10.1038/sj.cdd.4401837.
    1. Albensi B.C., Mattson M.P. Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity. Synapse. 2000;35:151–159. doi: 10.1002/(SICI)1098-2396(200002)35:2<151::AID-SYN8>;2-P.
    1. Mattson M.P., Culmsee C., Yu Z., Camandola S. Roles of nuclear factor kappaB in neuronal survival and plasticity. J. Neurochem. 2000;74:443–456. doi: 10.1046/j.1471-4159.2000.740443.x.
    1. Gutierrez H., Hale V.A., Dolcet X., Davies A. NF-kappaB signalling regulates the growth of neural processes in the developing PNS and CNS. Development. 2005;132:1713–1726. doi: 10.1242/dev.01702.
    1. Aimo L., Mackenzie G.G., Keenan A.H., Oteiza P.I. Gestational zinc deficiency affects the regulation of transcription factors AP-1, NF-kappaB and NFAT in fetal brain. J. Nutr. Biochem. 2010;21:1069–1075. doi: 10.1016/j.jnutbio.2009.09.003.
    1. Serrano-Perez M.C., Fernandez M., Neria F., Berjon-Otero M., Doncel-Perez E., Cano E., Tranque P. NFAT transcription factors regulate survival, proliferation, migration, and differentiation of neural precursor cells. Glia. 2015;63:987–1004. doi: 10.1002/glia.22797.
    1. Baldwin A.S., Jr. The NF-kappa B and I kappa B proteins: New discoveries and insights. Annu. Rev. Immunol. 1996;14:649–683. doi: 10.1146/annurev.immunol.14.1.649.
    1. Karin M. How NF-kappaB is activated: The role of the IkappaB kinase (IKK) complex. Oncogene. 1999;18:6867–6874. doi: 10.1038/sj.onc.1203219.
    1. Nuttall J.R., Supasai S., Kha J., Vaeth B.M., Mackenzie G.G., Adamo A.M., Oteiza P.I. Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway. J. Nutr. Biochem. 2015;26:1116–1123. doi: 10.1016/j.jnutbio.2015.05.007.
    1. Nuttall J.R., Oteiza P.I. Zinc and the ERK kinases in the developing brain. Neurotox. Res. 2012;21:128–141. doi: 10.1007/s12640-011-9291-6.
    1. Adamo A.M., Liu X., Mathieu P., Nuttall J.R., Supasai S., Oteiza P.I. Early Developmental Marginal Zinc Deficiency Affects Neurogenesis Decreasing Neuronal Number and Altering Neuronal Specification in the Adult Rat Brain. Front. Cell. Neurosci. 2019;13:62. doi: 10.3389/fncel.2019.00062.
    1. McAllister B.B., Dyck R.H. Zinc transporter 3 (ZnT3) and vesicular zinc in central nervous system function. Neurosci. Biobehav. Rev. 2017;80:329–350. doi: 10.1016/j.neubiorev.2017.06.006.
    1. Hancock S.M., Portbury S.D., Gunn A.P., Roberts B.R., Bush A.I., Adlard P.A. Zinc Transporter-3 Knockout Mice Demonstrate Age-Dependent Alterations in the Metalloproteome. Int. J. Mol. Sci. 2020;21:839. doi: 10.3390/ijms21030839.
    1. Choi B.Y., Hong D.K., Jeong J.H., Lee B.E., Koh J.Y., Suh S.W. Zinc transporter 3 modulates cell proliferation and neuronal differentiation in the adult hippocampus. Stem Cells. 2020;38:994–1006. doi: 10.1002/stem.3194.
    1. McAllister B.B., Thackray S.E., de la Orta B.K.G., Gosse E., Tak P., Chipak C., Rehal S., Valverde Rascon A., Dyck R.H. Effects of enriched housing on the neuronal morphology of mice that lack zinc transporter 3 (ZnT3) and vesicular zinc. Behav. Brain Res. 2020;379:112336. doi: 10.1016/j.bbr.2019.112336.
    1. Kempermann G., Brandon E.P., Gage F.H. Environmental stimulation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus. Curr. Biol. 1998;8:939–942. doi: 10.1016/S0960-9822(07)00377-6.
    1. Kempermann G., Kuhn H.G., Gage F.H. More hippocampal neurons in adult mice living in an enriched environment. Nature. 1997;386:493–495. doi: 10.1038/386493a0.
    1. Boon J. Master’s Thesis. University of Calgary; Calgary, AB, Canada: 2016. Experience-Dependent Modulation of Adult Hippocampal Neurogenesis in Female Mice.
    1. Chrusch M. Ph.D. Thesis. University of Calgary; Calgary, AB, Canada: 2015. The role of synaptic zinc in experience-dependent plasticity.
    1. McAllister B.B., Pochakom A., Fu S., Dyck R.H. Effects of social defeat stress and fluoxetine treatment on neurogenesis and behavior in mice that lack zinc transporter 3 (ZnT3) and vesicular zinc. Hippocampus. 2020;30:623–637. doi: 10.1002/hipo.23185.
    1. McAllister B.B., Kiryanova V., Dyck R.H. Behavioural outcomes of perinatal maternal fluoxetine treatment. Neuroscience. 2012;226:356–366. doi: 10.1016/j.neuroscience.2012.09.024.
    1. McAllister B.B., Wright D.K., Wortman R.C., Shultz S.R., Dyck R.H. Elimination of vesicular zinc alters the behavioural and neuroanatomical effects of social defeat stress in mice. Neurobiol. Stress. 2018;9:199–213. doi: 10.1016/j.ynstr.2018.10.003.
    1. Krishnan V., Han M.H., Graham D.L., Berton O., Renthal W., Russo S.J., Laplant Q., Graham A., Lutter M., Lagace D.C., et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404. doi: 10.1016/j.cell.2007.09.018.
    1. Gates M.A., Thomas L.B., Howard E.M., Laywell E.D., Sajin B., Faissner A., Gotz B., Silver J., Steindler D.A. Cell and molecular analysis of the developing and adult mouse subventricular zone of the cerebral hemispheres. J. Comp. Neurol. 1995;361:249–266. doi: 10.1002/cne.903610205.
    1. Bovetti S., Hsieh Y.C., Bovolin P., Perroteau I., Kazunori T., Puche A.C. Blood vessels form a scaffold for neuroblast migration in the adult olfactory bulb. J. Neurosci. 2007;27:5976–5980. doi: 10.1523/JNEUROSCI.0678-07.2007.
    1. Barkho B.Z., Munoz A.E., Li X., Li L., Cunningham L.A., Zhao X. Endogenous matrix metalloproteinase (MMP)-3 and MMP-9 promote the differentiation and migration of adult neural progenitor cells in response to chemokines. Stem Cells. 2008;26:3139–3149. doi: 10.1634/stemcells.2008-0519.
    1. Lee S.R., Kim H.Y., Rogowska J., Zhao B.Q., Bhide P., Parent J.M., Lo E.H. Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke. J. Neurosci. 2006;26:3491–3495. doi: 10.1523/JNEUROSCI.4085-05.2006.
    1. Wang L., Zhang Z.G., Zhang R.L., Gregg S.R., Hozeska-Solgot A., LeTourneau Y., Wang Y., Chopp M. Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. J. Neurosci. 2006;26:5996–6003. doi: 10.1523/JNEUROSCI.5380-05.2006.
    1. Zhao X., Drlica K. Reactive oxygen species and the bacterial response to lethal stress. Curr. Opin. Microbiol. 2014;21:1–6. doi: 10.1016/j.mib.2014.06.008.
    1. Feno S., Butera G., Vecellio Reane D., Rizzuto R., Raffaello A. Crosstalk between Calcium and ROS in Pathophysiological Conditions. Oxid. Med. Cell. Longev. 2019;2019:9324018. doi: 10.1155/2019/9324018.
    1. Lee S.R. Critical Role of Zinc as Either an Antioxidant or a Prooxidant in Cellular Systems. Oxid. Med. Cell. Longev. 2018;2018:9156285. doi: 10.1155/2018/9156285.
    1. Maghzal G.J., Krause K.H., Stocker R., Jaquet V. Detection of reactive oxygen species derived from the family of NOX NADPH oxidases. Free Radic. Biol. Med. 2012;53:1903–1918. doi: 10.1016/j.freeradbiomed.2012.09.002.
    1. Souza H.P., Liu X., Samouilov A., Kuppusamy P., Laurindo F.R., Zweier J.L. Quantitation of superoxide generation and substrate utilization by vascular NAD(P)H oxidase. Am. J. Physiol. Heart Circ. Physiol. 2002;282:H466–H474. doi: 10.1152/ajpheart.00482.2001.
    1. Lee S.H., Choi B.Y., Kho A.R., Jeong J.H., Hong D.K., Kang D.H., Kang B.S., Song H.K., Choi H.C., Suh S.W. Inhibition of NADPH Oxidase Activation by Apocynin Rescues Seizure-Induced Reduction of Adult Hippocampal Neurogenesis. Int. J. Mol. Sci. 2018;19:3087. doi: 10.3390/ijms19103087.
    1. Sidhu P., Garg M.L., Dhawan D.K. Protective effects of zinc on oxidative stress enzymes in liver of protein-deficient rats. Drug Chem. Toxicol. 2005;28:211–230. doi: 10.1081/DCT-52551.
    1. Bharti K., Pandey N., Shankhdhar D., Srivastava P.C., Shankhdhar S.C. Effect of different zinc levels on activity of superoxide dismutases & acid phosphatases and organic acid exudation on wheat genotypes. Physiol. Mol. Biol. Plants. 2014;20:41–48.
    1. Marreiro D.D., Cruz K.J., Morais J.B., Beserra J.B., Severo J.S., de Oliveira A.R. Zinc and Oxidative Stress: Current Mechanisms. Antioxidants. 2017;6:24. doi: 10.3390/antiox6020024.
    1. Pace N.J., Weerapana E. Zinc-binding cysteines: Diverse functions and structural motifs. Biomolecules. 2014;4:419–434. doi: 10.3390/biom4020419.
    1. Formigari A., Irato P., Santon A. Zinc, antioxidant systems and metallothionein in metal mediated-apoptosis: Biochemical and cytochemical aspects. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 2007;146:443–459. doi: 10.1016/j.cbpc.2007.07.010.
    1. Ruttkay-Nedecky B., Nejdl L., Gumulec J., Zitka O., Masarik M., Eckschlager T., Stiborova M., Adam V., Kizek R. The role of metallothionein in oxidative stress. Int. J. Mol. Sci. 2013;14:6044–6066. doi: 10.3390/ijms14036044.
    1. Role of zinc in enzyme regulation and protection of essential thiol groups. Nutr. Rev. 1986;44:309–311.
    1. Maret W. Oxidative metal release from metallothionein via zinc-thiol/disulfide interchange. Proc. Natl. Acad. Sci. USA. 1994;91:237–241. doi: 10.1073/pnas.91.1.237.
    1. Rickli E.E., Edsall J.T. Zinc binding and the sulfhydryl group of human carbonic anhydrase. J. Biol. Chem. 1962;237:PC258–PC260.
    1. Ziegler D.M. Role of reversible oxidation-reduction of enzyme thiols-disulfides in metabolic regulation. Annu. Rev. Biochem. 1985;54:305–329. doi: 10.1146/annurev.bi.54.070185.001513.
    1. Arrigo A.P. Gene expression and the thiol redox state. Free Radic. Biol. Med. 1999;27:936–944. doi: 10.1016/S0891-5849(99)00175-6.
    1. Dickinson D.A., Forman H.J. Cellular glutathione and thiols metabolism. Biochem. Pharmacol. 2002;64:1019–1026. doi: 10.1016/S0006-2952(02)01172-3.
    1. Aras M.A., Aizenman E. Redox regulation of intracellular zinc: Molecular signaling in the life and death of neurons. Antioxid. Redox Signal. 2011;15:2249–2263. doi: 10.1089/ars.2010.3607.
    1. Aizenman E., Loring R.H., Reynolds I.J., Rosenberg P.A. The Redox Biology of Excitotoxic Processes: The NMDA Receptor, TOPA Quinone, and the Oxidative Liberation of Intracellular Zinc. Front. Neurosci. 2020;14:778. doi: 10.3389/fnins.2020.00778.
    1. Pal S., He K., Aizenman E. Nitrosative stress and potassium channel-mediated neuronal apoptosis: Is zinc the link? Pflügers Arch. 2004;448:296–303. doi: 10.1007/s00424-004-1256-7.
    1. Tonelli C., Chio I.I.C., Tuveson D.A. Transcriptional Regulation by Nrf2. Antioxid. Redox Signal. 2018;29:1727–1745. doi: 10.1089/ars.2017.7342.
    1. Li B., Cui W., Tan Y., Luo P., Chen Q., Zhang C., Qu W., Miao L., Cai L. Zinc is essential for the transcription function of Nrf2 in human renal tubule cells in vitro and mouse kidney in vivo under the diabetic condition. J. Cell. Mol. Med. 2014;18:895–906. doi: 10.1111/jcmm.12239.
    1. Bhalla P., Chadha V.D., Dhar R., Dhawan D.K. Neuroprotective effects of zinc on antioxidant defense system in lithium treated rat brain. Indian J. Exp. Biol. 2007;45:954–958.
    1. Prasad A.S., Bao B., Beck F.W., Kucuk O., Sarkar F.H. Antioxidant effect of zinc in humans. Free Radic. Biol. Med. 2004;37:1182–1190. doi: 10.1016/j.freeradbiomed.2004.07.007.
    1. Foster M., Samman S. Zinc and regulation of inflammatory cytokines: Implications for cardiometabolic disease. Nutrients. 2012;4:676–694. doi: 10.3390/nu4070676.
    1. Beck F.W., Prasad A.S., Kaplan J., Fitzgerald J.T., Brewer G.J. Changes in cytokine production and T cell subpopulations in experimentally induced zinc-deficient humans. Am. J. Physiol. 1997;272 Pt 1:E1002–E1007. doi: 10.1152/ajpendo.1997.272.6.E1002.
    1. Prasad A.S., Meftah S., Abdallah J., Kaplan J., Brewer G.J., Bach J.F., Dardenne M. Serum thymulin in human zinc deficiency. J. Clin. Investig. 1988;82:1202–1210. doi: 10.1172/JCI113717.
    1. Honscheid A., Rink L., Haase H. T-lymphocytes: A target for stimulatory and inhibitory effects of zinc ions. Endocr. Metab. Immune Disord. Drug Targets. 2009;9:132–144. doi: 10.2174/187153009788452390.
    1. Prasad A.S. Zinc: Role in immunity, oxidative stress and chronic inflammation. Curr. Opin. Clin. Nutr. Metab. Care. 2009;12:646–652. doi: 10.1097/MCO.0b013e3283312956.
    1. Aloisi F. Immune function of microglia. Glia. 2001;36:165–179. doi: 10.1002/glia.1106.
    1. Lenz K.M., Nelson L.H. Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function. Front. Immunol. 2018;9:698. doi: 10.3389/fimmu.2018.00698.
    1. Kauppinen T.M., Higashi Y., Suh S.W., Escartin C., Nagasawa K., Swanson R.A. Zinc triggers microglial activation. J. Neurosci. 2008;28:5827–5835. doi: 10.1523/JNEUROSCI.1236-08.2008.
    1. Frederickson C.J. Neurobiology of zinc and zinc-containing neurons. Int. Rev. Neurobiol. 1989;31:145–238.
    1. Blakemore L.J., Trombley P.Q. Zinc as a Neuromodulator in the Central Nervous System with a Focus on the Olfactory Bulb. Front. Cell. Neurosci. 2017;11:297. doi: 10.3389/fncel.2017.00297.
    1. Cole T.B., Wenzel H.J., Kafer K.E., Schwartzkroin P.A., Palmiter R.D. Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. Proc. Natl. Acad. Sci. USA. 1999;96:1716–1721. doi: 10.1073/pnas.96.4.1716.
    1. Qian J., Noebels J.L. Exocytosis of vesicular zinc reveals persistent depression of neurotransmitter release during metabotropic glutamate receptor long-term depression at the hippocampal CA3-CA1 synapse. J. Neurosci. 2006;26:6089–6095. doi: 10.1523/JNEUROSCI.0475-06.2006.
    1. Ketterman J.K., Li Y.V. Presynaptic evidence for zinc release at the mossy fiber synapse of rat hippocampus. J. Neurosci. Res. 2008;86:422–434. doi: 10.1002/jnr.21488.
    1. Li Y., Hough C.J., Suh S.W., Sarvey J.M., Frederickson C.J. Rapid translocation of Zn(2+) from presynaptic terminals into postsynaptic hippocampal neurons after physiological stimulation. J. Neurophysiol. 2001;86:2597–2604. doi: 10.1152/jn.2001.86.5.2597.
    1. Smart T.G., Xie X., Krishek B.J. Modulation of inhibitory and excitatory amino acid receptor ion channels by zinc. Prog. Neurobiol. 1994;42:393–441. doi: 10.1016/0301-0082(94)90082-5.
    1. Bitanihirwe B.K., Cunningham M.G. Zinc: The brain’s dark horse. Synapse. 2009;63:1029–1049. doi: 10.1002/syn.20683.
    1. Nakashima A.S., Dyck R.H. Zinc and cortical plasticity. Brain Res. Rev. 2009;59:347–373. doi: 10.1016/j.brainresrev.2008.10.003.
    1. Mayer M.L., Vyklicky L., Jr. The action of zinc on synaptic transmission and neuronal excitability in cultures of mouse hippocampus. J. Physiol. 1989;415:351–365. doi: 10.1113/jphysiol.1989.sp017725.
    1. Frederickson C.J., Koh J.Y., Bush A.I. The neurobiology of zinc in health and disease. Nat. Rev. Neurosci. 2005;6:449–462. doi: 10.1038/nrn1671.
    1. Malenka R.C., Bear M.F. LTP and LTD: An embarrassment of riches. Neuron. 2004;44:5–21. doi: 10.1016/j.neuron.2004.09.012.
    1. Vogler N.W., Betti V.M., Goldberg J.M., Tzounopoulos T. Mechanisms Underlying Long-Term Synaptic Zinc Plasticity at Mouse Dorsal Cochlear Nucleus Glutamatergic Synapses. J. Neurosci. 2020;40:4981–4996. doi: 10.1523/JNEUROSCI.0175-20.2020.
    1. Frederickson C.J., Hernandez M.D., Goik S.A., Morton J.D., McGinty J.F. Loss of zinc staining from hippocampal mossy fibers during kainic acid induced seizures: A histofluorescence study. Brain Res. 1988;446:383–386. doi: 10.1016/0006-8993(88)90899-2.
    1. Suh S.W., Thompson R.B., Frederickson C.J. Loss of vesicular zinc and appearance of perikaryal zinc after seizures induced by pilocarpine. Neuroreport. 2001;12:1523–1525. doi: 10.1097/00001756-200105250-00044.
    1. Noh K.M., Koh J.Y. Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes. J. Neurosci. 2000;20:RC111. doi: 10.1523/JNEUROSCI.20-23-j0001.2000.
    1. Li M.S., Adesina S.E., Ellis C.L., Gooch J.L., Hoover R.S., Williams C.R. NADPH oxidase-2 mediates zinc deficiency-induced oxidative stress and kidney damage. Am. J. Physiol. Cell Physiol. 2017;312:C47–C55. doi: 10.1152/ajpcell.00208.2016.
    1. Chen F., Yu Y., Haigh S., Johnson J., Lucas R., Stepp D.W., Fulton D.J. Regulation of NADPH oxidase 5 by protein kinase C isoforms. PLoS ONE. 2014;9:e88405. doi: 10.1371/journal.pone.0088405.
    1. Ma M.W., Wang J., Zhang Q., Wang R., Dhandapani K.M., Vadlamudi R.K., Brann D.W. NADPH oxidase in brain injury and neurodegenerative disorders. Mol. Neurodegener. 2017;12:7. doi: 10.1186/s13024-017-0150-7.
    1. El-Benna J., Dang P.M., Gougerot-Pocidalo M.A., Marie J.C., Braut-Boucher F. p47phox, the phagocyte NADPH oxidase/NOX2 organizer: Structure, phosphorylation and implication in diseases. Exp. Mol. Med. 2009;41:217–225. doi: 10.3858/emm.2009.41.4.058.
    1. Nguyen G.T., Green E.R., Mecsas J. Neutrophils to the ROScue: Mechanisms of NADPH Oxidase Activation and Bacterial Resistance. Front. Cell. Infect Microbiol. 2017;7:373. doi: 10.3389/fcimb.2017.00373.
    1. Xiong Y., Mahmood A., Chopp M. Animal models of traumatic brain injury. Nat. Rev. Neurosci. 2013;14:128–142. doi: 10.1038/nrn3407.
    1. Fernandez-Gajardo R., Matamala J.M., Carrasco R., Gutierrez R., Melo R., Rodrigo R. Novel therapeutic strategies for traumatic brain injury: Acute antioxidant reinforcement. CNS Drugs. 2014;28:229–248. doi: 10.1007/s40263-013-0138-y.
    1. Isaev N.K., Stelmashook E.V., Genrikhs E.E., Korshunova G.A., Sumbatyan N.V., Kapkaeva M.R., Skulachev V.P. Neuroprotective properties of mitochondria-targeted antioxidants of the SkQ-type. Rev. Neurosci. 2016;27:849–855. doi: 10.1515/revneuro-2016-0036.
    1. Arundine M., Tymianski M. Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell. Mol. Life Sci. 2004;61:657–668. doi: 10.1007/s00018-003-3319-x.
    1. Hellmich H.L., Eidson K.A., Capra B.A., Garcia J.M., Boone D.R., Hawkins B.E., Uchida T., Dewitt D.S., Prough D.S. Injured Fluoro-Jade-positive hippocampal neurons contain high levels of zinc after traumatic brain injury. Brain Res. 2007;1127:119–126. doi: 10.1016/j.brainres.2006.09.094.
    1. Suh S.W., Chen J.W., Motamedi M., Bell B., Listiak K., Pons N.F., Danscher G., Frederickson C.J. Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury. Brain Res. 2000;852:268–273. doi: 10.1016/S0006-8993(99)02095-8.
    1. Suh S.W., Listiack K., Bell B., Chen J., Motamedi M., Silva D., Danscher G., Whetsell W., Thompson R., Frederickson C. Detection of pathological zinc accumulation in neurons: Methods for autopsy, biopsy, and cultured tissue. J. Histochem. Cytochem. 1999;47:969–972. doi: 10.1177/002215549904700715.
    1. Suh S.W., Frederickson C.J., Danscher G. Neurotoxic zinc translocation into hippocampal neurons is inhibited by hypothermia and is aggravated by hyperthermia after traumatic brain injury in rats. J. Cereb. Blood Flow Metab. 2006;26:161–169. doi: 10.1038/sj.jcbfm.9600176.
    1. Choi B.Y., Kim J.H., Kim H.J., Lee B.E., Kim I.Y., Sohn M., Suh S.W. Zinc chelation reduces traumatic brain injury-induced neurogenesis in the subgranular zone of the hippocampal dentate gyrus. J. Trace Elem. Med. Biol. 2014;28:474–481. doi: 10.1016/j.jtemb.2014.07.007.
    1. Zhao L., Liu Q., Ma S., Zhang Y., Liang P. TPEN Attenuates Neural Autophagy Induced by Synaptically-released Zinc Translocation and Improves Histological Outcomes after Traumatic Brain Injury in Rats. Ann. Clin. Lab. Sci. 2018;48:446–452.
    1. Leuner B., Gould E., Shors T.J. Is there a link between adult neurogenesis and learning? Hippocampus. 2006;16:216–224. doi: 10.1002/hipo.20153.
    1. Dominguez M.I., Blasco-Ibanez J.M., Crespo C., Marques-Mari A.I., Martinez-Guijarro F.J. Zinc chelation during non-lesioning overexcitation results in neuronal death in the mouse hippocampus. Neuroscience. 2003;116:791–806. doi: 10.1016/S0306-4522(02)00731-5.
    1. Hellmich H.L., Eidson K., Cowart J., Crookshanks J., Boone D.K., Shah S., Uchida T., DeWitt D.S., Prough D.S. Chelation of neurotoxic zinc levels does not improve neurobehavioral outcome after traumatic brain injury. Neurosci. Lett. 2008;440:155–159. doi: 10.1016/j.neulet.2008.05.068.
    1. Doering P., Stoltenberg M., Penkowa M., Rungby J., Larsen A., Danscher G. Chemical blocking of zinc ions in CNS increases neuronal damage following traumatic brain injury (TBI) in mice. PLoS ONE. 2010;5:e10131. doi: 10.1371/journal.pone.0010131.
    1. Li Y., Hawkins B.E., DeWitt D.S., Prough D.S., Maret W. The relationship between transient zinc ion fluctuations and redox signaling in the pathways of secondary cellular injury: Relevance to traumatic brain injury. Brain Res. 2010;1330:131–141. doi: 10.1016/j.brainres.2010.03.034.
    1. Levenson C.W. Zinc and Traumatic Brain Injury: From Chelation to Supplementation. Med. Sci. 2020;8:36. doi: 10.3390/medsci8030036.
    1. Scrimgeour A.G., Carrigan C.T., Condlin M.L., Urso M.L., van den Berg R.M., van Helden H.P.M., Montain S.J., Joosen M.J.A. Dietary Zinc Modulates Matrix Metalloproteinases in Traumatic Brain Injury. J. Neurotrauma. 2018;35:2495–2506. doi: 10.1089/neu.2017.5614.
    1. Abdul-Muneer P.M., Pfister B.J., Haorah J., Chandra N. Role of Matrix Metalloproteinases in the Pathogenesis of Traumatic Brain Injury. Mol. Neurobiol. 2016;53:6106–6123. doi: 10.1007/s12035-015-9520-8.
    1. Cope E.C., Morris D.R., Scrimgeour A.G., Levenson C.W. Use of zinc as a treatment for traumatic brain injury in the rat: Effects on cognitive and behavioral outcomes. Neurorehabil. Neural Repair. 2012;26:907–913. doi: 10.1177/1545968311435337.
    1. Khazdouz M., Mazidi M., Ehsaei M.R., Ferns G., Kengne A.P., Norouzy A.R. Impact of Zinc Supplementation on the Clinical Outcomes of Patients with Severe Head Trauma: A Double-Blind Randomized Clinical Trial. J. Diet Suppl. 2018;15:1–10. doi: 10.1080/19390211.2017.1304486.
    1. Rosenthal J.M., Amiel S.A., Yaguez L., Bullmore E., Hopkins D., Evans M., Pernet A., Reid H., Giampietro V., Andrew C.M., et al. The effect of acute hypoglycemia on brain function and activation: A functional magnetic resonance imaging study. Diabetes. 2001;50:1618–1626. doi: 10.2337/diabetes.50.7.1618.
    1. Auer R.N. Hypoglycemic brain damage. Metab. Brain Dis. 2004;19:169–175. doi: 10.1023/B:MEBR.0000043967.78763.5b.
    1. Cryer P.E. Hypoglycemia, functional brain failure, and brain death. J. Clin. Investig. 2007;117:868–870. doi: 10.1172/JCI31669.
    1. Kumar P., Lal N.R., Mondal A.K., Mondal A., Gharami R.C., Maiti A. Zinc and skin: A brief summary. Dermatol. Online J. 2012;18:1.
    1. Suh S.W., Garnier P., Aoyama K., Chen Y., Swanson R.A. Zinc release contributes to hypoglycemia-induced neuronal death. Neurobiol. Dis. 2004;16:538–545.
    1. Ali A.A.E., Timinszky G., Arribas-Bosacoma R., Kozlowski M., Hassa P.O., Hassler M., Ladurner A.G., Pearl L.H., Oliver A.W. The zinc-finger domains of PARP1 cooperate to recognize DNA strand breaks. Nat. Struct. Mol. Biol. 2012;19:685–692. doi: 10.1038/nsmb.2335.
    1. Langelier M.F., Ruhl D.D., Planck J.L., Kraus W.L., Pascal J.M. The Zn3 domain of human poly(ADP-ribose) polymerase-1 (PARP-1) functions in both DNA-dependent poly(ADP-ribose) synthesis activity and chromatin compaction. J. Biol. Chem. 2010;285:18877–18887. doi: 10.1074/jbc.M110.105668.
    1. Suh S.W., Fan Y., Hong S.M., Liu Z., Matsumori Y., Weinstein P.R., Swanson R.A., Liu J. Hypoglycemia induces transient neurogenesis and subsequent progenitor cell loss in the rat hippocampus. Diabetes. 2005;54:500–509. doi: 10.2337/diabetes.54.2.500.
    1. Suh S.W., Gum E.T., Hamby A.M., Chan P.H., Swanson R.A. Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase. J. Clin. Investig. 2007;117:910–918. doi: 10.1172/JCI30077.
    1. Kho A.R., Choi B.Y., Kim J.H., Lee S.H., Hong D.K., Lee S.H., Jeong J.H., Sohn M., Suh S.W. Prevention of hypoglycemia-induced hippocampal neuronal death by N-acetyl-L-cysteine (NAC) Amino Acids. 2017;49:367–378. doi: 10.1007/s00726-016-2370-5.
    1. Yamasaki Y., Suzuki T., Yamaya H., Matsuura N., Onodera H., Kogure K. Possible involvement of interleukin-1 in ischemic brain edema formation. Neurosci. Lett. 1992;142:45–47. doi: 10.1016/0304-3940(92)90616-F.
    1. Johansen F.F., Tonder N., Berg M., Zimmer J., Diemer N.H. Hypothermia protects somatostatinergic neurons in rat dentate hilus from zinc accumulation and cell death after cerebral ischemia. Mol. Chem. Neuropathol. 1993;18:161–172. doi: 10.1007/BF03160030.
    1. Tonder N., Johansen F.F., Frederickson C.J., Zimmer J., Diemer N.H. Possible role of zinc in the selective degeneration of dentate hilar neurons after cerebral ischemia in the adult rat. Neurosci. Lett. 1990;109:247–252. doi: 10.1016/0304-3940(90)90002-Q.
    1. Kitamura Y., Iida Y., Abe J., Mifune M., Kasuya F., Ohta M., Igarashi K., Saito Y., Saji H. Release of vesicular Zn2+ in a rat transient middle cerebral artery occlusion model. Brain Res. Bull. 2006;69:622–625. doi: 10.1016/j.brainresbull.2006.03.004.
    1. Yang D.Y., Lee J.B., Lin M.C., Huang Y.L., Liu H.W., Liang Y.J., Cheng F.C. The determination of brain magnesium and zinc levels by a dual-probe microdialysis and graphite furnace atomic absorption spectrometry. J. Am. Coll. Nutr. 2004;23:552S–555S. doi: 10.1080/07315724.2004.10719402.
    1. Zhao Y., Pan R., Li S., Luo Y., Yan F., Yin J., Qi Z., Yan Y., Ji X., Liu K.J. Chelating intracellularly accumulated zinc decreased ischemic brain injury through reducing neuronal apoptotic death. Stroke. 2014;45:1139–1147. doi: 10.1161/STROKEAHA.113.004296.
    1. Lee J.M., Grabb M.C., Zipfel G.J., Choi D.W. Brain tissue responses to ischemia. J. Clin. Investig. 2000;106:723–731. doi: 10.1172/JCI11003.
    1. Pulsinelli W.A. Selective neuronal vulnerability: Morphological and molecular characteristics. Prog. Brain Res. 1985;63:29–37.
    1. Mellone M., Pelucchi S., Alberti L., Genazzani A.A., Di Luca M., Gardoni F. Zinc transporter-1: A novel NMDA receptor-binding protein at the postsynaptic density. J. Neurochem. 2015;132:159–168. doi: 10.1111/jnc.12968.
    1. Krall R.F., Moutal A., Phillips M.B., Asraf H., Johnson J.W., Khanna R., Hershfinkel M., Aizenman E., Tzounopoulos T. Synaptic zinc inhibition of NMDA receptors depends on the association of GluN2A with the zinc transporter ZnT1. Sci. Adv. 2020;6:eabb1515. doi: 10.1126/sciadv.abb1515.
    1. Bennett M.V., Pellegrini-Giampietro D.E., Gorter J.A., Aronica E., Connor J.A., Zukin R.S. The GluR2 hypothesis: Ca(++)-permeable AMPA receptors in delayed neurodegeneration. Cold Spring Harb. Symp. Quant. Biol. 1996;61:373–384.
    1. Sensi S.L., Jeng J.M. Rethinking the excitotoxic ionic milieu: The emerging role of Zn(2+) in ischemic neuronal injury. Curr. Mol. Med. 2004;4:87–111. doi: 10.2174/1566524043479211.
    1. Pellegrini-Giampietro D.E., Gorter J.A., Bennett M.V., Zukin R.S. The GluR2 (GluR-B) hypothesis: Ca(2+)-permeable AMPA receptors in neurological disorders. Trends Neurosci. 1997;20:464–470. doi: 10.1016/S0166-2236(97)01100-4.
    1. Calderone A., Jover T., Mashiko T., Noh K.M., Tanaka H., Bennett M.V., Zukin R.S. Late calcium EDTA rescues hippocampal CA1 neurons from global ischemia-induced death. J. Neurosci. 2004;24:9903–9913. doi: 10.1523/JNEUROSCI.1713-04.2004.
    1. Calderone A., Jover T., Noh K.M., Tanaka H., Yokota H., Lin Y., Grooms S.Y., Regis R., Bennett M.V., Zukin R.S. Ischemic insults derepress the gene silencer REST in neurons destined to die. J. Neurosci. 2003;23:2112–2121. doi: 10.1523/JNEUROSCI.23-06-02112.2003.
    1. Shabanzadeh A.P., Shuaib A., Yang T., Salam A., Wang C.X. Effect of zinc in ischemic brain injury in an embolic model of stroke in rats. Neurosci. Lett. 2004;356:69–71. doi: 10.1016/j.neulet.2003.10.073.
    1. Ji S.G., Medvedeva Y.V., Wang H.L., Yin H.Z., Weiss J.H. Mitochondrial Zn(2+) Accumulation: A Potential Trigger of Hippocampal Ischemic Injury. Neuroscientist. 2019;25:126–138. doi: 10.1177/1073858418772548.
    1. Zhao Y., Yan F., Yin J., Pan R., Shi W., Qi Z., Fang Y., Huang Y., Li S., Luo Y., et al. Synergistic Interaction Between Zinc and Reactive Oxygen Species Amplifies Ischemic Brain Injury in Rats. Stroke. 2018;49:2200–2210. doi: 10.1161/STROKEAHA.118.021179.
    1. Wortmann M. Dementia: A global health priority—Highlights from an ADI and World Health Organization report. Alzheimers Res. Ther. 2012;4:40. doi: 10.1186/alzrt143.
    1. Lovell M.A. A potential role for alterations of zinc and zinc transport proteins in the progression of Alzheimer’s disease. J. Alzheimer’s Dis. 2009;16:471–483. doi: 10.3233/JAD-2009-0992.
    1. Bush A.I., Pettingell W.H., Multhaup G., d Paradis M., Vonsattel J.P., Gusella J.F., Beyreuther K., Masters C.L., Tanzi R.E. Rapid induction of Alzheimer A beta amyloid formation by zinc. Science. 1994;265:1464–1467. doi: 10.1126/science.8073293.
    1. Zhang L.H., Wang X., Stoltenberg M., Danscher G., Huang L., Wang Z.Y. Abundant expression of zinc transporters in the amyloid plaques of Alzheimer’s disease brain. Brain Res. Bull. 2008;77:55–60. doi: 10.1016/j.brainresbull.2008.03.014.
    1. Xu Y., Xiao G., Liu L., Lang M. Zinc transporters in Alzheimer’s disease. Mol. Brain. 2019;12:106. doi: 10.1186/s13041-019-0528-2.
    1. Pradier L., Carpentier N., Delalonde L., Clavel N., Bock M.D., Buee L., Mercken L., Tocque B., Czech C. Mapping the APP/presenilin (PS) binding domains: The hydrophilic N-terminus of PS2 is sufficient for interaction with APP and can displace APP/PS1 interaction. Neurobiol. Dis. 1999;6:43–55. doi: 10.1006/nbdi.1998.0212.
    1. Lyubartseva G., Smith J.L., Markesbery W.R., Lovell M.A. Alterations of zinc transporter proteins ZnT-1, ZnT-4 and ZnT-6 in preclinical Alzheimer’s disease brain. Brain Pathol. 2010;20:343–350. doi: 10.1111/j.1750-3639.2009.00283.x.
    1. Zhang L.H., Wang X., Zheng Z.H., Ren H., Stoltenberg M., Danscher G., Huang L., Rong M., Wang Z.Y. Altered expression and distribution of zinc transporters in APP/PS1 transgenic mouse brain. Neurobiol. Aging. 2010;31:74–87. doi: 10.1016/j.neurobiolaging.2008.02.018.
    1. Adlard P.A., Parncutt J.M., Finkelstein D.I., Bush A.I. Cognitive loss in zinc transporter-3 knock-out mice: A phenocopy for the synaptic and memory deficits of Alzheimer’s disease? J. Neurosci. 2010;30:1631–1636. doi: 10.1523/JNEUROSCI.5255-09.2010.
    1. Koh J.Y., Choi D.W. Zinc toxicity on cultured cortical neurons: Involvement of N-methyl-D-aspartate receptors. Neuroscience. 1994;60:1049–1057. doi: 10.1016/0306-4522(94)90282-8.
    1. Ledo J.H., Azevedo E.P., Clarke J.R., Ribeiro F.C., Figueiredo C.P., Foguel D., De Felice F.G., Ferreira S.T. Amyloid-beta oligomers link depressive-like behavior and cognitive deficits in mice. Mol. Psychiatry. 2013;18:1053–1054. doi: 10.1038/mp.2012.168.
    1. Takeda A., Tamano H., Tempaku M., Sasaki M., Uematsu C., Sato S., Kanazawa H., Datki Z.L., Adlard P.A., Bush A.I. Extracellular Zn(2+) Is Essential for Amyloid beta1-42-Induced Cognitive Decline in the Normal Brain and Its Rescue. J. Neurosci. 2017;37:7253–7262. doi: 10.1523/JNEUROSCI.0954-17.2017.
    1. Abramovitch-Dahan C., Asraf H., Bogdanovic M., Sekler I., Bush A.I., Hershfinkel M. Amyloid beta attenuates metabotropic zinc sensing receptor, mZnR/GPR39, dependent Ca(2+), ERK1/2 and Clusterin signaling in neurons. J. Neurochem. 2016;139:221–233. doi: 10.1111/jnc.13760.
    1. Nyborg J.K., Peersen O.B. That zincing feeling: The effects of EDTA on the behaviour of zinc-binding transcriptional regulators. Biochem. J. 2004;381 Pt 3:e3–e4. doi: 10.1042/BJ20041096.
    1. Maketon W., Zenner C.Z., Ogden K.L. Removal efficiency and binding mechanisms of copper and copper-EDTA complexes using polyethyleneimine. Environ. Sci. Technol. 2008;42:2124–2129. doi: 10.1021/es702420h.
    1. Radford R.J., Lippard S.J. Chelators for investigating zinc metalloneurochemistry. Curr. Opin. Chem. Biol. 2013;17:129–136. doi: 10.1016/j.cbpa.2013.01.009.
    1. Heyland D.K., Jones N., Cvijanovich N.Z., Wong H. Zinc supplementation in critically ill patients: A key pharmaconutrient? JPEN J. Parenter. Enter. Nutr. 2008;32:509–519. doi: 10.1177/0148607108322402.
    1. Cope E.C., Morris D.R., Levenson C.W. Improving treatments and outcomes: An emerging role for zinc in traumatic brain injury. Nutr. Rev. 2012;70:410–413. doi: 10.1111/j.1753-4887.2012.00486.x.
    1. Adamo A.M., Oteiza P.I. Zinc deficiency and neurodevelopment: The case of neurons. Biofactors. 2010;36:117–124. doi: 10.1002/biof.91.
    1. Young B., Ott L., Kasarskis E., Rapp R., Moles K., Dempsey R.J., Tibbs P.A., Kryscio R., McClain C. Zinc supplementation is associated with improved neurologic recovery rate and visceral protein levels of patients with severe closed head injury. J. Neurotrauma. 1996;13:25–34. doi: 10.1089/neu.1996.13.25.
    1. Hoffman H.N., 2nd, Phyliky R.L., Fleming C.R. Zinc-induced copper deficiency. Gastroenterology. 1988;94:508–512. doi: 10.1016/0016-5085(88)90445-3.
    1. Botash A.S., Nasca J., Dubowy R., Weinberger H.L., Oliphant M. Zinc-induced copper deficiency in an infant. Am. J. Dis. Child. 1992;146:709–711. doi: 10.1001/archpedi.1992.02160180069019.
    1. Willis M.S., Monaghan S.A., Miller M.L., McKenna R.W., Perkins W.D., Levinson B.S., Bhushan V., Kroft S.H. Zinc-induced copper deficiency: A report of three cases initially recognized on bone marrow examination. Am. J. Clin. Pathol. 2005;123:125–131. doi: 10.1309/V6GVYW2QTYD5C5PJ.

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