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Intracellular Zinc Liberation: A Trigger for Oxidative Stress-Induced Toxicity to Neurons and Neuroglia

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Metal Ion in Stroke

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

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Abstract

Oxidative and nitrosative stress is a common feature in the initiation and propagation of many neurological and neurodegenerative diseases. Although multiple and distinct signaling cascades are involved in the toxicity of various neural cells, increasing evidence suggests that intracellular zinc liberation is an early initiator and trigger for the subsequent cell death pathways. Activation of protein kinase c (PKC) and mitogen-activated protein kinase (MAPK) by intracellularly released zinc not only contributes to the toxicity of neurons, but also to the toxicity of neuroglia, including oligodendrocytes, astrocytes, and microglia. Therefore, maintenance of the intracellular zinc homeostasis and targeting the downstream signaling molecules may provide therapeutic strategies for the treatment of neurological disorders, in which multiple neural cells may be involved and injured under stressful and pathological conditions.

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References

  • Aizenman E, McCord MC, Saadi RA, Hartnett KA, He K (2010) Complex role of zinc in methamphetamine toxicity in vitro. Neuroscience 171:31–39

    Article  PubMed  CAS  Google Scholar 

  • Aizenman E, Stout AK, Hartnett KA, Dineley KE, McLaughlin B, Reynolds IJ (2000) Induction of neuronal apoptosis by thiol oxidation: putative role of intracellular zinc release. J Neurochem 75:1878–1888

    Article  PubMed  CAS  Google Scholar 

  • Aras MA, Aizenman E (2011) Redox regulation of intracellular zinc: molecular signaling in the life and death of neurons. Antioxid Redox Signal 15:2249–2263

    Article  PubMed  CAS  Google Scholar 

  • Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A 87:1620–1624

    Article  PubMed  CAS  Google Scholar 

  • Besser L, Chorin E, Sekler I, Silverman WF, Atkin S, Russell JT, Hershfinkel M (2009) Synaptically released zinc triggers metabotropic signaling via a zinc-sensing receptor in the hippocampus. J Neurosci 29:2890–2901

    Article  PubMed  CAS  Google Scholar 

  • Bishop GM, Dringen R, Robinson SR (2007) Zinc stimulates the production of toxic reactive oxygen species (ROS) and inhibits glutathione reductase in astrocytes. Free Radic Biol Med 42:1222–1230

    Article  PubMed  CAS  Google Scholar 

  • Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69

    Article  PubMed  CAS  Google Scholar 

  • Bonanni L, Chachar M, Jover-Mengual T, Li H, Jones A, Yokota H, Ofengeim D, Flannery RJ, Miyawaki T, Cho CH, Polster BM, Pypaert M, Hardwick JM, Sensi SL, Zukin RS, Jonas EA (2006) Zinc-dependent multi-conductance channel activity in mitochondria isolated from ischemic brain. J Neurosci 26:6851–6862

    Article  PubMed  CAS  Google Scholar 

  • Bossy-Wetzel E, Talantova MV, Lee WD, Scholzke MN, Harrop A, Mathews E, Gotz T, Han J, Ellisman MH, Perkins GA, Lipton SA (2004) Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels. Neuron 41:351–365

    Article  PubMed  CAS  Google Scholar 

  • Chang CY, Ou YC, Kao TK, Pan HC, Lin SY, Liao SL, Wang WY, Lu HC, Chen CJ (2010) Glucose exacerbates zinc-induced astrocyte death. Toxicol Lett 199:102–109

    Article  PubMed  CAS  Google Scholar 

  • Cheng EH, Kirsch DG, Clem RJ, Ravi R, Kastan MB, Bedi A, Ueno K, Hardwick JM (1997) Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 278:1966–1968

    Article  PubMed  CAS  Google Scholar 

  • Chu CT, Levinthal DJ, Kulich SM, Chalovich EM, DeFranco DB (2004) Oxidative neuronal injury. The dark side of ERK1/2. Eur J Biochem 271:2060–2066

    Article  PubMed  CAS  Google Scholar 

  • Chung RS, Penkowa M, Dittmann J, King CE, Bartlett C, Asmussen JW, Hidalgo J, Carrasco J, Leung YK, Walker AK, Fung SJ, Dunlop SA, Fitzgerald M, Beazley LD, Chuah MI, Vickers JC, West AK (2008) Redefining the role of metallothionein within the injured brain: extracellular metallothioneins play an important role in the astrocyte-neuron response to injury. J Biol Chem 283:15349–15358

    Article  PubMed  CAS  Google Scholar 

  • Dineley KE, Scanlon JM, Kress GJ, Stout AK, Reynolds IJ (2000) Astrocytes are more resistant than neurons to the cytotoxic effects of increased [Zn(2+)](i). Neurobiol Dis 7:310–320

    Article  PubMed  CAS  Google Scholar 

  • Doering P, Danscher G, Larsen A, Bruhn M, Sondergaard C, Stoltenberg M (2007) Changes in the vesicular zinc pattern following traumatic brain injury. Neuroscience 150:93–103

    Article  PubMed  CAS  Google Scholar 

  • Doering P, Stoltenberg M, Penkowa M, Rungby J, Larsen A, Danscher G (2010) Chemical blocking of zinc ions in CNS increases neuronal damage following traumatic brain injury (TBI) in mice. PLoS One 5:e10131

    Article  PubMed  Google Scholar 

  • Du S, McLaughlin B, Pal S, Aizenman E (2002) In vitro neurotoxicity of methylisothiazolinone, a commonly used industrial and household biocide, proceeds via a zinc and extracellular ­signal-regulated kinase mitogen-activated protein kinase-dependent pathway. J Neurosci 22:7408–7416

    PubMed  CAS  Google Scholar 

  • Frederickson CJ (1989) Neurobiology of zinc and zinc-containing neurons. Int Rev Neurobiol 31:145–238

    Article  PubMed  CAS  Google Scholar 

  • Frederickson CJ, Koh JY, Bush AI (2005) The neurobiology of zinc in health and disease. Nat Rev Neurosci 6:449–462

    Article  PubMed  CAS  Google Scholar 

  • Fukada T, Yamasaki S, Nishida K, Murakami M, Hirano T (2011) Zinc homeostasis and signaling in health and diseases: zinc signaling. J Biol Inorg Chem 16(7):1123–1124

    Article  PubMed  CAS  Google Scholar 

  • Giorgi C, Agnoletto C, Baldini C, Bononi A, Bonora M, Marchi S, Missiroli S, Patergnani S, Poletti F, Rimessi A, Zavan B, Pinton P (2010) Redox control of protein kinase C: cell- and disease-specific aspects. Antioxid Redox Signal 13:1051–1085

    Article  PubMed  CAS  Google Scholar 

  • Gopalakrishna R, Jaken S (2000) Protein kinase C signaling and oxidative stress. Free Radic Biol Med 28:1349–1361

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto K, Hayashi Y, Watabe K, Inuzuka T, Hozumi I (2011) Metallothionein-III prevents neuronal death and prolongs life span in amyotrophic lateral sclerosis model mice. Neuroscience 189:293–298

    Article  PubMed  CAS  Google Scholar 

  • Hayashi K, Altman A (2007) Protein kinase C theta (PKCtheta): a key player in T cell life and death. Pharmacol Res 55:537–544

    Article  PubMed  CAS  Google Scholar 

  • Ho Y, Samarasinghe R, Knoch ME, Lewis M, Aizenman E, DeFranco DB (2008) Selective inhibition of mitogen-activated protein kinase phosphatases by zinc accounts for extracellular signal-regulated kinase 1/2-dependent oxidative neuronal cell death. Mol Pharmacol 74:1141–1151

    Article  PubMed  CAS  Google Scholar 

  • Hongpaisan J, Sun MK, Alkon DL (2011) PKC epsilon activation prevents synaptic loss, Abeta elevation, and cognitive deficits in Alzheimer’s disease transgenic mice. J Neurosci 31:630–643

    Article  PubMed  CAS  Google Scholar 

  • Jonas EA, Hickman JA, Hardwick JM, Kaczmarek LK (2005) Exposure to hypoxia rapidly induces mitochondrial channel activity within a living synapse. J Biol Chem 280:4491–4497

    Article  PubMed  CAS  Google Scholar 

  • Kauppinen TM, Higashi Y, Suh SW, Escartin C, Nagasawa K, Swanson RA (2008) Zinc triggers microglial activation. J Neurosci 28:5827–5835

    Article  PubMed  CAS  Google Scholar 

  • Khanna S, Roy S, Slivka A, Craft TK, Chaki S, Rink C, Notestine MA, DeVries AC, Parinandi NL, Sen CK (2005) Neuroprotective properties of the natural vitamin E alpha-tocotrienol. Stroke 36:2258–2264

    Article  PubMed  Google Scholar 

  • Kim J, Kim TY, Hwang JJ, Lee JY, Shin JH, Gwag BJ, Koh JY (2009) Accumulation of labile zinc in neurons and astrocytes in the spinal cords of G93A SOD-1 transgenic mice. Neurobiol Dis 34:221–229

    Article  PubMed  CAS  Google Scholar 

  • Kim YH, Koh JY (2002) The role of NADPH oxidase and neuronal nitric oxide synthase in zinc-induced poly(ADP-ribose) polymerase activation and cell death in cortical culture. Exp Neurol 177:407–418

    Article  PubMed  CAS  Google Scholar 

  • Knoch ME, Hartnett KA, Hara H, Kandler K, Aizenman E (2008) Microglia induce neurotoxicity via intraneuronal Zn(2+) release and a K(+) current surge. Glia 56:89–96

    Article  PubMed  Google Scholar 

  • Koh JY, Suh SW, Gwag BJ, He YY, Hsu CY, Choi DW (1996) The role of zinc in selective neuronal death after transient global cerebral ischemia. Science 272:1013–1016

    Article  PubMed  CAS  Google Scholar 

  • Kohda Y, Matsunaga Y, Shiota R, Satoh T, Kishi Y, Kawai Y, Gemba M (2006) Involvement of Raf-1/MEK/ERK1/2 signaling pathway in zinc-induced injury in rat renal cortical slices. J Toxicol Sci 31:207–217

    Article  PubMed  CAS  Google Scholar 

  • Koumura A, Hamanaka J, Shimazawa M, Honda A, Tsuruma K, Uchida Y, Hozumi I, Satoh M, Inuzuka T, Hara H (2009) Metallothionein-III knockout mice aggravates the neuronal damage after transient focal cerebral ischemia. Brain Res 1292:148–154

    Article  PubMed  CAS  Google Scholar 

  • Kudo I, Murakami M (2002) Phospholipase A2 enzymes. Prostaglandins Other Lipid Mediat 68–69:3–58

    Article  PubMed  Google Scholar 

  • Land PW, Aizenman E (2005) Zinc accumulation after target loss: an early event in retrograde degeneration of thalamic neurons. Eur J Neurosci 21:647–657

    Article  PubMed  Google Scholar 

  • Latchoumycandane C, Anantharam V, Jin H, Kanthasamy A (2011) Dopaminergic neurotoxicant 6-OHDA induces oxidative damage through proteolytic activation of PKCdelta in cell culture and animal models of Parkinson’s disease. Toxicol Appl Pharmacol 256(3):314–323

    Article  PubMed  CAS  Google Scholar 

  • Lee JY, Cole TB, Palmiter RD, Koh JY (2000) Accumulation of zinc in degenerating hippocampal neurons of ZnT3-null mice after seizures: evidence against synaptic vesicle origin. J Neurosci 20(11):RC79

    PubMed  CAS  Google Scholar 

  • Lee SJ, Koh JY (2010) Roles of zinc and metallothionein-3 in oxidative stress-induced lysosomal dysfunction, cell death, and autophagy in neurons and astrocytes. Mol Brain 3:30

    Article  PubMed  Google Scholar 

  • Lee SJ, Cho KS, Koh JY (2009) Oxidative injury triggers autophagy in astrocytes: the role of endogenous zinc. Glia 57:1351–1361

    Article  PubMed  Google Scholar 

  • Lee SJ, Park MH, Kim HJ, Koh JY (2010) Metallothionein-3 regulates lysosomal function in cultured astrocytes under both normal and oxidative conditions. Glia 58:1186–1196

    Article  PubMed  Google Scholar 

  • Li J, Baud O, Vartanian T, Volpe JJ, Rosenberg PA (2005) Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proc Natl Acad Sci U S A 102:9936–9941

    Article  PubMed  CAS  Google Scholar 

  • Li S, Lin W, Tchantchou F, Lai R, Wen J, Zhang Y (2011) Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes. Mol Cell Neurosci 48:62–71

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Maher P, Schubert D (1997) A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion. Neuron 19:453–463

    Article  PubMed  CAS  Google Scholar 

  • Liao SL, Ou YC, Lin SY, Kao TK, Pan HC, Chang CY, Lai CY, Lu HC, Wang WY, Chen CJ (2011) Signaling cascades mediate astrocyte death induced by zinc. Toxicol Lett 204:108–117

    Article  PubMed  CAS  Google Scholar 

  • Luo Y, DeFranco DB (2006) Opposing roles for ERK1/2 in neuronal oxidative toxicity: distinct mechanisms of ERK1/2 action at early versus late phases of oxidative stress. J Biol Chem 281:16436–16442

    Article  PubMed  CAS  Google Scholar 

  • Malaiyandi LM, Dineley KE, Reynolds IJ (2004) Divergent consequences arise from metallothionein overexpression in astrocytes: zinc buffering and oxidant-induced zinc release. Glia 45:346–353

    Article  PubMed  Google Scholar 

  • Malaiyandi LM, Vergun O, Dineley KE, Reynolds IJ (2005) Direct visualization of mitochondrial zinc accumulation reveals uniporter-dependent and -independent transport mechanisms. J Neurochem 93:1242–1250

    Article  PubMed  CAS  Google Scholar 

  • Maret W (2008) Metallothionein redox biology in the cytoprotective and cytotoxic functions of zinc. Exp Gerontol 43:363–369

    Article  PubMed  CAS  Google Scholar 

  • Maret W, Vallee BL (1998) Thiolate ligands in metallothionein confer redox activity on zinc clusters. Proc Natl Acad Sci U S A 95:3478–3482

    Article  PubMed  CAS  Google Scholar 

  • Masters BA, Quaife CJ, Erickson JC, Kelly EJ, Froelick GJ, Zambrowicz BP, Brinster RL, Palmiter RD (1994) Metallothionein III is expressed in neurons that sequester zinc in synaptic vesicles. J Neurosci 14:5844–5857

    PubMed  CAS  Google Scholar 

  • McLaughlin B, Pal S, Tran MP, Parsons AA, Barone FC, Erhardt JA, Aizenman E (2001) p38 activation is required upstream of potassium current enhancement and caspase cleavage in thiol oxidant-induced neuronal apoptosis. J Neurosci 21:3303–3311

    PubMed  CAS  Google Scholar 

  • Medvedeva YV, Lin B, Shuttleworth CW, Weiss JH (2009) Intracellular Zn2+ accumulation contributes to synaptic failure, mitochondrial depolarization, and cell death in an acute slice oxygen-glucose deprivation model of ischemia. J Neurosci 29:1105–1114

    Article  PubMed  CAS  Google Scholar 

  • Newton AC (2010) Protein kinase C: poised to signal. Am J Physiol Endocrinol Metab 298:E395–402

    Article  PubMed  CAS  Google Scholar 

  • Noh KM, Koh JY (2000) Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes. J Neurosci 20:RC111

    PubMed  CAS  Google Scholar 

  • Noh KM, Kim YH, Koh JY (1999) Mediation by membrane protein kinase C of zinc-induced oxidative neuronal injury in mouse cortical cultures. J Neurochem 72:1609–1616

    Article  PubMed  CAS  Google Scholar 

  • Nolte C, Gore A, Sekler I, Kresse W, Hershfinkel M, Hoffmann A, Kettenmann H, Moran A (2004) ZnT-1 expression in astroglial cells protects against zinc toxicity and slows the accumulation of intracellular zinc. Glia 48:145–155

    Article  PubMed  Google Scholar 

  • Pal S, He K, Aizenman E (2004) Nitrosative stress and potassium channel-mediated neuronal apoptosis: is zinc the link? Pflugers Arch 448:296–303

    Article  PubMed  CAS  Google Scholar 

  • Pal S, Hartnett KA, Nerbonne JM, Levitan ES, Aizenman E (2003) Mediation of neuronal apoptosis by Kv2.1-encoded potassium channels. J Neurosci 23:4798–4802

    PubMed  CAS  Google Scholar 

  • Pal SK, Takimoto K, Aizenman E, Levitan ES (2006) Apoptotic surface delivery of K+ channels. Cell Death Differ 13:661–667

    Article  PubMed  CAS  Google Scholar 

  • Palmiter RD (1987) Molecular biology of metallothionein gene expression. Experientia Suppl 52:63–80

    PubMed  CAS  Google Scholar 

  • Park JA, Koh JY (1999) Induction of an immediate early gene egr-1 by zinc through extracellular signal-regulated kinase activation in cortical culture: its role in zinc-induced neuronal death. J Neurochem 73:450–456

    Article  PubMed  CAS  Google Scholar 

  • Park MH, Lee SJ, Byun HR, Kim Y, Oh YJ, Koh JY, Hwang JJ (2011) Clioquinol induces autophagy in cultured astrocytes and neurons by acting as a zinc ionophore. Neurobiol Dis 42:242–251

    Article  PubMed  CAS  Google Scholar 

  • Puttaparthi K, Gitomer WL, Krishnan U, Son M, Rajendran B, Elliott JL (2002) Disease progression in a transgenic model of familial amyotrophic lateral sclerosis is dependent on both neuronal and non-neuronal zinc binding proteins. J Neurosci 22:8790–8796

    PubMed  CAS  Google Scholar 

  • Quaife CJ, Findley SD, Erickson JC, Froelick GJ, Kelly EJ, Zambrowicz BP, Palmiter RD (1994) Induction of a new metallothionein isoform (MT-IV) occurs during differentiation of stratified squamous epithelia. Biochemistry 33:7250–7259

    Article  PubMed  CAS  Google Scholar 

  • Redman PT, Hartnett KA, Aras MA, Levitan ES, Aizenman E (2009) Regulation of apoptotic potassium currents by coordinated zinc-dependent signalling. J Physiol 587:4393–4404

    Article  PubMed  CAS  Google Scholar 

  • Redman PT, He K, Hartnett KA, Jefferson BS, Hu L, Rosenberg PA, Levitan ES, Aizenman E (2007) Apoptotic surge of potassium currents is mediated by p38 phosphorylation of Kv2.1. Proc Natl Acad Sci U S A 104:3568–3573

    Article  PubMed  CAS  Google Scholar 

  • Rohrdanz E, Schmuck G, Ohler S, Tran-Thi QH, Kahl R (2001) Changes in antioxidant enzyme expression in response to hydrogen peroxide in rat astroglial cells. Arch Toxicol 75:150–158

    Article  PubMed  CAS  Google Scholar 

  • Ryu R, Shin Y, Choi JW, Min W, Ryu H, Choi CR, Ko H (2002) Depletion of intracellular glutathione mediates zinc-induced cell death in rat primary astrocytes. Exp Brain Res 143:257–263

    Article  PubMed  CAS  Google Scholar 

  • Sensi SL, Jeng JM (2004) Rethinking the excitotoxic ionic milieu: the emerging role of Zn(2+) in ischemic neuronal injury. Curr Mol Med 4:87–111

    Article  PubMed  CAS  Google Scholar 

  • Sensi SL, Rockabrand E, Canzoniero LM (2006) Acidosis enhances toxicity induced by kainate and zinc exposure in aged cultured astrocytes. Biogerontology 7:367–374

    Article  PubMed  CAS  Google Scholar 

  • Sensi SL, Paoletti P, Bush AI, Sekler I (2009) Zinc in the physiology and pathology of the CNS. Nat Rev Neurosci 10:780–791

    Article  PubMed  CAS  Google Scholar 

  • Sensi SL, Ton-That D, Sullivan PG, Jonas EA, Gee KR, Kaczmarek LK, Weiss JH (2003) Modulation of mitochondrial function by endogenous Zn2+ pools. Proc Natl Acad Sci U S A 100:6157–6162

    Article  PubMed  CAS  Google Scholar 

  • Shimizu T, Wolfe LS (1990) Arachidonic acid cascade and signal transduction. J Neurochem 55:1–15

    Article  PubMed  CAS  Google Scholar 

  • Sivasankaran R, Pei J, Wang KC, Zhang YP, Shields CB, Xu XM, He Z (2004) PKC mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration. Nat Neurosci 7:261–268

    Article  PubMed  CAS  Google Scholar 

  • Stanciu M, Wang Y, Kentor R, Burke N, Watkins S, Kress G, Reynolds I, Klann E, Angiolieri MR, Johnson JW, DeFranco DB (2000) Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures. J Biol Chem 275:12200–12206

    Article  PubMed  CAS  Google Scholar 

  • Stork CJ, Li YV (2006) Intracellular zinc elevation measured with a “calcium-specific” indicator during ischemia and reperfusion in rat hippocampus: a question on calcium overload. J Neurosci 26:10430–10437

    Article  PubMed  CAS  Google Scholar 

  • Stork CJ, Li YV (2009) Rising zinc: a significant cause of ischemic neuronal death in the CA1 region of rat hippocampus. J Cereb Blood Flow Metab 29:1399–1408

    Article  PubMed  CAS  Google Scholar 

  • Suh SW, Listiack K, Bell B, Chen J, Motamedi M, Silva D, Danscher G, Whetsell W, Thompson R, Frederickson C (1999) Detection of pathological zinc accumulation in neurons: methods for autopsy, biopsy, and cultured tissue. J Histochem Cytochem 47:969–972

    Article  PubMed  CAS  Google Scholar 

  • Sun MK, Alkon DL (2009) Protein kinase C activators as synaptogenic and memory therapeutics. Arch Pharm (Weinheim) 342:689–698

    Article  CAS  Google Scholar 

  • van Leyen K, Kim HY, Lee SR, Jin G, Arai K, Lo EH (2006) Baicalein and 12/15-lipoxygenase in the ischemic brain. Stroke 37:3014–3018

    Article  PubMed  Google Scholar 

  • Vander Jagt TA, Connor JA, Weiss JH, Shuttleworth CW (2009) Intracellular Zn2+ increases contribute to the progression of excitotoxic Ca2+ increases in apical dendrites of CA1 pyramidal neurons. Neuroscience 159:104–114

    Article  PubMed  CAS  Google Scholar 

  • Ventura R, Harris KM (1999) Three-dimensional relationships between hippocampal synapses and astrocytes. J Neurosci 19:6897–6906

    PubMed  CAS  Google Scholar 

  • Wang H, Li J, Follett PL, Zhang Y, Cotanche DA, Jensen FE, Volpe JJ, Rosenberg PA (2004) 12-Lipoxygenase plays a key role in cell death caused by glutathione depletion and arachidonic acid in rat oligodendrocytes. Eur J Neurosci 20:2049–2058

    Article  PubMed  Google Scholar 

  • Weiss JH, Sensi SL, Koh JY (2000) Zn(2+): a novel ionic mediator of neural injury in brain ­disease. Trends Pharmacol Sci 21:395–401

    Article  PubMed  CAS  Google Scholar 

  • Wen J, Ribeiro R, Zhang Y (2011) Specific PKC isoforms regulate LPS-stimulated iNOS induction in murine microglial cells. J Neuroinflammation 8:38

    Article  PubMed  CAS  Google Scholar 

  • West AK, Hidalgo J, Eddins D, Levin ED, Aschner M (2008) Metallothionein in the central nervous system: roles in protection, regeneration and cognition. Neurotoxicology 29:489–503

    Article  PubMed  CAS  Google Scholar 

  • Willis CL, Meske DS, Davis TP (2010) Protein kinase C activation modulates reversible increase in cortical blood–brain barrier permeability and tight junction protein expression during hypoxia and posthypoxic reoxygenation. J Cereb Blood Flow Metab 30:1847–1859

    Article  PubMed  CAS  Google Scholar 

  • Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326–1331

    Article  PubMed  CAS  Google Scholar 

  • Xie Z, Wei M, Morgan TE, Fabrizio P, Han D, Finch CE, Longo VD (2002) Peroxynitrite mediates neurotoxicity of amyloid beta-peptide1-42- and lipopolysaccharide-activated microglia. J Neurosci 22:3484–3492

    PubMed  CAS  Google Scholar 

  • Yamasaki S, Sakata-Sogawa K, Hasegawa A, Suzuki T, Kabu K, Sato E, Kurosaki T, Yamashita S, Tokunaga M, Nishida K, Hirano T (2007) Zinc is a novel intracellular second messenger. J Cell Biol 177:637–645

    Article  PubMed  CAS  Google Scholar 

  • Yenari MA, Kauppinen TM, Swanson RA (2010) Microglial activation in stroke: therapeutic targets. Neurotherapeutics 7:378–391

    Article  PubMed  CAS  Google Scholar 

  • Zhang D, Anantharam V, Kanthasamy A, Kanthasamy AG (2007a) Neuroprotective effect of protein kinase C delta inhibitor rottlerin in cell culture and animal models of Parkinson’s disease. J Pharmacol Exp Ther 322:913–922

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Aizenman E, DeFranco DB, Rosenberg PA (2007b) Intracellular zinc release, 12-lipoxygenase activation and MAPK dependent neuronal and oligodendroglial death. Mol Med 13:350–355

    PubMed  CAS  Google Scholar 

  • Zhang Y, Wang H, Li J, Jimenez DA, Levitan ES, Aizenman E, Rosenberg PA (2004) Peroxynitrite-induced neuronal apoptosis is mediated by intracellular zinc release and 12-lipoxygenase ­activation. J Neurosci 24:10616–10627

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Wang H, Li J, Dong L, Xu P, Chen W, Neve RL, Volpe JJ, Rosenberg PA (2006) Intracellular zinc release and ERK phosphorylation are required upstream of 12-lipoxygenase activation in peroxynitrite toxicity to mature rat oligodendrocytes. J Biol Chem 281:9460–9470

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Anatomy, Physiology and Genetics and Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, USA

    Yumin Zhang

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  1. , Department of Biomedical Sciences, Ohio University, 346 Irvine Hall, Athens, 45701, Ohio, USA

    Yang V. Li

  2. Loma Linda University, 11234 Anderson Street, Room 2562B, Loma Linda, 92354, California, USA

    John H. Zhang

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Zhang, Y. (2012). Intracellular Zinc Liberation: A Trigger for Oxidative Stress-Induced Toxicity to Neurons and Neuroglia. In: Li, Y., Zhang, J. (eds) Metal Ion in Stroke. Springer Series in Translational Stroke Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9663-3_8

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