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Logo of jclinneuroJournal of Clinical NeurologyAboutFor Contributorse-SubmissionThis Article
 
J Clin Neurol. 2005 October; 1(2): 121–133.
Published online 2005 October 20. doi:  10.3988/jcn.2005.1.2.121
PMCID: PMC2854917

This article has been retractedRetraction in: J Clin Neurol. 2010 June 30; 6(2): 109    See also: PMC Retraction Policy

Endogenous Zinc in Neurological Diseases

Jae-Yong Koh, M.D., Ph.D.corresponding author

Abstract

The use of zinc in medicinal skin cream was mentioned in Egyptian papyri from 2000 BC (for example, the Smith Papyrus), and zinc has apparently been used fairly steadily throughout Roman and modern times (for example, as the American lotion named for its zinc ore, 'Calamine'). It is, therefore, somewhat ironic that zinc is a relatively late addition to the pantheon of signal ions in biology and medicine. However, the number of biological functions, health implications and pharmacological targets that are emerging for zinc indicate that it might turn out to be 'the calcium of the twenty-first century'. Here neurobiological roles of endogenous zinc is summarized.

Keywords: Ischemia, Stroke, Alzheimer, Amyotrophic lateral sclerosis

INTRODUCTION AND OVERVIEW

In medicine and biology, zinc has several connotations. It is an essential micronutrient,1 a component of enzymes and other proteins,2 and a toxic pollutant3 as well.

To neuroscientists, zinc is also an ionic signal, Zn2+ enters cells through gated channels,4,5 and moves among various organelles and storage depots within cells,6,7 modulating protein function by binding to and detaching from zinc-dependent proteins.7-9 Like calcium, excess free zinc in tissue is toxic.10

Zn2+ is selectively stored in, and released from, the presynaptic vesicles of a specific type of neurons in the mammalian brain. These zinc-releasing neurons also release glutamate, so the term "gluzinergic" has been proposed to describe them.11,12 By and large, the gluzinergic neurons all have their cell bodies in either the cerebral cortex or in the limbic structures of the forebrain.13 Thus the gluzinergic neuronal system comprises a vast cortical-limbic associational network that unites limbic and cerebrocortical functions. The gluzinergic message is the exclusive voice of the cerebrocortical and limbic systems.

In the fifty years since the first identification of chelatable zinc in the brain,14 a broad outline of the function of gluzinergic neurons has slowly come into focus. First, zinc appears to modulate the overall excitability of the brain via effects on glutamate, and probably GABA receptors. Clinical links to epileptic disorders have been a major theme in the literature of zinc neurobiology.15 Secondly, perhaps because it is preferentially located in cerebrocortical associational pathways, zinc may be important in synaptic plasticity.16,17

However, excess free zinc ion is toxic. Indeed, a major portion of current interest in the neurobiology of zinc is driven by the idea that the zinc ion is a causal contributor in both the acute brain injury of stroke, head trauma, seizures, or cardiac arrest,10 and the slow and relentless brain injury of the neurodegenerative disorders such as Alzheimer's disease (AD) and possibly amyotrophic lateral sclerosis (ALS).18

In the present paper, current evidence that implicates endogenous zinc in pathophysiology of both acute brain damage and degenerative brain diseases is reviewed.

BASIC NEUROPHYSIOLOGY OF ZINC

Maske first identified the zinc-containing mossy-fiber terminals.14 Subsequently, it was found that many of the intrinsic, glutamatergic pathways of the cerebral cortex are comprised of gluzinergic neurons. The "intrinsic" is here emphasized because corticofugal and corticopedal long-axon pathways, though also glutamatergic, are generally devoid of zinc.

Surprisingly little is known about the biological life cycle of zinc in the glutamatergic vesicles of the forebrain. There is a protein, zinc transporter-3 (ZnT-3), that co-localizes with zinc vesicles, and mice lacking the gene for that protein (znt-3 knockouts) show no staining for zinc in their presynaptic terminals.19 These data indicate that the ZnT-3 protein plays a role in sequestering vesicular zinc, but exactly what that role is remains uncertain.20

Like other neurotransmitters packed in vesicles, zinc is released with neuronal activity. A number of groups have found very robust and reliable release of zinc from boutons upon electrical stimulation21,22 or simple elapsed time.23 Most recently, the release of zinc has been elegantly demonstrated on a pulse-by-pulse basis, with each action potential releasing zinc.24

The soma and dendrites of mammalian neurons are studded with a variety of zinc-permeable ion channels. These include the NMDA channel, voltage-gated calcium channels, and the calcium-permeable AMPA/Kainate (Ca-A/K) channel. Zinc influx through these channels has been demonstrated.25-30

Because presynaptic terminals release zinc and the postsynaptic soma and dendrites have zinc-permeable channels, it follows that zinc ions will travel from inside a presynaptic neuron to inside a post synaptic neuron (translocate) under favorable conditions. Because both glutamate and depolarization open the zinc-permeable channels,4,28-30 one expects the maximum zinc translocation during intense neuronal activity with depolarization. Much evidence discussed below indicates that such translocation contributes to zinc-induced cell injury in excitotoxicity. There is also evidence that a smaller-volume translocation may occur during normal physiological synaptic signaling, with the translocated zinc perhaps triggering further signal cascades in the postsynaptic neuron.31

In addition to the zinc that can be released from presynaptic terminals into the extracellular fluid, it is clear that there is also a pool of zinc stored in perikarya that can be "released" into the cytoplasm. One source of this zinc is the metallothionein family of proteins (MTs), from which zinc can be released at an especially high rate by nitrosylation of the thiol ligands by NO.32,33 Of three isoforms of MTs, MT-3 has only been found in brain and testes, whereas the others are more widespread.34,35 In brain injury, the absence of MT-3 significantly reduces cell injury in hippocampal field CA1 and the thalamus,36 implying that zinc released off MT3 can contribute to cell injury. In contrast, in hippocampal field CA3, the absence of MT-3 increases cell death in excitotoxic injury, presumably because the presynaptic release of zinc is so pronounced in CA3,37,38 that the postsynaptic MT-3 serves more as a zinc sink than a zinc source.39,40

One of the very first neuronal receptors found sensitive to Zn2+ was the NMDA-type glutamate ionophore, which was shown to be inhibited by Zn2+ in 1987.41 The sensitivity of the NMDA-type receptor-ionophore is now understood to be mediated by two separate mechanisms, a voltage-independent site on the NR2A subunit that has an IC50 in the single-digit nanomolar range42,43 and a less sensitive, voltage-dependent site on the NR2B44 subunit where ionic current is decreased by low-micromolar concentrations of Zn2+. Another potentially critical aspect of the zinc-NMDA relationship is that prior exposure to zinc apparently causes a delayed increase in the sensitivity of the receptor to agonists. This delayed effect (over hours) is mediated by increased phosphorylation of the NR2A and NR2B subunits, thereby decreasing their sensitivity to the tonic inhibition by zinc.45,46

The second receptor that has been studied intensively for zinc sensitivity is the GABA receptor, which was first shown to be inhibited by Zn2+ in 1987.41,47 Although most of the data concerning the GABA sensitivity to zinc have come from experiments in which exogenous zinc was added to tissue baths, several exemplary experiments have used the blockade (chelation) paradigm to reveal effects of endogenous zinc signals.48,49 Changes in the zinc modulation of GABA receptor have been implicated in the etiology of epilepsy. Mody, Coulter and others50-52 have suggested that the seizure-induced sprouting of zinc-releasing axons into ectopic locations could result in ectopic release of zinc, thus reducing GABA-A receptor-mediated inhibition, and enhancing seizure susceptibility.51 In addition to the sprouting of zinc-releasing axons, there are additional changes in zinc modulation of the GABA receptor that could contribute to the progressive epileptogenesis.53,54

ZINC IN ACUTE BRAIN INJURY

1. Zinc accumulation as a cause of neuronal death

Although zinc lacks redox activity, and was traditionally regarded as relatively non-toxic,55 an increasing body of evidence demonstrates that zinc is in fact a potent killer of neurons and glial cells. As mentioned earlier, the toxicity of free zinc (even 1 µM) in streams and oceans is well known to environmental scientists.3,56

In 1986, we have demonstrated that brief (15 min) exposure to 300-600 µM zinc results in extensive neuronal death in cortical cell culture.57 Combined with the realization that neurons store up to 300 µM of free zinc in their terminals58 and release that zinc when they are depolarized,59-61 the fact that zinc was cytotoxic suggested the possibility that zinc might play an active role in neuronal injury.

The facts that (i) minutes of exposure to µM zinc kills brain cells in culture, and (ii) zinc is massively released in acute brain injury, suggest that zinc toxicity could contribute to neuronal injury in vivo. Staining of brain sections of ischemia- or epilepsy-subjected animals with a zinc fluorescent dye and acid fuchsin, revealed a striking correlation between zinc accumulation in cell bodies and their death. It was demonstrated that both neuronal death and zinc accumulation in transient cerebral ischemia, were reduced or prevented by an extracellular zinc chelator, CaEDTA.62 Subsequently, the principle of endogenous zinc toxicity as a contributing mechanism has been examined and determined valid in other injury models such as blunt head trauma.63 focal ischemia,64 oxygen-glucose deprivation in vitro65 and glucose deprivation in vivo.66

Because histochemically-reactive zinc in synaptic vesicles was initially considered the only releasable pool of zinc,67 it was postulated that the zinc that appeared in postsynaptic neuronal somata was likely presynaptic zinc that had been released and "translocated" into the postsynaptic neurons. However, while useful for a time, the "zinc translocation" hypothesis is now recognized as incomplete. First, zinc accumulation in degenerating neurons has always been observed to some extent in areas only lightly innervated by gluzinergic fibers. For instance, thalamic neurons are surrounded by terminals that lack vesicle zinc.11,68 Still, these neurons exhibit zinc accumulation following ischemia and seizures.62,68 Second, even in znt3-null mice that lack synaptic zinc, extensive zinc accumulation in degenerating CA1 and thalamic neurons was observed.69 Finally, the fairly recent discovery that extracellular CaEDTA can remove zinc from inside of cells and even presynaptic vesicles70 (presumably by creating extremely steep transmembrane gradients) brought the interpretation of CaEDTA data into direct question. Specifically, blockade by CaEDTA could no longer be accepted as evidence that the zinc had traveled through the extracellular fluids.

Zinc accumulation in degenerating neurons of znt-3-null mice indicates that there are other zinc sources besides synaptic vesicle zinc. One such source is the zinc that can be mobilized off MT-3 (and possibly from mitochondria) discussed above. As mentioned previously, such intracellular zinc release could lead to a somatic release of zinc into the extracellular fluid with subsequent zinc translocation into neighboring cells. The direct role of Nitric oxide in releasing this MT3 pool of zinc during excitotoxicity was recently demonstrated by Wei.71

2. Zinc-initiated cell death pathways

Regardless of specific sources or routes involved, increased levels of reactive or "free" zinc inside cells is toxic. This toxic effect of zinc was initially puzzling to some because zinc had been considered relatively innocuous metal, and zinc was known to inhibit apoptosis in diverse cell systems.72

Although zinc is not an oxidizer, several lines of evidence have shown that zinc toxicity is mediated largely by oxidative stress. First zinc-induced cell death is accompanied by increased levels of superoxides and lipoperoxides, markers for oxidative injury.73-75 Second, zinc-induced cell death is attenuated by various antioxidative measures.76,77 Third, free radical-generating enzymes such as NADPH oxidase are induced and activated after zinc exposure, and their inhibitors attenuate zinc toxicity.78

With brief exposure to high concentrations of zinc, neurons exhibit signs of necrosis, such as cell body swelling and destruction of intracellular organelles.73 However, in less fulminant zinc toxicity, signs of apoptosis such as DNA fragmentation and caspase activation, are also observed.76,79 The fact that zinc exposure induces apoptosis was puzzling, since depletion of zinc also induces caspase activation and apoptosis.80,81 However, elevated zinc does indeed produce apoptosis, and mechanisms for zinc-triggered apoptosis are now being identified. For example, in zinc-exposed neurons, both p75NTR and p75NTR-associated death executor (NADE), are Induced,82 a combination that can induce caspase activation and apoptosis.83 In addition to this pathway, zinc can trigger the release of pro-apoptotic proteins such as cytochrome C and apoptosis inducing factor (AIF) from mitochondria.84 Whether and how much apoptosis contributes to zinc-related acute brain injury is unknown. However, in rat models of ischemia and seizures where the role of zinc as a neurotoxin is likely, p75NTR and NADE are co-induced in neurons that undergo cell death,82,85 strengthening the possible involvement of this apoptogenic cascade in vivo.

Another pivotal factor in zinc toxicity is nitric oxide (NO). NO releases 7 zinc ions from each single MT molecule,86-88 and the brain-specific MT-3 isoform has a considerably lower threshold for zinc release by NO than the other isoforms.89,90 Because inhibition of NO synthase (NOS) dramatically reduces the release of zinc from brain slices,71 and reduces the appearance of zinc staining after hypoglycemic brain injury,66 it is clear that NO release of zinc from MT plays a crucial role in excitotoxic zinc toxicity. NO also rapidly releases zinc from presynaptic terminals,91 thus contributing to cell death via the zinc translocation mechanism. Whereas NO releases zinc, elevated Intracellular zinc also induces and activates neuronal NOS in cultured cortical neurons.92 Thus regardless whether zinc or NO is the initial trigger, a destructive cycle is easily induced.

The final pathway to zinc-induced cell necrosis seems to be poly-ADP-ribose polymerase (PARP) activation,92 as in other cases of predominantly necrotic cell death.93 DNA damage induced by oxidative and nitrosative stresses activates PARP, an enzyme that transfers the ADP-ribose moiety from NAD+ to various target proteins. Since up to several hundred moieties are transferred to a molecule of protein, continued activation of PARP results in a drastic depletion of NAD+ and ATP.94 Consistent with the idea that PARP activation is limited only to necrosis type cell death,93 chronic exposure to low concentrations of zinc, which preferentially induces apoptosis,79 is not attenuated by deletion of PARP-1.95

ZINC IN NEURODEGENRATIVE DISEASES

1. Alzheimer's Disease

Alzheimer's disease (AD) is characterized by loss of cortical neurons and progressive deterioration of cognitive function, memory, and self-care. The pathological hallmark of AD is marked accumulation of amyloid-β (Aβ) protein, neurofibrillary tangles (NFTs) and neuropil threads in the neocortex.96 Aβ (39-43 amino acid residues, ~4 kDa), is the main constituent of both senile plaques and cerebrovascular amyloid deposits.97,98 The Aβ peptide is produced from the proteolytic cleavage of a much larger transmembrane precursor, the Amyloid Protein Precursor (APP).98 Mutations of APP (on chromosome 21) within or adjacent to the Aβ domain cause aggressive familial AD, indicating that abnormal Aβ and APP metabolism can give rise to the disease.

Since the discovery that Zn2+ precipitates Aβ,99,100 considerable evidence has emerged that free Zn2+ in the extracellular fluid induces amyloid deposition. Aβ1-40 specifically and saturably binds zinc with a 1 : 1 (zinc : Aβ) stoichiometry. Because zinc concentrations of the extracellular brain milieu are apparently in 1 to 10 nM range, one would expect Aβ1-40 to bind very little zinc under normal conditions. However, events leading to a sustained increase in extracellular zinc levels, such as a transient hypoperfusion, head trauma, or even local paroxysmal neuronal firing101 could easily lead to zinc binding to Aβ.

The zinc binding site was mapped to a stretch of contiguous residues between positions 6-28 of the Aβ sequence, and the histidine at residue 13 plays a critical role in Zn2+ mediated aggregation.102 Occupation of the zinc binding site, which straddles the lysine 16 position of α-secretase cleavage,103 by zinc inhibits β-secretase type cleavage and so may influence the generation of Aβ from APP, and may increase the biological half-life of Aβ by protecting the peptide from proteolytic attack.99 Zinc concentrations above 300 nM rapidly precipitate synthetic human Aβ1-40.100 Importantly, Zn2+-induced precipitation is completely reversed with chelation treatment.104

Zinc-induced Aβ precipitation at pH 7.4 is highly specific for zinc; however, Cu2+ and FE3+ can induce partial aggregation at pH 7.4 which increases substantially under mildly acidic conditions (pH 6.6).105 Raman spectroscopy has recently shown that Zn2+ binds to the N(tau) atom of the histidine imidazole ring and that the peptide aggregates through intermolecular His(N(tau))-Zn2+-His(N(tau)) bridges.106

Aβ binds Cu2+ and Zn2+ through selective binding sites. When synthetic Aβ is coincubated with excess but equal amounts of Cu2+ and Zn2+, ≈1.5 equivalents of each metal ion binds to each mole of peptide. Because the affinity of the Cu2+ binding sites on Aβ is much higher than that of Zn2+ binding sites, the finding that Cu2+ does not compete for all of the available metal binding sites when co-incubated with Zn2+ implies that Aβ possesses separate and selective Cu2+ and Zn2+ binding sites.107 Zn2+, Cu2+ and FE2+ are markedly enriched in amyloid plaques,108 but only Cu and Zn co-purify with Aβ extracted from post-mortem human brain109 and have been determined by Raman spectroscopy to coordinate with Aβ in plaques.110

In mouse brain Cu2+ and Fe2+ levels rise with age.111 One idea is that Aβ, which can bind up to 3.5 moles of Cu and Zn per monomer108 becomes hypermetallated (overloaded) with age, and abnormally oxidized while handling Cu2+ physiologically.18 Such a hypothetical abnormal binding of Cu2+ to Aβ would yield two adverse outcomes: (i) toxicity mediated by redox activity, and (ii) oxidative modification of Aβ.

Aβ : Cu2+ complexes are strongly reducing, and generate H2O2 catalytically from biological reducing agents including cholesterol.109,112,113 The redox activity is stronger for human Aβ1-42, than human 1-40 or the rat Aβ peptide, correlating with the toxicity of the peptide in cell culture.114

Cu2+-mediated oxidation of Aβ causes damage to histidine and tyrosine side-chains,115 dityrosine cross-linking116 and sulfoxidation of the sole methionine at residue 35.117 This latter methionine is essential for keeping metallated Aβ in its normal (redox-silent) location within lipid membranes.118,119 Therefore, oxidation of the Aβ by Cu2+ may be the first step in liberating Aβ species that can later be precipitated by Zn2+. This may explain why virtually all of the Aβ that deposits in the brain in AD is oxidized.120

Generation of H2O2 by soluble, but oxidized forms of Aβ,121 may explain the association of brain Aβ accumulation with the severe peroxidative damage that is characteristic of the AD-affected brain.122

Events leading to a sustained increase in extracellular zinc in combination with oxidative stress, such as stroke, head trauma, cardiac arrest, or epilepsy, would increase the likelihood of soluble Aβ precipitation into plaque and are indeed risk factors for AD.

Zn/Cu chelators reverse Zn/Cu-induced aggregation of synthetic Aβ in vitro,104 inhibit Aβ-mediated H2O2 formation,109,113,123,124 and solubilize Aβ from amyloid deposits in post-mortem AD-affected brain tissue.122

Studies of the impact of the genetic ablation of ZnT3 in the Tg2576 mouse model of AD have provided evidence that synaptically-released zinc underlies amyloid pathology in this model. We found that the complete absence of any staining for synaptic vesicle zinc in the knockout mouse was accompanied by a reduction of the cerebral plaque load by approximately 80%.125 Interestingly, synaptic zinc levels (as measured by histofluorescence for zinc) as well as plaque loads increased to a greater degree with age in female mice than in male, suggesting the influence of sex hormones on synaptic zinc levels.125 Preliminary evidence suggests that estrogen may reduce the level of synaptic vesicle zinc, perhaps by modulating the expression level of the adaptor protein 3 (AP3) complex, which is required for the correct insertion of ZnT3 into vesicular membrane.126 Cerebral amyloid angiopathy (CAA) is also decreased in ZnT-3 knock outl/Tg2576 compared to Tg2576 controls.

2. Amyotrophic Lateral Sclerosis (ALS)

Two abnormalities of zinc-metalloproteins have implicated zinc in the pathophysiology of ALS (lou Gehrig's dsease). First, it is the well-established fact that familial form of ALS in man is accompanied by mutations in the metalloenzyme Cu-Zn-superoxide dismutase (SOD).127,128 Mutations in SOD are also associated with ALS-resembling spinal motor defects in mice, with different mutants having different amounts of wild-type enzymatic activity, ranging from 0% (e.g. H46R and G85R) to 100% (e.g. G37R). SOD1 knockout mice do not develop the ALS phenotype,129 and the age of onset and duration of disease in ALS transgenic mice is unaffected by levels of wild-type SOD1 activity.129 Thus, the toxicity of mutant SOD1 (mSOD1) is a gain-of-function.

Several gain-of-function redox reactions have been proposed for mSOD1, and at least two currently appear plausible. Increased peroxidase activity has been reported in vitro130,131 in the H48Q, A4V, and G93A variants, although not consistently.132 Increased peroxidase activity in vivo has been reported in the A4V and G93A132 species. Cu replete, Zn deficient SOD1 has been reported to confer toxicity by producing peroxynitrite according to these reactions, and loss of Zn from mSOD1 has been proposed as a primary pathogenic event.133

The second zinc metalloprotein that is aberrant in ALS patients is metallothionein, immunoreactivity to which is elevated in the brain and liver.127,128 The same pattern of elevated metallothionein immunoreactivity occurs in a transgenic model of ALS: SOD1-G93A transgenic mice demonstrate increased MT-1, MT-2, and MT-3 expression in astrocytes and increased MT-3 in neurons.134 Metallothionein elevation is likely compensatory and protective. In the G93A mutant SOD1 transgenic model of ALS, deficiency of MT-1, MT-2 or MT-3 exacerbates the ALS phenotype.135,136

ZINC AS A THERAPEUTIC TARGET IN NEUROLOGICAL DISEASES

1. Buffering Free Zinc

There are three general directions for effective zinc-based drug development. (i) Zinc buffers with equilibrium constants at the optimal value, preventing excess zinc damage while avoiding zinc deficiency of the brain; (ii) for acute brain injuries (stroke, trauma, ischemia, hypo-perfusion), a very short-lived chelator with tighter-binding compounds that allow some control of zinc toxicity with minimal untoward effects of lowered zinc; (iii) "pro-buffers" or "tethered buffers" which could be designed to act upon zinc only whenever or wherever such zinc buffering is therapeutically required.

The first strategy, that of using a relatively weak chelator, has already produced promising results. The quinoline compound clioquinol, which binds zinc in the mid nanomolar range, has been shown to reduce the amount of amlyoid plaque in transgenic mice dramatically137,138 and to slow the rate of cognitive decline in human patients18,139 with AD. Unfortunately, the phase III trial with clioquinol was discontinued due to a problem in the manufacturing process. Other candidate chelators are considered as alternatives.

Another promising use of the low-affinity approach has been reported for acute zinc-toxicity. In those studies it was shown that, pyrithione (Kd~1 µM) can rescue cultured cells from zinc toxicity if administered at the right time.140,141 Pyrithione moves freely through membranes and presumably transports free zinc down its concentration gradient, thus rescuing cells from zinc toxicity when intracellular zinc levels are higher than extracellular zinc levels.

The idea of a "pro-drug chelator" is also under active investigation as a treatment for Alzheimer's disease. In this case, a classical strong chelator (BAPTA) has been rendered lipophilic and inactive by the addition of alkyl chains. Once through the blood brain barrier and embedded in a cell wall (lipid membrane) the non-chelating drug (DP-109) can be transformed into the active BAPTA by membrane lipases. Hence it is expected that DP-109 will chelate metals predominantly in the vicinity of cell membranes. In Tg2576 mice, DP-109 significantly reduced Aβ plaque load by about 60-80% without noticeable side effects.68 A related compound (DPb99) has also been tested in small samples of human patients as a neuroprotective qagainst the zinc-mediated injury in stroke, and during the coronary bypass surgery.

2. Downstream Control of Zinc-Triggered Toxic Signals

Therapies targeting later events are also promising. As discussed above, diverse serial and parallel events contribute to zinc-induced cell death. First, as zinc toxicity is largely mediated by oxidative and nitrosative stress,73,75,92,142 antioxidants and NOS inhibitors may be useful.

Another approach would target inhibition of PARP, which appears to be a key downstream event in zinc toxicity,92,95 may be effective in reducing zinc toxicity. Third, anti-apoptosis measures such as caspase inhibition may be a possibility. Although these mechanisms have been demonstrated to contribute to zinc toxicity in cell culture, they are considered more or less general mechanisms of cell death in acute brain injury. At the moment, it is not known whether any particular neuroprotectant is better against zinc toxicity than other injury mechanisms. Hence, more studies may be needed to zoom in on drug targets that are more specific to zinc toxicity.

Pyruvate protects against zinc-induced cell death in cortical culture143 and oligodendrocyte progenitor cell culture.144 Pyruvate protection is somewhat specific to zinc toxicity, because pyruvate does not attenuate calcium-overload excitotoxicity in the same cortical cell culture.145 Consistently, in a rat model of transient global ischemia where the role of zinc is established,62 pyruvate almost completely blocks zinc accumulation as well as neuronal death throughout the brain.145 Pyruvate also reduces retinal cell death following zinc exposure in culture or following pressure-induced ischemia in rats.146 Protection by pyruvate against zinc-triggered cell death is applicable not only to neurons and glial cells, but also to pancreatic beta cells. Streptozotocin-induced beta cell death to which paracrine toxic effect of endogenous zinc contributes, is markedly attenuated by pyruvate administration.147 Direct antioxidative effect and/or normalization of NAD+ levels may contribute to cytoprotection by pyruvate.143,148

Another possible neuroprotectant with specificity against zinc-mediated injury is tPA, which is currently used for thrombolysis in human patients.149 Although most of tPA's biological effect, including its excitotoxicity-potentiating effect, is mediated by its protease action,150 blockade of zinc toxicity by tPA takes place even in the presence of excess protease inhibitors.151 Although the protective mechanism is still unclear, tPA had no effect on zinc influx into cells, excluding the possibility that the protection occurs by the chelation of zinc in the media. Rather, a subsequent study showed that tPA increases zinc influx into cells.152 A preliminary result suggests that certain membrane receptors with tyrosine kinase activity may mediate this effect, since EGF receptor tyrosine kinase inhibitor C56 can reverse the protection (Koh unpublished). If the effective moiety and its cognate membrane receptors can be identified, development of tPA-derived peptides that prevent zinc toxicity, may be a possibility.

CONCLUSION

Like calcium, zinc is proving to be an essential and ubiquitous ionic signal in a myriad of cells and tissues. Because fluorescent calcium probes frequently respond to zinc as well, separating calcium signals from zinc signals will be mandatory in future research. Therapies based on manipulating zinc signals by preventing release, blocking channels, altering transport and buffering zinc of target tissues are all likely to have increasingly important roles in twenty-first century medicine.

Footnotes

Supported by National Creative Research Initiatives of Korean Ministry of Science and Technology.

References

1. Sandstead HH. Causes of iron and zinc deficiencies and their effects on brain. J Nutr. 2000;130:347S–349S. [PubMed]
2. Berg JM. Zinc fingers and other metal-binding domains. Elements for interactions between macromolecules. J Biol Chem. 1990;265:6513–6516. [PubMed]
3. Lock K, Janssen CR. Comparative toxicity of a zinc salt, zinc powder and zinc oxide to Eisenia fetida, Enchytraeus albidus and Folsomia candida. Chemosphere. 2003;53:851–856. [PubMed]
4. Sensi SL, Yin HZ, Weiss JH. AMPA/kainate receptor-triggered Zn2+ entry into cortical neurons induces mitochondrial Zn2+ uptake and persistent mitochondrial dysfunction. Eur J Neurosci. 2000;12:3813–3818. [PubMed]
5. Weiss JH, Sensi SL, Koh JY. Zn(2+): a novel ionic mediator of neural injury in brain disease. Trends Pharmacol Sci. 2000;21:395–401. [PubMed]
6. Sensi SL, Ton-That D, Weiss JH. Mitochondrial sequestration and Ca2+-dependent release of cytosolic Zn2+ loads in cortical neurons. Neurobiol Dis. 2000;10:100–108. [PubMed]
7. Haase H, Maret W. Intracellular zinc fluctuations modulate protein tyrosine phosphatase activity in insulin/insulin-like growth factor-1 signaling. Exp Cell Res. 2003;291:289–298. [PubMed]
8. Maret W, Yetman CA, Jiang L. Enzyme regulation by reversible zinc inhibition: glycerol phosphate dehydrogenase as an example. Chem Biol Interact. 2001;130-132:891–901. [PubMed]
9. Maret W, Jacob C, Vallee BL, Fischer EH. Inhibitory sites in enzymes: zinc removal and reactivation by thionein. Proc Natl Acad Sci U S A. 1999;96:1936–1940. [PubMed]
10. Choi DW, Koh JY. Zinc and brain injury. Annu Rev Neurosci. 1998;21:347–375. [PubMed]
11. Frederickson CJ. Neurobiology of zinc and zinc-containing neurons. Int Rev Neurobiol. 1989;31:145–238. [PubMed]
12. Frederickson CJ, Bush AI. Synaptically released zinc: physiological functions and pathological effects. Biometals. 2001;14:353–366. [PubMed]
13. Slomianka L, Danscher G, Frederickson CJ. Labeling of the neurons of origin of zinc-containing pathways by intraperitoneal injections of sodium selenite. Neuroscience. 1990;38:843–854. [PubMed]
14. MASKE H. A new method for demonstrating A and B cells in the islands of Langerhans. Klin Wochenschr. 1955;33:1058. [PubMed]
15. Ben Ari Y. Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience. 1985;14:375–403. [PubMed]
16. Li Y, Hough CJ, Frederickson CJ, Sarvey JM. Induction of mossy fiber --> CA3 long-term potentiation requires translocation of synaptically released Zn2+ J Neurosci. 2001;21:8015–8025. [PubMed]
17. Brown CE, Dyck RH. Rapid, experience-dependent changes in levels of synaptic zinc in primary somatosensory cortex of the adult mouse. J Neurosci. 2002;22:2617–2625. [PubMed]
18. Bush AI. The metallobiology of Alzheimer's disease. Trends Neurosci. 2003;26:207–214. [PubMed]
19. Cole TB, Wenzel HJ, Kafer KE, Schwartzkroin PA, Palmiter RD. Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. Proc Natl Acad Sci U S A. 1999;96:1716–1721. [PubMed]
20. Ohana E, Segal D, Palty R, Ton-Tat D, Moran A, Sensi SL, et al. A sodium zinc exchange mechanism is mediating extrusion of zinc in mammalian cells. J Biol Chem. 2004;279:4278–4284. [PubMed]
21. Budde T, Minta A, White JA, Kay AR. Imaging free zinc in synaptic terminals in live hippocampal slices. Neuroscience. 1997;79:347–358. [PubMed]
22. Varea E, Ponsoda X, Molowny A, Danscher G, Lopez-Garcia C. Imaging synaptic zinc release in living nervous tissue. J Neurosci Methods. 2001;110:57–63. [PubMed]
23. Perez-Clausell J, Danscher G. Release of zinc sulphide accumulations into synaptic clefts after in vivo injection of sodium sulphide. Brain Res. 1986;362:358–361. [PubMed]
24. Quinta-Ferreira ME, Matias CM. Hippocampal mossy fiber calcium transients are maintained during long-term potentiation and are inhibited by endogenous zinc. Brain Res. 2004;1004:52–60. [PubMed]
25. Frederickson CJ, Hernandez MD, Goik SA, Morton JD, McGinty JF. Loss of zinc staining from hippocampal mossy fibers during kainic acid induced seizures: a histofluorescence study. Brain Res. 1988;446:383–386. [PubMed]
26. Marin P, Israel M, Glowinski J, Premont J. Routes of zinc entry in mouse cortical neurons: role in zinc-induced neurotoxicity. Eur J Neurosci. 2000;12:8–18. [PubMed]
27. Thompson RB, Maliwal BP, Zeng HH. Zinc biosensing with multiphoton excitation using carbonic anhydrase and improved fluorophores. J Biomed Opt. 2000;5:17–22. [PubMed]
28. Atar D, Backx PH, Appel MM, Gao WD, Marban E. Excitation-transcription coupling mediated by zinc influx through voltage-dependent calcium channels. J Biol Chem. 1995;270:2473–2477. [PubMed]
29. Kerchner GA, Canzoniero LM, Yu SP, Ling C, Choi DW. Zn2+ current is mediated by voltage-gated Ca2+ channels and enhanced by extracellular acidity in mouse cortical neurones. J Physiol. 2000;528(Pt 1):39–52. [PubMed]
30. Yin HZ, Ha DH, Carriedo SG, Weiss JH. Kainate-stimulated Zn2+uptake labels cortical neurons with Ca2+-permeable AMPA/kainate channels. Brain Res. 1998;781:45–55. [PubMed]
31. Li Y, Hough CJ, Suh SW, Sarvey JM, Frederickson CJ. Rapid translocation of Zn(2+) from presynaptic terminals into postsynaptic hippocampal neurons after physiological stimulation. J Neurophysiol. 2001;86:2597–2604. [PubMed]
32. Maret W. The function of zinc metallothionein: a link between cellular zinc and redox state. J Nutr. 2000;130:1455S–1458S. [PubMed]
33. Maret W. Oxidative metal release from metallothionein via zinc-thiol/disulfide interchange. Proc Natl Acad Sci U S A. 1994;91:237–241. [PubMed]
34. Uchida Y, Taiko K, Titani KIY, Tomonaga M. The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 aminoacid metallothionein-like protein. Neuron. 1991;31:337–347. [PubMed]
35. Palmiter RD, Findley SD, Whitmore TE, Durnam DM. MT-III, a brain-specific member of the metallothionein gene family. Proc Natl Acad Sci U S A. 1992;89:6333–6337. [PubMed]
36. Lee JY, Kim JH, Palmiter RD, Koh JY. Zinc released from metallothionein-iii may contribute to hippocampal CA1 and thalamic neuronal death following acute brain injury. Exp Neurol. 2003;184:337–347. [PubMed]
37. Howell GA, Welch MG, Frederickson CJ. Stimulation-induced uptake and release of zinc in hippocampal slices. Nature. 1984;308:736–738. [PubMed]
38. Li Y, Hough CJ, Suh SW, Sarvey JM, Frederickson CJ. Rapid translocation of Zn(2+ from presynaptic terminals into postsynaptic hippocampal neurons after physiological stimulation. J Neurophysiol. 2001;86:2597–2604. [PubMed]
39. Erickson JC, Hollopeter G, Thomas SA, Froelick GJ, Palmiter RD. Disruption of the metallothionein-III gene in mice: analysis of brain zinc, behavior, and neuron vulnerability to metals, aging, and seizures. J Neurosci. 1997;17:1271–1281. [PubMed]
40. Lee JY, Kim JH, Palmiter RD, Koh JY. Zinc released from metallothionein-iii may contribute to hippocampal CA1 and thalamic neuronal death following acute brain injury. Exp Neurol. 2003;184:337–347. [PubMed]
41. Peters S, Koh J, Choi DW. Zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons. Science. 1987;236:589–593. [PubMed]
42. Paoletti P, Ascher P, Neyton J. High-affinity zinc inhibition of NMDA NR1-NR2A receptors. J Neurosci. 1997;17:5711–5725. [PubMed]
43. Low CM, Zheng F, Lyuboslavsky P, Traynelis SF. Molecular determinants of coordinated proton and zinc inhibition of N-methyl-D-aspartate NR1/NR2A receptors. Proc Natl Acad Sci U S A. 2000;97:11062–11067. [PubMed]
44. Coughenour LL, Barr BM. Use of trifluoroperazine isolates a [(3)H]Ifenprodil binding site in rat brain membranes with the pharmacology of the voltage-independent ifenprodil site on N-methyl-D-aspartate receptors containing NR2B subunits. J Pharmacol Exp Ther. 2001;296:150–159. [PubMed]
45. Manzerra P, Behrens MM, Canzoniero LM, Wang XO, Heidinger V, Ichinose T, et al. Zinc induces a Src family kinase-mediated up-regulation of NMDA receptor activity and excitotoxicity. Proc Natl Acad Sci U S A. 2001;98:11055–11061. [PubMed]
46. Kim TY, Hwang JJ, Yun SH, Jung MW, Koh JY. Augmentation by zinc of NMDA receptor-mediated synaptic responses in CA1 of rat hippocampal slices: mediation by Src family tyrosine kinases. Synapse. 2002;46:49–56. [PubMed]
47. Westbrook GL, Mayer ML. Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons. Nature. 1987;328:640–643. [PubMed]
48. Ruiz A, Walker MC, Fabian-Fine R, Kullmann DM. Endogenous zinc inhibits GABA(A) receptors in a hippocampal pathway. J Neurophysiol. 2004;91:1091–1096. [PubMed]
49. Xie X, Hider RC, Smart TG. Modulation of GABA-mediated synaptic transmission by endogenous zinc in the immature rat hippocampus in vitro. J Physiol. 1994;478:75–86. [PubMed]
50. Buhl EH, Otis TS, Mody I. Zinc-induced collapse of augmented inhibition by GABA in a temporal lobe epilepsy model. Science. 1996;271:369–373. [PubMed]
51. Coulter DA. Epilepsy-associated plasticity in gamma-aminobutyric acid receptor expression, function, and inhibitory synaptic properties. Int Rev Neurobiol. 2001;45:237–252. [PubMed]
52. Shumate MD, Lin DD, Gibbs JW, III, Holloway KL, Coulter DA. GABA(A) receptor function in epileptic human dentate granule cells: comparison to epileptic and control rat. Epilepsy Res. 1998;32:114–128. [PubMed]
53. Banerjee PK, Olsen RW, Snead OC., III Zinc inhibition of gamma-aminobutyric acid(A) receptor function is decreased in the cerebral cortex during pilocarpine-induced status epilepticus. J Pharmacol Exp Ther. 1999;291:361–366. [PubMed]
54. Murphy JV. Intoxication following ingestion of elemental zinc. JAMA. 1970;212:2119–2120. [PubMed]
55. Taban CH, Cathieni M, Burkard P. Changes in newt brain caused by zinc water-pollution. Experientia. 1982;38:683–685. [PubMed]
56. Dethloff GM, Schlenk D, Hamm JT, Bailey HC. Alterations in physiological parameters of rainbow trout (Oncorhynchus mykiss) with exposure to copper and copper/zinc mixtures. Ecotoxicol Environ Saf. 1999;42:253–264. [PubMed]
57. Yokoyama M, Koh J, Choi DW. Brief exposure to zinc is toxic to cortical neurons. Neurosci Lett. 1986;71:351–355. [PubMed]
58. Frederickson CJ, Klitenick MA, Manton WI, Kirkpatrick JB. Cytoarchitectonic distribution of zinc in the hippocampus of man and the rat. Brain Res. 1983;273:335–339. [PubMed]
59. Sloviter RS. A selective loss of hippocampal mossy fiber Timm stain accompanies granule cell seizure activity induced by perforant path stimulation. Brain Res. 1985;330:150–153. [PubMed]
60. Assaf SY, Chung SH. Release of endogenous Zn2+ from brain tissue during activity. Nature. 1984;308:734–736. [PubMed]
61. Ueno S, Tsukamoto M, Hirano T, Kikuchi K, Yamada MK, Nishiyama N, et al. Mossy fiber Zn2+ spillover modulates heterosynaptic N-methyl-D-aspartate receptor activity in hippocampal CA3 circuits. J Cell Biol. 2002;158:215–220. [PMC free article] [PubMed]
62. Koh JY, Suh SW, Gwag BJ, He JJ, Shu CY, Choi DW. The role of zinc in selective neuronal death after transient global cerebral ischemia. Science. 1996;272:1013–1016. [PubMed]
63. Suh SW, Chen JW, Motamedi M, Bell B, Lstiak K, Pons NF, et al. Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury. Brain Res. 2000;852:268–273. [PubMed]
64. Lee JM, Zipfel GJ, Park KH, He YY, Shu CY, Choi DW. Zinc translocation accelerates infarction after mild transient focal ishcemia. Neuroscience. 2002;115:871–878. [PubMed]
65. Yin HZ, Sensi SL, Ogoshi F, Weiss JH. Blockade of Ca2+-permeable AMPA/kainate channels decreases oxygen-glucose deprivation-induced Zn2+ accumulation and neuronal loss in hippocampal pyramid neurons. J Neurosci. 2002;22:1273–1279. [PubMed]
66. Suh SW, Garnier P, Aoyama K, Chen Y, Swanson RA. Zinc release contributes to hypoglycemia-induced neuronal death. Neurobiol Dis. 2004;16:538–545. [PubMed]
67. Frederickson CJ, Hernandez MD, McGinty JF. Translocation of zinc may contribute to seizure-induced death of neurons. Brain Res. 1989;480:317–321. [PubMed]
68. Lee JY, Friedman JE, Angel I, Kozak A, Koh JY. The lipophilic metal chelator DP-109 reduces amyloid pathology in brains of human amyloid precursor protein transgenic mice. Neurobiol Aging. 2004 in press. [PubMed]
69. Lee JY, Cole TB, Palmiter RD, Koh JY. Accumulation of zinc in degenerating hippocampal neurons of ZnT3-null mice after seizures: evidence against synaptic vesicle origin. J Neurosci. 2000;20:RC79. [PubMed]
70. Frederickson CJ, Suh SW, Koh JT, Cha YK, Thompson RB, LaBuda CJ, et al. Depletion of intracellular zinc from neurons by use of an extracellular chelator in vivo and in vitro. J Histochem Cytochem. 2000;50:1659–1662. [PubMed]
71. Wei G, Hough CJ, Li Y, Sarvey JM. Characterization of extracellular accumulation of Zn(2+) during ischemia and reperfusion of hippocampus slices in rat. Neuroscience. 2004;125:867–877. [PubMed]
72. Sunderman FW., Jr The influence of zinc on apoptosis. Ann Clin Lab Sci. 1995;25:134–142. [PubMed]
73. Kim EY, Koh JY, Kim YH, Sohn S, Joe EH, Gwag BJ. Zn2+ entry produces oxidative neuronal necrosis in cortical cell cultures. Eur J Neurosci. 1999;11:327–334. [PubMed]
74. Sensi SL, Yin HZ, Weiss JH. Glutamate triggers preferential Zn2+ flux through Ca2+ permeable AMPA channels and consequent ROS production. Neuroreport. 1999;10:1723–1727. [PubMed]
75. Noh KM, Kim YH, Koh JY. Mediation by membrane protein kinase C of zinc-induced oxidative neuronal injury in mouse cortical cultures. J Neurochem. 1999;72:1609–1616. [PubMed]
76. Kim YH, Kim EY, Gwag BJ, Sohn S, Koh JY. Zinc-induced cortical neuronal death with features of apoptosis and necrosis: mediation by free radicals. Neuroscience. 1999;89:175–182. [PubMed]
77. Seo SR, Chong SA, Lee SL, Sung JY, Ahn YS, Chong KC, et al. Zn2+-induced ERK activation mediated by reactive oxygen species cause cell death in differentiated PC12 cells. J Neurochem. 2001;78:600–610. [PubMed]
78. Noh KM, Koh JY. Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes. J Neurosci. 2000;20:RC111. [PubMed]
79. Lobner D, Canzoniero LM, Manzerra P, Gottron F, Yang H, Knudson M, et al. Zinc-induced neuronal death in cortical neurons. Cell Mol Biol. 2000;46:797–806. [PubMed]
80. McCabe MJ, Jr, Jiang SA, Orrenius S. Chelation of intracellular zinc triggers apoptosis in mature thymocytes. Lab Invest. 1993;69:101–110. [PubMed]
81. Ahn YH, Kim YH, Hong SH, Koh JY. Depletion of intracellular zinc induces protein synthesis-dependent neuronal apoptosis in mouse cortical culture. Exp Neurol. 1998;154:47–56. [PubMed]
82. Park JA, Lee JY, Sato TA, Koh JY. Co-induction of p75NTR and p75NTR-associated death executor in neurons after zinc exposure in cortical culture or transient ischemia in the rat. J Neurosci. 2000;20:9096–9103. [PubMed]
83. Mukai J, Hachiya T, Shoji-Hoshino S, Kimura MT, Nadano D, Suvanto P, et al. NADE, a p75NTR-associated cell death executor, is involved in signal trnsduction mediated by the common neurotrophin receptor p75NTR. J Biol Chem. 2000;275:17566–17570. [PubMed]
84. Jiang D, Sullivan PG, Sensi SL, Steward O, Weiss JH. Zn(2+) induces permeability transition pore opening and release of pro-apoptotic peptides from neuronal mitochondria. J Biol Chem. 2001;276:47524–47529. [PubMed]
85. Yi JS, Lee SK, Sato TA, Koh JY. Co-induction of p75NTR and the associated death executor NADE in degenerating hippocampal neurons after kainate-induced seizures in the rat. Neurosci Lett. 2003;347:126–130. [PubMed]
86. Aravindakumar CT, Ceulemans J, De Ley M. Nitric oxide induces Zn2+ release from metallothionein by destroying zinc-sulphur clusters without concomitant formation of S-nitrosothiol. Biochem J. 1999;344:253–258. [PubMed]
87. Maret W. The function of zinc metallothionein: a link between cellular zinc and redox state. J Nutr. 2000;130:1455S–1458S. [PubMed]
88. St Croix CM, Wasserloos KJ, Dineley KE, Reynolds IJ, Levutan ES, Pitt BR. Nitric oxide-induced changes in intracellular zinc homeostasis are mediated by metallothionein/thionein. Am J Physiol Lung Cell Mol Physiol. 2002;282:L185–L192. [PubMed]
89. Jacob C, Maret W, Vallee BL. Control of zinc transfer between thionein, metallothionein, and zinc proteins. Proc Natl Acad Sci U S A. 1998;95:3489–3494. [PubMed]
90. Maret W. The function of zinc metallothionein: a link between cellular zinc and redox state. J Nutr. 2000;130:1455S–1458S. [PubMed]
91. Frederickson CJ, Cuajungco MP, LaBuda CJ, Suh SW. Nitric oxide causes apparent release of zinc from presynaptic boutons. Neuroscience. 2002;115:471–474. [PubMed]
92. Kim YH, Koh JY. 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. 2002;177:407–418. [PubMed]
93. Ha HC, Snyder SH. Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci U S A. 1999;96:13978–13982. [PubMed]
94. Szabo C, Dawson VL. Role of poly (ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci. 1998;19:287–298. [PubMed]
95. Sheline CT, Wang H, Cai AL, Dawson VL, Choi DW. Involvement of poly ADP ribosyl polymerase-1 in acute but not chronic zinc toxicity. Eur J Neurosci. 2003;18:1402–1409. [PubMed]
96. Terry RD, Katzman R. Senile dementia of the Alzheimer type. Annals Neurol. 1983;14:497–506. [PubMed]
97. Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984;120:885–890. [PubMed]
98. Masters CL, Simms G, Weinzman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985;82:4245–4249. [PubMed]
99. Bush AI, Pettingell WH, Jr, Paradis MD, Tanzi RE. Modulation of A beta adhesiveness and secretase site cleavage by zinc. J Biol Chem. 1994;269:12152–12158. [PubMed]
100. Bush AI, Pettingell WH, Multhaup G, di Paradis M, Vonsattel JP, Gusella JF, et al. Rapid induction of Alzheimer A beta amyloid formation by zinc. Science. 1994;265:1464–1467. [PubMed]
101. Frederickson CJ, Maret W, Cuajungco MP. Zinc and excitotoxic brain injury: a new model. Neuroscientist. 2004;10:18–25. [PubMed]
102. Liu ST, Howlett G, Barrow CJ. Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the A beta peptide of Alzheimer's disease. Biochemistry. 1999;38:9373–9378. [PubMed]
103. Esch FS, Keim PS, Beattie ES, Blchor RW, Cultwell AR, Oltersdorf T, et al. Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science. 1990;248:1122–1124. [PubMed]
104. Huang X, Atwood CS, Moir RD, Hartshom MA, Vonsattel JP, Tanzi RE, et al. Zinc-induced Alzheimer's Abeta1-40 aggregation is mediated by conformational factors. J Biol Chem. 1997;272:26464–26470. [PubMed]
105. Atwood CS, Moir RD, Huang X, Scarpa RC, Bacurra VM, Romano DM, et al. Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem. 1998;273:12817–12826. [PubMed]
106. Miura T, Suzuki K, Kohata N, Takeuchi H. Metal binding modes of Alzheimer's amyloid beta-peptide in insoluble aggregates and soluble complexes. Biochemistry. 2000;39:7024–7031. [PubMed]
107. Atwood CS, Scarpa RC, Huang X, Moir RD, Jones WD, Fairlie DP, et al. Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42. J Neurochem. 2000;75:1219–1233. [PubMed]
108. Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR. Copper, iron and zinc in Alzheimer's disease senile plaques. J Neurol Sci. 1998;158:47–52. [PubMed]
109. Opazo C, Hwang X, Cherny RA, Moir RD, Roher AE, White AR, et al. Metalloenzyme-like activity of Alzheimer's disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H(2)O(2) J Biol Chem. 2002;277:40302–40308. [PubMed]
110. Dong J, Atwood CS, Anderson VE, Siedlak SL, Smith MA, Perry G. Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence. Biochemistry. 2003;42:2768–2773. [PubMed]
111. Maynard CJ, Cappai R, Volitakis I, Cherny RA, White AR, Beyreuther K, et al. Overexpression of Alzheimer's disease amyloid-beta opposes the age-dependent elevations of brain copper and iron. J Biol Chem. 2002;277:44670–44676. [PubMed]
112. Huang X, Cuajungco MP, Atqood CS, Hartshom MA, Tyndall JD, Hanson GR, et al. Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem. 1999;274:37111–37116. [PubMed]
113. Huang X, Atwood CS, Hartshom MA, Multhaup G, Goldstein LE, Scarpa RC, et al. The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry. 1999;38:7609–7616. [PubMed]
114. Rottkamp CA, Raina AK, Zhu X, Gaier E, Bush AI, Atwood CS, Chevion M, et al. Redox-active iron mediates amyloid-beta toxicity. Free Radic Biol Med. 2001;30:447–450. [PubMed]
115. Atwood CS, Huang X, Khani A, Scarpa RC, Kim YS, Moir RD, et al. Copper catalyzed oxidation of Alzheimer Abeta. Cell Mol Biol. 2000;46:777–783. [PubMed]
116. Atwood CS, Perry G, Zeng H, Kato Y, Jones WD, Ling KO, et al. Copper mediates dityrosine cross-linking of Alzheimer's amyloid-beta. Biochemistry. 2004;43:560–568. [PubMed]
117. Barnham KJ, Ciccotosto GD, Tickler AK, Ali FE, Smith DG, Williamson NA, et al. Neurotoxic, redox-competent Alzheimer's beta-amyloid is released from lipid membrane by methionine oxidation. J Biol Chem. 2003;278:42959–42965. [PubMed]
118. McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MS, Beyruether K, et al. Soluble pool of Ab amyloid as a determinant of severity of neurodegenertion in Alzheimer's disease. Ann Neurol. 1996;46:860–866. [PubMed]
119. Cherny RA, Legg JT, McLean CA, Fairlie DP, Huang X, Atwood CS, et al. Aqueous dissolution of Alzheimer's disease Abeta amyloid deposits by biometal depletion. J Biol Chem. 1999;274:23223–23228. [PubMed]
120. Head E, Garzon-Rodriguez M, Johnson JK, Lott IT, Cotman CW, et al. Oxidation of Abeta and plaque biogenesis in Alzheimer's disease and Down syndrome. Neurobiol Dis. 2001;8:792–806. [PubMed]
121. Turnbull S, Tabner BJ, El Agnaf OM, Twyman LJ, Allsop D. New evidence that the Alzheimer beta-amyloid peptide does not spontaneously form free radicals: an ESR study using a series of spin-traps. Free Radic Biol Med. 2001;30:1154–1162. [PubMed]
122. Hensley K, Hall N, Subaramanian R, Cole P, Askenov M, Gabbita SP, et al. Brain regional correspondence between Alzheimer's disease histopathology and biomarkers of protein oxidation. J Neurochem. 1995;65:2146–2156. [PubMed]
123. Smith MA, Hirai K, Hsiao K, Pappolla MA, Harnis PL, Siedlack SL, et al. Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem. 1998;70:2212–2215. [PubMed]
124. Cuajungco MP, et al. Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of abeta by zinc. J Biol Chem. 2000;275:19439–19442. [PubMed]
125. Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY. Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proc Natl Acad Sci U S A. 2002;99:7705–7710. [PubMed]
126. Lee JY, Kim JH, Hong SH, Lee JY, Cherny RA, Bush AI, et al. Estrogen decreases zinc transporter 3 expression and synaptic vesicle zinc in mouse brain. J Biol Chem. 2004;279:8602–8607. [PubMed]
127. Sillevis Smitt PA, Mulder TP, Verspaget HW, Blaauwgeers HG, Troost D, de Jong JM. Metallothionein in amyotrophic lateral sclerosis. Biol Signals. 1994;3:193–197. [PubMed]
128. Sillevis Smitt PA, Blaauwgeers HG, Troost D, de Jong JM. Metallothionein immunoreactivity is increased in the spinal cord of patients with amyotrophic lateral sclerosis. Neurosci Lett. 1992;144:107–110. [PubMed]
129. Reaume AG, Elliott JL, Hoffman EK, Kowall NW, Ferrante RJ, Siwek DF, et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet. 1996;13:43–47. [PubMed]
130. Liochev SI, Chen LL, Hallewell RA, Fridovich I. Superoxide-dependent peroxidase activity of H48Q: a superoxide dismutase variant associated with familial amyotrophic lateral sclerosis. Arch Biochem Biophys. 1997;346:263–268. [PubMed]
131. Singh RJ, Karoui H, Gunther MR, Beckman JS, Mason RP, Kalyanaraman B. Reexamination of the mechanism of hydroxyl radical adducts formed from the reaction between familial amyotrophic lateral sclerosis-associated Cu, Zn superoxide dismutase mutants and H2O2. Proc Natl Acad Sci U S A. 1998;95:6675–6680. [PubMed]
132. Roe JA, Wiedau-Pazos M, Moy VN, Goto JJ, Gralla EB, Valentine JS. In vivo peroxidative activity of FALS-mutant human CuZnSODs expressed in yeast. Free Radic Biol Med. 2002;32:169–174. [PubMed]
133. Estevez AG, Crow JP, Sampson JB, Reiter C, Zhuang Y, Richardson GJ, Tarpey MM, et al. Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. Science. 1999;286:2498–2500. [PubMed]
134. Gong YH, Elliott JL. Metallothionein expression is altered in a transgenic murine model of familial amyotrophic lateral sclerosis. Exp Neurol. 2000;162:27–36. [PubMed]
135. Nagano S, et al. Reduction of metallothioneins promotes the disease expression of familial amyotrophic lateral sclerosis mice in a dose-dependent manner. Eur J Neurosci. 2001;13:1363–1370. [PubMed]
136. Puttaparthi K, Gitomer WL, Krishnan U, Son M, Rajendra B, Elliott JL. Disease progression in a transgenic model of familial amyotrophic lateral sclerosis is dependent on both neuronal and non-neuronal zinc binding proteins. J Neurosci. 2002;22:8790–8796. [PubMed]
137. Cherny RA, Atwood CS, Xilinas ME, Gay DN, Jones WD, McLean CA, et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron. 2001;30:665–676. [PubMed]
138. Regland B, Lehmann W, Abedini I, Blennon K, Jonsson M, Karlson I, et al. Treatment of Alzheimer's disease with clioquinol. Dement Geriatr Cogn Disord. 2001;12:408–414. [PubMed]
139. Ritchie CW, Bush AI, Mackinnon K, Mcfarrens S, Mastwyk M, MacGregor L, et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol. 2003;60:1685–1691. [PubMed]
140. Canzoniero LM, Manzerra P, Sheline CT, Choi DW. Membrane-permeant chelators can attenuate Zn2+-induced cortical neuronal death. Neuropharmacology. 2003;45:420–428. [PubMed]
141. Sensi SL, Ton-That D, Weiss JH. Mitochondrial sequestration and Ca2+-dependent release of cytosolic Zn2+ loads in cortical neurons. Neurobiol Dis. 2002;10:100–108. [PubMed]
142. Noh KM, Kim YH, Koh JY. Mediation by membrane protein kinase C of zinc-induced oxidative neuronal injury in mouse cortical cultures. J Neurochem. 1999;72:1609–1616. [PubMed]
143. Sheline CT, Behrens MM, Choi DW. Zinc-induced cortical neuronal death: contribution of energy failure attributable to loss of NAD(+) and inhibition of glycolysis. J Neurosci. 2000;20:3139–3146. [PubMed]
144. Kelland EE, Kelly MD, Toms NJ. Pyruvate limits zinc-induced rat oligodendrocyte progenitor cell death. Eur J Neurosci. 2004;19:287–294. [PubMed]
145. Lee JY, Kim YH, Koh JY. Protection by pyruvate against transient forebrain ischemia in rats. J Neurosci. 2001;21:RC171. [PubMed]
146. Yoo MH, Lee JY, Lee SE, Koh JY, Yoon YH. Protection by Pyruvate of Rat Retinal Cells against Zinc Toxicity In Vitro, and Pressure-Induced Ischemia In Vivo. Invest Ophthalmol Vis Sci. 2004;45:1523–1530. [PubMed]
147. Chang I, Cho N, Koh JY, Lee MS. Pyruvate inhibits zinc-mediated pancreatic islet cell death and diabetes. Diabetologia. 2003;46:1220–1227. [PubMed]
148. Dobsak P, Courderot-Masuyer C. Antioxidative properties of pyruvate and protection of the ischemic rat heart during cardioplegia. J Cardiovasc Pharmacol. 1999;34:651–659. [PubMed]
149. Albers GW. Advances in intravenous thrombolytic therapy for treatment of acute stroke. Neurology. 2001;57(5 Suppl 2):S77–S81. [PubMed]
150. Tsirka SE, Rogove AD, Strickland S. Neuronal cell death and tPA. Nature. 1996;384:123–124. [PubMed]
151. Kim YH, Park JH, Hong SH, Koh JY. Nonproteolytic neuroprotection by human recombinant tissue plasminogen activator. Science. 1999;284:647–650. [PubMed]
152. Siddiq MM, Tsirka SE. Modulation of zinc toxicity by tissue plasminogen activator. Mol Cell Neurosci. 2004;25:162–171. [PubMed]

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