Zinc: indications in brain disorders

Prakash, Atish; Bharti, Kanchan; Majeed, Abu Bakar Abdul

doi:10.1111/fcp.12110

Cited by 107 publications

(70 citation statements)

References 175 publications

(230 reference statements)

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“…Zinc is known to modulate synaptic activity and neuronal plasticity which are directly related to cognitive function [5, 44, 45]. Studies on zinc intake and cognitive function in humans have mixed results.…”

Section: Discussionmentioning

confidence: 99%

Adverse effects of parental zinc deficiency on metal homeostasis and embryonic development in a zebrafish model

Beaver

Nkrumah‐Elie

Truong

et al. 2017

The Journal of Nutritional Biochemistry

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The high prevalence of zinc deficiency is a global public health concern, and suboptimal maternal zinc consumption has been associated with adverse effects ranging from impaired glucose tolerance to low birthweights. The mechanisms that contribute to altered development and poor health in zinc deficient offspring are not completely understood. To address this gap, we utilized the Danio rerio model and investigated the impact of dietary zinc deficiency on adults and their developing progeny. Zinc deficient adult fish were significantly smaller in size, and had decreases in learning and fitness. We hypothesized that parental zinc deficiency would have an impact on their offspring’s mineral homeostasis and embryonic development. Results from mineral analysis showed that parental zinc deficiency caused their progeny to be zinc deficient. Furthermore, parental dietary zinc deficiency had adverse consequences for their offspring including a significant increase in mortality and decreased physical activity. Zinc deficient embryos had altered expression of genes that regulate metal homeostasis including several zinc transporters (ZnT8, ZnT9) and the metal-regulatory transcription factor 1 (MTF-1). Zinc deficiency was also associated with decreased expression of genes related to diabetes and pancreatic development in the embryo (Insa, Pax4, Pdx1). Decreased expression of DNA methyltransferases (Dnmt4, Dnmt6) was also found in zinc deficient offspring, which suggests that zinc deficiency in parents may cause altered epigenetic profiles for their progeny. These data should inform future studies regarding zinc deficiency and pregnancy and suggest that supplementation of zinc deficient mothers prior to pregnancy may be beneficial.

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Section: Discussionmentioning

confidence: 99%

Adverse effects of parental zinc deficiency on metal homeostasis and embryonic development in a zebrafish model

Beaver

Nkrumah‐Elie

Truong

et al. 2017

The Journal of Nutritional Biochemistry

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“…It has been generally observed that also the level of zinc transporters (ZnT3, ZIP 1, and 6 as well as ZnT1, 4, and 6) undergo various age-related changes in the brain, and in AD patients (Prakash et al, 2015). Indeed, treatment of ZnT3 KO mice with clioquinol has been found to restore the hippocampal zinc levels and up-regulated key proteins particularly relevant for cognition functions (e.g., presynaptic SNAP-25 and synaptophysin, post-synaptic spinophilin and PSD-95, cell supporting pro-BDNF and DCX, glutamate receptors AMPAR, and NMDAR2a/2b).…”

Section: Discussionmentioning

confidence: 99%

The Inorganic Side of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor

Pandini

Satriano

Pietropaolo³

et al. 2016

Front. Neurosci.

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The nerve growth factor (NGF) N-terminus peptide, NGF(1–14), and its acetylated form, Ac-NGF(1–14), were investigated to scrutinize the ability of this neurotrophin domain to mimic the whole protein. Theoretical calculations demonstrated that non-covalent forces assist the molecular recognition of TrkA receptor by both peptides. Combined parallel tempering/docking simulations discriminated the effect of the N-terminal acetylation on the recognition of NGF(1–14) by the domain 5 of TrkA (TrkA-D5). Experimental findings demonstrated that both NGF(1–14) and Ac-NGF(1–14) activate TrkA signaling pathways essential for neuronal survival. The NGF-induced TrkA internalization was slightly inhibited in the presence of Cu2+ and Zn2+ ions, whereas the metal ions elicited the NGF(1–14)-induced internalization of TrkA and no significant differences were found in the weak Ac-NGF(1–14)-induced receptor internalization. The crucial role of the metals was confirmed by experiments with the metal-chelator bathocuproine disulfonic acid, which showed different inhibitory effects in the signaling cascade, due to different metal affinity of NGF, NGF(1–14) and Ac-NGF(1–14). The NGF signaling cascade, activated by the two peptides, induced CREB phosphorylation, but the copper addition further stimulated the Akt, ERK and CREB phosphorylation in the presence of NGF and NGF(1–14) only. A dynamic and quick influx of both peptides into PC12 cells was tracked by live cell imaging with confocal microscopy. A significant role of copper ions was found in the modulation of peptide sub-cellular localization, especially at the nuclear level. Furthermore, a strong copper ionophoric ability of NGF(1–14) was measured. The Ac-NGF(1–14) peptide, which binds copper ions with a lower stability constant than NGF(1–14), exhibited a lower nuclear localization with respect to the total cellular uptake. These findings were correlated to the metal-induced increase of CREB and BDNF expression caused by NGF(1–14) stimulation. In summary, we here validated NGF(1–14) and Ac-NGF(1–14) as first examples of monomer and linear peptides able to activate the NGF-TrkA signaling cascade. Metal ions modulated the activity of both NGF protein and the NGF-mimicking peptides. Such findings demonstrated that NGF(1–14) sequence can reproduce the signal transduction of whole protein, therefore representing a very promising drug candidate for further pre-clinical studies.

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“…Zinc is also tightly regulated in the brain, with higher levels in the amygdala, hippocampus and cortex, predominantly located within glutamatergic neurons known as “zinc enriched neurons” (ZEN) (Nowak et al, 2003b; Prakash et al, 2015). About 15% of all zinc in the CNS is in vesicular form within ZENs (Nowak, 2001).…”

Section: Zinc Homeostasis and Regulationmentioning

confidence: 99%

“…Its general actions are well reviewed, as briefly described in this paper and several excellent reviews (Marger et al, 2014; Nowak, 2015; Prakash et al, 2015), but a role for zinc homeostasis with respect to clinical depression and psychosis is not well appreciated by psychiatrists. Zinc is the second most abundant divalent cation after calcium and is a component in hundreds of enzymes and proteins.…”

Section: Introductionmentioning

confidence: 96%

The Emerging Role for Zinc in Depression and Psychosis

et al. 2017

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Zinc participation is essential for all physiological systems, including neural functioning, where it participates in a myriad of cellular processes. Converging clinical, molecular, and genetic discoveries illuminate key roles for zinc homeostasis in association with clinical depression and psychosis which are not yet well appreciated at the clinical interface. Intracellular deficiency may arise from low circulating zinc levels due to dietary insufficiency, or impaired absorption from aging or medical conditions, including alcoholism. A host of medications commonly administered to psychiatric patients, including anticonvulsants, oral medications for diabetes, hormones, antacids, anti-inflammatories and others also impact zinc absorption. Furthermore, inefficient genetic variants in zinc transporter molecules that transport the ion across cellular membranes impede its action even when circulating zinc concentrations is in the normal range. Well powered clinical studies have shown beneficial effects of supplemental zinc in depression and it important to pursue research using zinc as a potential therapeutic option for psychosis as well. Meta-analyses support the adjunctive use of zinc in major depression and a single study now supports zinc for psychotic symptoms. This manuscript reviews the biochemistry and bench top evidence on putative molecular mechanisms of zinc as a psychiatric treatment.

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Zinc: indications in brain disorders

Cited by 107 publications

References 175 publications

Adverse effects of parental zinc deficiency on metal homeostasis and embryonic development in a zebrafish model

Adverse effects of parental zinc deficiency on metal homeostasis and embryonic development in a zebrafish model

The Inorganic Side of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor

The Emerging Role for Zinc in Depression and Psychosis

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