Zinc is a nutritionally fundamental trace element, essential to the structure and function of numerous macromolecules, including enzymes regulating cellular processes and cellular signaling pathways. The mineral modulates immune response and exhibits antioxidant and anti-inflammatory activity. Zinc retards oxidative processes on a long-term basis by inducing the expression of metallothioneins. These metal-binding cysteine-rich proteins are responsible for maintaining zinc-related cell homeostasis and act as potent electrophilic scavengers and cytoprotective agents. Furthermore, zinc increases the activation of antioxidant proteins and enzymes, such as glutathione and catalase. On the other hand, zinc exerts its antioxidant effect via two acute mechanisms, one of which is the stabilization of protein sulfhydryls against oxidation. The second mechanism consists in antagonizing transition metal-catalyzed reactions. Zinc can exchange redox active metals, such as copper and iron, in certain binding sites and attenuate cellular site-specific oxidative injury. Studies have demonstrated that physiological reconstitution of zinc restrains immune activation, whereas zinc deficiency, in the setting of severe infection, provokes a systemic increase in NF-κB activation. In vitro studies have shown that zinc decreases NF-κB activation and its target genes, such as TNF-α and IL-1β, and increases the gene expression of A20 and PPAR-α, the two zinc finger proteins with anti-inflammatory properties. Alternative NF-κB inhibitory mechanism is initiated by the inhibition of cyclic nucleotide phosphodiesterase, whereas another presumed mechanism consists in inhibition of IκB kinase in response to infection by zinc ions that have been imported into cells by ZIP8.

Essential elements are very important for the proper functioning of the human body. They are required for fundamental life processes such as cell division and differentiation and protein synthesis. Thus a deficiency of these essential elements is associated with an enormous health risk that can ultimately lead to death. In recent years, studies have provided valuable information on the involvement of essential elements in psychiatric disorders, in particular depression and anxiety. There is strong evidence indicating that deficiency of essential elements can lead to the development of depressive and/or anxiogenic behaviour and supplementation can enhance therapeutic effect of antidepressants and anxiolytics. This review presents the most important results from preclinical and clinical studies showing involvement of essential elements such as zinc, magnesium, lithium, iron, calcium and chromium in depression and anxiety. From these studies it is evident that different types of depression and anxiety respond to treatment at different receptors indicating that the underlying mechanisms are slightly different. Furthermore, administration of low dose antidepressants supplemented with an element is effective and can reduce unwanted side effects in different types of depression/anxiety.

Background:Zinc may act as a neurotransmitter in the central nervous system by activation of the GPR39 metabotropic receptors.Methods:In the present study, we investigated whether GPR39 knockout would cause depressive-like and/or anxiety-like behavior, as measured by the forced swim test, tail suspension test, and light/dark test. We also investigated whether lack of GPR39 would change levels of cAMP response element-binding protein (CREB),brain-derived neurotrophic factor (BDNF) and tropomyosin related kinase B (TrkB) protein in the hippocampus and frontal cortex of GPR39 knockout mice subjected to the forced swim test, as measured by Western-blot analysis.Results:In this study, GPR39 knockout mice showed an increased immobility time in both the forced swim test and tail suspension test, indicating depressive-like behavior and displayed anxiety-like phenotype. GPR39 knockout mice had lower CREB and BDNF levels in the hippocampus, but not in the frontal cortex, which indicates region specificity for the impaired CREB/BDNF pathway (which is important in antidepressant response) in the absence of GPR39. There were no changes in TrkB protein in either structure. In the present study, we also investigated activity in the hypothalamus-pituitary-adrenal axis under both zinc- and GPR39-deficient conditions. Zinc-deficient mice had higher serum corticosterone levels and lower glucocorticoid receptor levels in the hippocampus and frontal cortex.Conclusions:There were no changes in the GPR39 knockout mice in comparison with the wild-type control mice, which does not support a role of GPR39 in hypothalamus-pituitary-adrenal axis regulation. The results of this study indicate the involvement of the GPR39 Zn2+-sensing receptor in the pathophysiology of depression with component of anxiety.