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.

Depression is a serious psychiatric illness that affects millions of people worldwide. Weeks of antidepressant therapy are required to relieve depressive symptoms, and new drugs are still being extensively researched. The latest studies have shown that in depression, there is an imbalance between the main excitatory (glutamatergic) and inhibitory (GABAergic) systems. Administration of antagonists of the glutamatergic system, including zinc, has shown an antidepressant effect in preclinical as well as clinical studies. Zinc inhibits the NMDA receptor via its binding site located on one of its subunits. This is thought to be the main mechanism explaining the antidepressant properties of zinc. In the present review, a link between zinc and the glutamatergic system is discussed in the context of depressive disorder.