**Abstract**

Zinc is a trace metal ion that has a role in both physiological and pathological processes, making it one of the most common and necessary components involved in brain function. Besides, zinc is required for cell proliferation control in a variety of mechanisms, including hormonal regulation of cell division. Also, zinc serves as a biochemical signal to immune cells and transcription factors involved in the synthesis of inflammatory cytokines. On the other hand, zinc has a variety of crucial roles in neurogenesis and also acts as a neuromodulator on a wide range of membrane receptors, ion channels, and transporters. Zinc is produced by neurons under several conditions to activate microglia. The link between zinc dysregulation and psychiatric disorder was that zinc acts as an inhibitory modulator at the N-methyl-D aspartic acid (NMDA) glutamate receptor. Ionophores are ion carrier molecules that reversibly bind and transport ions through biological membranes. Ionophores can be natural or synthetic products. Zinc ionophores such as quercetin, epigallocatechin gallate (EGCG), hinokitol, and proanthocyanidins have been shown to protect brain health, particularly in depression clinically significant depression and depressive symptoms in post-COVID-19 syndrome may have severe implications as it relates to life outcomes quality, herein according to previous research studies, we showed zinc deficiency as a possible risk factor for depression symptoms, which were commonly observed following severe infection of COVID-19.

**Keywords:** ionophore, zinc, cytokines, quercetin, EGCG, hinokitol, proanthocyanidins

### **1. Introduction**

Zinc is a trace metal ion that has a role in both physiological and pathological processes, making it one of the most common and necessary components involved in brain function. The cortex, amygdala, olfactory bulb, and hippocampus neurons all carry "free ionic zinc" (Zn2+), which appears to have the largest concentration of zinc in the brain. Zinc is involved in the physiochemical function of enzymes, proteins, and signal transcription factors, as well as the maintenance of numerous homeostatic systems, functioning as structural, regulatory, and catalytic cofactors for enzymes including DNA and RNA polymerases, histone deacetylases, and DNA ligases. Zinc is also required for cell proliferation and genomic integrity [1–5].

As a neuromodulator, zinc is produced during synaptic transmission and attaches to presynaptic or postsynaptic membrane receptors, allowing it to translocate from presynaptic terminals to postsynaptic neurons [6, 7]. Zinc can be found in glutamatergic neurons' synaptic vesicles. Zinc is therefore liberated from glutamatergic synaptic vesicles and then interacts with excitatory and inhibitory amino acid receptors (N-methyl-D aspartic acid (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and γ-aminobutyric acid (GABA) [8–10]. Because of its actions on numerous voltage-gated ion channels, extracellular Zn2+ can modify the excitability of nerve cells [11–13].

Besides, zinc is required for cell proliferation control in a variety of mechanisms, including hormonal regulation of cell division. Also, zinc serves as a biochemical signal to immune cells and transcription factors involved in the synthesis of inflammatory cytokines. Zinc supplementation has been proven in trials to reduce rates of infection and proinflammatory cytokine secretion. Zinc also possesses metal-binding characteristics and is widely recognized for its antioxidant qualities [14, 15]. Zinc deficiency causes apoptosis in neurons via the mitochondrial pathway [16, 17]. Zinc has just lately been discovered to have a role in intracellular signaling as a second messenger. It is also used by immune cells as a molecular signal. Zinc controls a variety of transcription factors that control gene expression and are engaged in the signal transduction of inflammatory cytokines and adhesion molecules. Zinc helps to preserve genomic stability by regulating redox homeostasis, DNA repair, synthesis, and methylation [18, 19].
