**3.1 Examples of zinc ionophores and their role in brain health, depression as an example**

#### *3.1.1 Quercetin*

Quercetin has attracted the attention of many researchers because of its capacity to pass the blood–brain barrier. It appears in the brain after hours of administration and plays a key function in the central nervous system [75]. Discoveries from animal *Role of Zinc and Zinc Ionophores in Brain Health and Depression Especially… DOI: http://dx.doi.org/10.5772/intechopen.102923*

#### **Figure 1.**

*Zinc ionophores mechanism in penetrating cell membranes. Two ionophore molecules can mediate intracellular zinc accumulation by exchanging extracellular Zn2+ with 2H+ [56]. Then, ionophore-zinc complex is taken up by endocytosis, followed by lysosomal disruption to release zinc into the cytoplasm [57].*


#### **Table 1.**

*Nature and synthetic zinc ionophores.*

model research reported that antioxidant, anti-inflammatory, and neuroprotective effects of quercetin keep neurons in healthy condition by inhibiting the formation of hydroperoxide, reducing free radicals, and restoring antioxidant enzymes. Further, the study of quercetin at rat models proves its antidepressant action [76, 77]. Also, quercetin can reduce stress and depressive-like symptoms [75].

#### *3.1.2 Epigallocatechin gallate (EGCG)*

EGCG may act as a new antidepressant by inhibiting neuroinflammation, which may help to alleviate depression. Models of chronic unexpected mild stress (CUMS) in rats have been created in experimental investigations of depression [78]. Although the etiology of depression is not well understood, one popular theory is that depressed

#### **Figure 2.**

*Natural zinc ionophores and their sources. Chemical structures of ionophores obtained from Pubchem database (Hinokitiol, CID: 3611; quercetin, CID: 5280343; EGCG, CID: 65064; Proanthocyanidin, CID: 108065).*

people have greater amounts of cytokines such as IL-6 due to lower levels of amines such as serotonin, noradrenaline, and dopamine [79]. EGCG injection improved depressed behavior in rats by reducing Il-6 levels in the hippocampus. As a result, EGCG was suggested to be used as a new antidepressant to reduce neuroinflammation, which could help to alleviate depression [80].

#### *3.1.3 Hinokitol*

Hinokitiol (β-thujaplicin) is a monoterpenoid that occurs naturally in the wood of Cupressaceae plants. It is a natural zinc ionophore that is safe to use. Because of its powerful, broad-spectrum antiviral, antibacterial, antifungal, anti-inflammatory, and anticancer effects, it is frequently employed in oral care and medicinal products. It is also a food additive that does not build up in the body. Throughout years of use, there have been no reports of allergic, poisonous, or adverse consequences in the literature. Hinokitiol is a safe zinc ionophore that increases the intracellular pool of labile zinc by facilitating zinc influx into cells [81].

#### *3.1.4 Proanthocyanidins*

Proanthocyanidins (GSPs), which comprise dimers, trimers, oligomers, and oligomers of catechin and epicatechin, are known to have antidepressant properties. Recent research has demonstrated the mechanism of GSPs' antidepressant effects in female juvenile prenatally stressed offspring rats. The main pathway was that GSPs work synergistically to inhibit oxidative stress and inflammatory response activator proteins [66].

### **4. Cross talk between zinc deficiency and depression caused by COVID-19**

High rates of neuropsychiatric symptoms (e.g., depression) have been observed among patients affected by COVID-19, suggesting an effect of COVID-19 on the human central nervous system (CNS) [82–85]. It was showed globally that depression is a leading cause of disability [86]. Accordingly, clinically significant depression and

#### *Role of Zinc and Zinc Ionophores in Brain Health and Depression Especially… DOI: http://dx.doi.org/10.5772/intechopen.102923*

depressive symptoms in post-COVID-19 syndrome may have severe implications as it relates to life outcomes quality [86]. 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. A meta-analysis of 17 observational studies found that blood Zn2+ concentrations were lower in depressed subjects than in control subjects [48]. Interestingly, a recent study showed that a significant number of patients with COVID-19 were zinc-deficient [87], and a higher number of zinc-deficient COVID-19 patients had prolonged hospital stay when compared with those with normal zinc levels and required intensive care unit (ICU) [87]. A significant positive correlation was observed between the prevalence of zinc deficiency and COVID-19 cases [88]. A pooled analysis of 1532 COVID-19 patients suggested that zinc deficiency was associated with a sixfold increased risk of severe disease and 16-fold increased risk of death via elevating LDH [89]. The elevated LDH in the present study was probably indicative of severe disease [87]. Because zinc has a critical role in regulating functions of the human brain, many disorders have been linked with Zn2+ deficiency, including neurological diseases, such as psychiatric disorders, (depression) [48, 89] and schizophrenia [90]. Consequently, the clinical picture, which is common in severe COVID-19 patients and is referred to as "Depression" [82–85], is nothing more than depression seen in zinc deficiency [48, 87–89]. Most likely, depression and other mental problems in these patients also develop due to zinc deficiency in nerve cells in the brain.

The first study revealing a relationship between depression and dietary zinc deficiency was conducted by Amani et al. [90]. This study included 23 young females diagnosed with moderate and severe depression and 23 healthy volunteers who were age-matched. The findings revealed that the depressive group's daily zinc consumption and serum zinc concentration were both lower than the healthy women's. Moreover, an inverse correlation between serum zinc concentration and the depression scores was obtained [90]. According to the World Health Organization (WHO), zinc deficiency affects at least one-third of the world's population [91]. The fact that zinc deficiency is linked to the risk of infection and severe advancement of COVID-19 [91] gives a first significant clue on a link between zinc deficiency and the risk of infection as well as its symptoms with unknown etiology such as depression and suggests possible benefits of zinc supplementation. Owing to Zn2+ neuroprotective properties, it is not surprising that Zn2+ supplementation could be effective not only on COVID-19-related symptoms but also on virus replication, as well as on COVID-19-related inflammation and neurological damage [92]. In vitro, Zn2+ inhibits Coronavirus and Arter virus RNA polymerase activity, and zinc ionophores prevent these viruses from replicating in cell culture [93]. Zinc ionophore may play a role in therapeutic management for COVID-19 [94].
