1. Introduction

Lithium possesses the ability to depolarize the resting membrane potential of the cell [28]. It has been proposed that lithium treats bipolar patients by membrane depolarization of neuronal cells that is triggered by quantum tunneling of lithium ions through sodium channels when lithium reaches its therapeutic concentration [29,30]. A consistent correlation between lithium actions and the effects of membrane depolarization on the cells can be constructed. Lithium and membrane depolarization have neuroprotective effects through enhancing the growth of neurons and inhibiting their death. This makes lithium very effective in treating bipolar patients [8,31–34]. Lithium and membrane depolarization can inhibit or stimulate the growth of cells in different ways according to their cell lines [8–10,35,36]. They also have immunomodulatory actions that affect the functions of immune cells [8,37–39]. Furthermore, they can effectively enhance wound healing and bone repair [8,40,41]. More interestingly, membrane depolarization is the trigger of phosphoinositide 3-kinase (PI3K) and protein kinase B(Akt) activation [42], which leads to serine phosphorylation that inhibits glycogen synthase kinase-3-beta (GSK-3-beta) [43], which is an important target that is also inhibited by lithium by the same mechanism [44]. This indicates that lithium could mediate its cellular effects via membrane depolarization.

As stated in Section 2, it is clear that membrane hyperpolarization is a fundamental trigger for the release of the virus and its pathogenesis, as well as immune-system dysregulation. On the other hand, the ability of lithium ions to depolarize the membrane can be concluded from experimental and theoretical observations and the consistent correlation between actions of lithium and membrane depolarization. Therefore, lithium has the potential to reverse the hyperpolarization through the action of depolarization. Consequently, all the pathological processes mediated by hyperpolarization will be blocked and prevented. Figure 1 illustrates how membrane depolarization by lithium interrupts the activation of NLRP3.

Figure 1. A theoretical scheme of how lithium depolarization interrupts the cascade that leads to NLRP3 activation.

2. Role of Lithium in SARS-CoV-2

Lithium has an important immunomodulatory role in fighting SARS-CoV-2 by depolarizing the membrane potential when the ions are transported through the sodium channels such as TRPM4 and Nav1.5, which are present in the membranes of immune cells [45]. This role can be explained in the context of COVID-19 by the following points:

1. Macrophages, the predominant driving cells of the cytokine storm [27], are modulated by membrane potential changes. It was found that membrane depolarization inhibits the release of pro-inflammatory cytokines such as TNF and IL-6 [46,47]. Interestingly, lithium affects the polarization of macrophages and modulates their release of pro-inflammatory cytokines in a manner that favors the attenuation of the inflammatory process [37,38]. This supports the consistent correlation between the actions of lithium and the membrane potential changes.
2. In regard to lymphocytes, it was found that lithium increases the production of antibodies from B-lymphocytes by membrane depolarization, which is an early step of B-lymphocyte activation [37–39]. This step is essential in fighting SARS-CoV because these antibodies work to block the virus’ entry [48]. Lithium can also augment the proliferation of T-lymphocytes [49–51] because membrane depolarization is required for T-lymphocyte activation [52,53]. On the other hand, hyperpolarization is also required to stimulate T-lymphocytes [52,53]. Hence, lithium might serve to inhibit T-lymphocyte activation and proliferation [37]. Moreover, lithium can modulate the secretion of interleukins from CD4+ and CD8+ lymphocytes. Both types of T-lymphocytes secrete IL-2 and IL-5 [54], and CD4+ cells also secrete IL-4, IL-6, IL-10, and IL-22 [54]. There is no clear consensus on the final effect of lithium on these interleukins secretions. However, we mention here the outcome obtained from the higher number of studies as the following [55]: 1. Lithium enhances the production of anti-inflammatory IL-2. 2. Lithium increases the levels of pro-inflammatory IL-4. 3. Many studies have demonstrated that lithium attenuates the production of the pro-inflammatory IL-6, but many studies also have shown that lithium enhances IL-6 secretion. 4. Lithium increases the production of the anti-inflammatory IL-10. Additionally, lithium decreases the anti-inflammatory IL-5 in co-cultured cortical cells and glial cells, but it increases its levels in co-cultured hippocampal cells and glial cells [56]. Also, lithium increased the levels of IL-22 in vitro [57], and this interleukin is implicated in pathogen defense, wound healing, and tissue reorganization [54]. Accordingly, it seems that lithium balances the regulation of the immune system in such a way that no over-activation takes place to damage the lung parenchyma, and no under-activation occurs to weaken the clearance of the virus from the body.

The immunomodulatory actions of lithium are important in the context of fighting coronavirus in terms of three aspects. First, lithium can mitigate the over-activated immune response, which is predominantly driven by macrophages and is responsible for the clinical deterioration and ARDS development. Second, inhibiting the pro-inflammatory cytokines will boost the function of T-lymphocytes [27] to clear the virus from the body. Third, lithium increases the production of neutralizing antibodies from B-lymphocytes that work to block the entry of the virus, and lithium can balance the activity of T-lymphocytes in the sense that no over-activation or under-activation takes place.

Based on the collective understanding presented in Sections 2 and 3, lithium has the potential to stop the progression of COVID-19, prevent its clinical deterioration, and decrease the number of patients requiring mechanical ventilation as part of ARDS or respiratory failure treatment. Also, it is concluded that lithium has the potential to regulate the immune response in a way that mitigates the over-activation of immune reactions, but preserves the capacity of immune cells to kill the virus.

Here, in the context of membrane depolarization induced by lithium, magnesium ions should be mentioned. Interestingly, magnesium also depolarizes the membrane potential [58–60]; hence magnesium can augment the antiviral actions of lithium. However, since the effect of membrane depolarization is determined by the ion transport through the sodium channels, lithium will have a higher tendency to depolarize the membrane potential because sodium channels are more selective for lithium than magnesium [61].

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This entry is adapted from the peer-reviewed paper 10.3390/scipharm89010011