**2. Mechanism of fluvoxamine**

#### **2.1 Inhibition of serotonin transporter**

The main mechanism of action for fluvoxamine, as a selective serotonin-reuptake inhibitor (SSRIs), in the brain is to inhibit the serotonin transporter (SERT) on the 5-HT neuron in the synaptic cleft leading to an increase in the level of the neurotransmitter serotonin [33, 37].

The serotonin transporter is also located on the platelet membranes [38] and in the gut. The serotonin plasma-platelet regulation is a complex biphasic mechanism. Specifically, an elevation in plasma serotonin is associated with reducing platelet SERT surface expression [39]. As a consequence of serotonin transporter inhibition in the platelets by fluvoxamine, this could reduce platelet aggregation [40]. In support of this, elevated circulating serotonin was reported in hypertensive patients [41]. In fact, previously proven that fluvoxamine should be used with caution in patients receiving NSAIDs, aspirin, or other drugs that may impair coagulation and peptic ulcer patients due to the antiplatelet activity mechanism SSRIs that can increase the risk of bleeding [42, 43]. Interestingly, a previous report indicated that transgenic mice harboring SERT construct mutation exhibited altered platelet aggregation [44]. Overall, the physiological role of SERT in Platelets includes maintaining system homeostasis, regulation of drugs' concentration, and function [39, 45].

Besides, the antiplatelet activity mechanism of fluvoxamine has a protective effect against myocardial infarction (MI) and a promising role for patients with thrombotic risk [46]. Clearly, fluvoxamine has anti-inflammatory properties in several animal and clinical studies through the mechanism of serotonin transporter inhibition [47, 48]. For instance, in a Parkinson's disease model, fluvoxamine has been shown to reduce inflammation in injured striatal neurons by elevating antiinflammatory cytokines and lowering inflammatory cytokines and lipid peroxidation in a 6-hydroxydopamine (6-OHDA) lesion-induced rat model [49]. In line with this, chronic administration of fluvoxamine to the 6-OHDA Parkinsonism model improves the Parkinson's-like symptoms, including a reduction in the dopaminergic neuronal degeneration, improvement in motor dysfunction, and normalization of corticosterone levels in the circuitry [50]. Another preclinical setting utilized the same model, the 6-OHDA Parkinsonism model, which indicated that chronic fluvoxamine treatment alters inflammatory hallmarks of Parkinsonism centrally using both the mRNA and the protein level analysis. The level of IL-1β, IL-6, and TNF-α was reduced following one month of Fluvoxamine treatment [49]. Highlighting the fluvoxaminemediated pharmacological link between serotonin – anti-inflammatory mechanisms at central and peripheral levels.

Likewise, another study revealed that fluvoxamine inhibits inflammation genes in *in vitro* settings [32]. In multiple sclerosis, fluvoxamine reduced the lymphocyte infiltration and the circulating IFN-γ in experimental autoimmune encephalomyelitis. It further affects the pathological demyelination of lumbar spinal cord in multiple sclerosis animal models [51]. In the context of dementia, a previous review highlighted the anti-inflammatory effects of SSRIs, and the evidence provided indicated that introducing SSRIs in neurodegenerative dementias has beneficial effects [52]. Previous studies have proven that fluvoxamine has potent anti-inflammatory properties in vitro and in vivo models. Besides being an effective anti-inflammatory agent, fluvoxamine was found to have antioxidant effects. In a rat model of ulcers, the stressinduced peptic ulcer model, compared to the control group, the fluvoxamine-treated group exhibited reduced biochemical measurements representing oxidative stress [53]. Most significantly, the serotonin transporter in rodents and humans is highly expressed by the lung, demonstrating that the serotonin transporter in lung endothelium controls the bioavailability of the potent vasoconstrictor serotonin [54, 55]. It was reported that inhibiting gut- and lung-serotonin modulates pulmonary hypertension [56]. Additionally, fluvoxamine can positively improve the lung function of chronic obstructive pulmonary disease (COPD) [57]. For depressed COPD patients, SSRIs are the first-line treatment [58]. However, there is a need for a further clinical study to clarify more about the role of fluvoxamine in the treatment of COVID-19 patients. Although other antidepressants can act on serotonin transporter as an inhibitor, they did not have the same favorable impact on COVID-19 patients [57]. As a result, it is unclear whether fluvoxamine's blockage of serotonin transporters plays a substantial role in its positive benefits for COVID-19 patients. The anti-inflammatory

*Perspective Chapter: New Use of the SSRI Fluvoxamine in the Treatment of COVID-19 Symptoms DOI: http://dx.doi.org/10.5772/intechopen.105023*

effects of serotonin transporter inhibition, on the other hand, may play a role in its positive benefits [55]. To support the potential use of SSRIs in the treatment of post-COVID-19 depression, a recent observational study showed that treatment with different SSRIs antidepressants has positive effects in patients with post-COVID-19 depression [59]. In support of this, another report highlighted that SSRIs might decrease the rate of mortality in COVID-19 patients [35]. However, different mechanism of action needs to be clarified more about the role of fluvoxamine in the treatment of COVID-19 patients. These mechanisms might be acid sphingomyelinase mediated [60], or melatonin receptor-mediated [61].

#### **2.2 The Sigma-1 receptor-mediated mechanism**

Several studies established the role of the sigma-1 receptor in the replication of SARS-CoV-2. Initially, it was recognized by its action as a cellular factor known as endoplasmic reticulum (ER) protein sigma-1 receptor that mediates the early steps of viral RNA replication but not the persistent hepatitis C virus (HCV) RNA replication [62]. The ER chaperones are required to control the production of glycosylated proteins in the cell, including those required for viral infection phases and those involved in immune escape [63]. Therefore, they play various important roles at various stages of the infectious cycle. A recent study recognized protein-protein interactions between SARS-CoV-2 and human proteins including the sigma-1 and sigma-2 receptors [64]. In line with this, a recent report linked this molecular pathway and SARS-CoV-2 replication [65]. Moreover, sigma-1 receptor agonists may protect against mitochondrial damage and ER stress in response to SARS-CoV-2 infection [66]. For that reason, the use of drugs with sigma-1 receptor ligand properties may enhance additive value in early intervention for COVID-19 patients [67].

Previous reports have linked sigma-1 receptor and psychiatric disorders, including anxiety [68], depression [69], and schizophrenia [70].

Cognitive deficit is a core feature of psychiatric disorders, including depression. Reports highlighted the role of the sigma-1 receptor in the fluvoxamine antidepressant mediated mechanism [71]. First, Sigma-1 receptors are expressed abundantly in cortical and motor brain regions [72], indicating functional involvement in the pathology of depression. Additionally, electrophysiological studies indicated that sigma-1 receptor modulated glutamatergic transmission in primary hippocampal neurons. Besides, they were found to be highly expressed in the olfactory bulb [72], a brain region involved in adult neurogenesis. Adult neurogenesis is involved in modulating synaptic plasticity [73] and disrupted in preclinical models of depression [74]. A previous study reported sigma-1 receptor's functional involvement in modulating adult neurogenesis [75]. In a model of Alzheimer's with cognitive impairment, sigma-1 receptors were found to promote spines' maintenance and maturation [76]. Recent studies highlight the role of spine modulation in promoting fast-acting antidepressant effects [77], signifying the role of Sigma-1 receptors in tacking pathological mechanisms of depression.

Besides, sigma-1 receptors were reported to modulate protein kinase signaling (pERK) molecularly in a neuropathic pain animal model [78], and this kinase pathway was found to be involved in depression [79].

In addition, a recent review found that the significant potentiation of the nerve growth factor (NGF) by SSRIs including fluvoxamine leading to induced neurite outgrowth in cell culture and brain plasticity via selective sigma-1 receptor agonistic activity [80]. In clinical settings, NGF was reported to be reduced in depressed patients [81],

this reduction was correlated with suicidal tendencies [82]. Moreover, preclinical studies in animal models of depression reported reduced NGF levels [83–85].

Additionally, modulation of the sigma-1 receptor pathway positively impacted inflammatory pathways such as IL-6 tumor necrosis factor-α (TNFα) [86]. In line with this, sigma-1 receptor agonist (the pRE-084) presented neuroprotective effects measured by a decreased infarct volume in an embolic stroke model. This was mostly regraded y a reduction in inflammatory cytokines, including TNF-alpha and multiple isoforms of IL in cortical tissues [87]. In another study utilizing a stroke model in rats, the sigma-1 receptor was reported to exert neuroprotective effects, and these modulations were mediated via targeting glutamate-induced excitotoxicity [88]. Also, in a rat model of renal ischemia, the fluvoxamine mediated sigma-1 receptor mechanism was reported to enhance the survival rate, renal function, and histological characteristics [89]. All these evidence suggest that molecular modulation of the sigma-1 receptor has beneficial effects. It further confirms that the neuroprotective effects of fluvoxamine render it to be considered a prophylactic therapeutic candidate to prevent COVID-19 risks. However, further studies are required to answer whether the anti-inflammatory and other fluvoxamine neuroprotective effects of fluvoxamine are clinically relevant for COVID-19 patients.


*TCA: Tricyclic antidepressants; SSRI: Selective serotonin reuptake inhibitor; SNRI: Serotonin norepinephrine reuptake inhibitor; NaSSA: Noradrenaline specific serotonergic antidepressant. The measure for sigma affinity indicates that potent = 17 nM, high to moderate = 30–400 nM, very week > 10,000 nM.*

#### **Table 1.**

*Affinity of the antidepressants for sigma-1 receptor.*

*Perspective Chapter: New Use of the SSRI Fluvoxamine in the Treatment of COVID-19 Symptoms DOI: http://dx.doi.org/10.5772/intechopen.105023*

For the most important part, which is the relation between the use of antidepressants and sigma-1 receptor, a study examined in an animal model the SSRIs binding affinity to the sigma-1 receptor [71]. As a result, the study revealed that different SSRIs, including sertraline, fluoxetine, citalopram, and fluvoxamine, have a significant functional impact ranging from high to moderate affinity for sigma-1 receptors in the rat brain (**Table 1**).
