Selective Serotonin Reuptake Inhibitors may Influence COVID-19 Prognosis through Antioxidant and Cytoprotective Pathways Mediated by Sigma 1 Receptor Agonism

To the Editor

We welcome Min et al.’s positive findings confirming that widely available and affordable selective serotonin reuptake inhibitor (SSRI)-type antidepressants are associated with lower risk of severe outcomes in coronavirus disease 2019 (COVID-19) [1]. We wish to comment on additional mechanisms that support SSRIs’ protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We have previously proposed that sigma-1 receptor (S1R) agonism engenders the anti-SARS-CoV-2 protection of fluvoxamine [2]. In the present study, the statistical significance of SSRI’s protective effect is mainly driven by escitalopram [1]. Escitalopram (Ki=288.3 nM) is also a S1R agonist, albeit not as potent as fluvoxamine (Ki=17.0 nM), sertraline (Ki=31.6 nM), or fluoxetine (Ki=191.2 nM), but more so than citalopram (Ki=403.8 nM), and paroxetine (Ki = 2041 nM) [3].

S1R is widely expressed in the endoplasmic reticulum (ER) and mitochondria and the ER-mitochondria interface [4]. Renin-angiotensin system (RAS) and angiotensin II (Ang II) dysregulation, the hallmarks of COVID-19, induce ER stress and initiate cardiovascular dysfunction [5] [6]. S1R is a pluripotent modulator, upregulated in times of ER stress, whose pleiotropic effects, and interactions with various cellular components, can potentially account for its SARS-CoV-2 protective actions [4]. S1R agonism-mediated SARS-CoV-2 and COVID-19 protection almost certainly occurs through the same downstream pathways that induce increases in protein kinase B (Akt) phosphorylation, endothelial nitric oxide (NO) synthase (eNOS) levels and eNOS phosphorylation, all of which are known to mediate SSRI’s robust cardioprotection [6] [7].

Moreover, S1R enhancement of the endoplasmic reticulum (ER) to nucleus signaling for antioxidant power attenuates free radical damage through nuclear factor erythroid-derived 2-like 2 (Nrf2) signaling [4]. Chronic S1R activation of the Nrf2/Heme Oxygenase (HO) 1-mediated antioxidant stress pathway protects right ventricular function and ameliorates structural remodeling [7]. SARS-CoV-2 represses the Nrf2/HO-1 antioxidant pathway while treatment of cells with Nrf2 agonists induced a strong antiviral program that limits SARS-CoV-2 replication [8]. Biopsies from COVID-19 patients show suppressed expression of Nrf2-dependent genes [8]. Treatment with S1R antagonists negated SSRI-mediated eNOS upregulation and Akt-mediated eNOS phosphorylation and reduced all SSRI’s cardioprotective effects, confirming that the S1R modulates eNOS activity in the heart and blood vessels [6] [7]. Moreover, substantial evidence supports S1R’s key role in systemic inflammation via reduction of cytokine production, potentially reducing the risk for a cytokine storm in COVID-19 [6]. Finally, known antioxidative stress and anti-inflammatory effects of S1R/Nrf2/HO-1 activation in a variety of cells, including neurons, retinal Müller glial cells and astrocytes have implications for treatment of long COVID-19 with neurological complications [3] [7].

Relevant to COVID-19-related lung afflictions, S1R agonism alleviates airway inflammation and airway remodeling via increased expression of AMP-activated protein kinase (AMPK) while AMPK antagonism reversed the protective effects [9]. Increased AMPK signaling is reported to reduce inflammatory responses in lung emphysema, mitigate pulmonary hypertension, and protect against lipopolysaccharide-induced acute lung injury and acute respiratory distress syndrome (ARDS) [10]. Moreover, AMPK will robustly induce eNOS in the endothelium and phosphorylate Nrf2 resulting in subsequent expression of protective antioxidant genes [10].

S1R’s Akt and AMPK-mediated effects on eNOS levels and phosphorylation, synergistically increase NO-production and bioavailability in the respiratory tract and its vascular endothelium that may counteract SARS-CoV-2-induced endotheliitis and even inhibit SARS-CoV-2 infection and replication at an early stage [2]. NO inhibits palmitoylation of the SARS-CoV-1/2 spike protein, essential for fusion to its cognate receptor, the angiotensin converting enzyme (ACE)2, as well as the SARS-CoV-2 main protease, necessary for early production of viral RNA. Both processes are critical for membrane fusion and virion infectivity [2]. In addition, inhibition of acetyl-CoA carboxylase by AMPK will directly inhibit palmitate synthesis further promoting anti-SARS-CoV-2 effects [10]. In severe COVID-19 and related ARDS, lower soluble eNOS levels have been reported implying that lifestyle and pharmaceutical interventions that increase NO-generation and bioavailability, may protect patients from severe lung complications [2] [10].

In conclusion, S1R facilitated eNOS induction (through Akt and AMPK with subsequent increases in NO-production and bioavailability) along with anti-inflammatory, antioxidant, and cytoprotective actions via the Nrf2/HO-1-pathway, promote early and delayed SARS-CoV-2 and COVID-19 protection. Thus, SSRIs’ robust cardiovascular and neuroprotective effects through S1R agonism support their clinical use in COVID-19.

Letters to the editor do not necessarily represent the opinion of the editor or publisher. The editor and publisher reserve the right to not publish letters to the editor, or to publish them abbreviated or in extract.

Publikationsverlauf

Artikel online veröffentlicht:
18. August 2022

• References

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