Letter to Editor

Fluvoxamine Mediates Specific, Early, and Delayed SARS-CoV-2 Protection through Antioxidant and Cytoprotective Pathways via Sigma-1 Receptor Agonism

To Editor,

Fluvoxamine is an affordable and widely available selective serotonin reuptake inhibitor (SSRI) antidepressant which is associated with reduced hospitalization, reduced severity, and mortality in outpatients with coronavirus disease 2019 (COVID-19).^1,2 Fluvoxamine’s mechanisms of action in COVID-19 have been extensively discussed and is mainly mediated via its potent (Ki = 36 nM) sigma-1 receptor (sigma-1R, σ1R, S1R) agonism.^3-5 Sigma-1R interferes with the early steps of virus-induced host cell reprogramming and protects against mitochondrial damage and endoplasmic reticulum (ER) stress in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.⁴ The reduction of cytokine production as indicated by sigma-1R’s key role in systemic inflammation is supported by substantial evidence.⁴ Finally, additional mechanisms may include acid sphingomyelinase (ASM) inhibition.⁴ SARS-CoV-2 activates host ASM leading to ceramide accumulation-a product of ASM catalyzed sphingomyelin-which aids in SARS-CoV-2 cell entry. Unlike fluvoxamine, chlorpromazine-another ASM inhibitor-did not lead to reduced mortality in patients with COVID-19 implying that ASM inhibition may not be clinically relevant.⁶

We wish to highlight additional sigma-1R pathways that may be more pertinent in engendering fluvoxamine’s specific, early, and delayed SARS-CoV-2 protection. Sigma-1R agonists fluvoxamine and dehydroepiandrosterone (DHEA) have been shown-in both in vivo and in vitro systems-to mediate robust cardioprotection through increases in protein kinase B (Akt) phosphorylation, endothelial nitric oxide (NO) synthase (eNOS) levels and eNOS phosphorylation.^7,8 In addition, fluvoxamine’s cardioprotective effect is mediated via upregulation of cardiac sigma-1R expression.⁷ Furthermore, stimulation of central nervous system sigma-1R may also inhibit sympathetic hyperactivation along with direct fluvoxamine stimulation of cardiac sigma-1R synergistically to improve hypertrophic cardiac dysfunction.⁷ Newer studies also suggest that fluvoxamine stimulation of sigma-1R reduces susceptibility to right ventricular dysfunction, atrial fibrillation, and ventricular arrhythmias and enhances cardiac function by upregulating sigma-1R protein content, mitigating myocardial fibrosis, sympathetic and electrical remodeling.⁹ Treatment with sigma-1R antagonists negated fluvoxamine-mediated eNOS upregulation and Akt-mediated eNOS phosphorylation. Moreover, all fluvoxamine-mediated cardioprotective effects are reduced, confirming that the sigma-1R modulates eNOS activity in the heart and blood vessels.^7,9 Pertinent to COVID-19-related lung afflictions, sigma-1R agonism alleviates airway inflammation and airway remodeling via increased expression of AMP-activated protein kinase (AMPK) and inhibition of C-X-C chemokine receptor type 4 (CXCR4) expression while sigma-1R, AMPK, and CXCR4 antagonisms reversed these protective effects.¹⁰ Increased AMPK signaling appears beneficial in lung pathology as it reduces inflammatory responses in lung emphysema, mitigates pulmonary hypertension, and protects against lipopolysaccharide-induced acute lung injury and acute respiratory distress syndrome (ARDS).¹¹ AMPK, a master cellular energy and redox-sensing protein, activated through several physiological and pathological conditions-such as hypoxia, caloric restriction, physiological exercise, aspirin and metformin-is also known to robustly induce eNOS in the endothelium.¹²

Sigma-1R’s direct and AMPK-mediated-indirect effects on eNOS levels and phosphorylation, synergistically increase NO-production and bioavailability that underlie fluvoxamine’s and DHEA’s cardio- and vasculo-protective actions and mechanistically support specific and immediate anti-SARS-CoV-2 effects.^3,5 Increased NO-generation and bioavailability may counteract SARS-CoV-2-induced endotheliitis and even inhibit SARS-CoV-2 replication and infection at an early stage as shown by the inhibition of (1) the palmitoylation of the SARS-CoV-1/2 spike protein, essential for fusion to the angiotensin converting enzyme (ACE)2, its obligate receptor, and (2) early production of viral RNA by inhibiting SARS-CoV-2 main protease. Both these processes are critical for membrane fusion and virion infectivity.¹³ In addition, inhibition of acetyl-CoA carboxylase by AMPK will directly inhibit palmitate synthesis further engendering anti-SARS-CoV-2 effects.¹⁴ Later in the course of SARS-CoV-2 infection, sigma-1R/AMPK/eNOS-induced increase in NO-production and bioavailability may promote delayed cardiopulmonary, renal and vascular protection through lower oxidative stress, apoptosis, and reduced systemic inflammatory responses.¹⁵ In severe COVID-19 and related ARDS, lower soluble eNOS levels have been reported implying that pharmaceutical interventions that increase NO-generation and bioavailability, may protect patients from severe lung complications.¹⁶

Finally, sigma-1R agonism significantly increases nuclear factor erythroid-derived 2-like 2 (Nrf2), a master regulator of inducible antioxidant responses, and heme oxygenase-1 (HO-1) expression in astrocytes. Thus, Nrf2 may have therapeutic potential in neuroinflammation and protection against oxidative stress with implications for long COVID-19 neurological complications.¹⁷ Sigma-1R induction of AMPK will also phosphorylate Nrf2 resulting in subsequent expression of antioxidant genes.¹² Interestingly, expression of Nrf2-dependent genes is suppressed in biopsies from COVID-19 patients.¹⁸ Recent data suggest that SARS-CoV-2 indeed 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.¹⁸

In conclusion, sigma-1R agonism promotes specific eNOS/NO-, AMPK-, and Nrf2/HO-1-mediated defense mechanisms that actively suppress SARS-CoV-2 replication and transmission along with robust cardiovascular and neuroprotective effects. We thus strongly support the use of fluvoxamine as an affordable and widely available sigma-1R agonist for specific, early, and delayed protection against SARS-CoV-2 infection.

Competing Interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval

Not applicable.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

References

1. Fluvoxamine for outpatient management of COVID-19 to prevent hospitalization: a systematic review and meta-analysis. JAMA Netw Open 2022; 5(4):e226269. doi: 10.1001/jamanetworkopen.2022.6269 [Crossref]
2. Mortality risk among patients with COVID-19 prescribed selective serotonin reuptake inhibitor antidepressants. JAMA Netw Open 2021; 4(11):e2133090. doi: 10.1001/jamanetworkopen.2021.33090 [Crossref]
3. Anti-SARS-CoV-2 action of fluvoxamine may be mediated by endothelial nitric oxide synthase. Pharmacopsychiatry 2022; 55(1):57. doi: 10.1055/a-1641-0357 [Crossref]
4. Mechanisms of action of fluvoxamine for COVID-19: a historical review. Mol Psychiatry 2022; 27(4):1898-907. doi: 10.1038/s41380-021-01432-3 [Crossref]
5. Anti-SARS-CoV-2 action of 5α-reductase inhibitors may be mediated by dehydroepiandrosterone. Letter. J Urol 2022; 207(5):1163-4. doi: 10.1097/ju.0000000000002469 [Crossref]
6. Observational study of chlorpromazine in hospitalized patients with COVID-19. Clin Drug Investig 2021; 41(3):221-33. doi: 10.1007/s40261-021-01001-0 [Crossref]
7. Crucial interactions between selective serotonin uptake inhibitors and sigma-1 receptor in heart failure. J Pharmacol Sci 2013; 121(3):177-84. doi: 10.1254/jphs.12r13cp [Crossref]
8. Is the sigma-1 receptor a potential pharmacological target for cardiac pathologies? A systematic review. Int J Cardiol Heart Vasc 2020; 26:100449. doi: 10.1016/j.ijcha.2019.100449 [Crossref]
9. Chronic sigma-1 receptor activation ameliorates ventricular remodeling and decreases susceptibility to ventricular arrhythmias after myocardial infarction in rats. Eur J Pharmacol 2020; 889:173614. doi: 10.1016/j.ejphar.2020.173614 [Crossref]
10. Sigma-1 receptor alleviates airway inflammation and airway remodeling through AMPK/CXCR4 signal pathway. Inflammation 2022; 45(3):1298-312. doi: 10.1007/s10753-022-01621-4 [Crossref]
11. Ethyl ferulate protects against lipopolysaccharide-induced acute lung injury by activating AMPK/Nrf2 signaling pathway. Acta Pharmacol Sin 2021; 42(12):2069-81. doi: 10.1038/s41401-021-00742-0 [Crossref]
12. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell 2017; 66(6):789-800. doi: 10.1016/j.molcel.2017.05.032 [Crossref]
13. Mitigation of the replication of SARS-CoV-2 by nitric oxide in vitro. Redox Biol 2020; 37:101734. doi: 10.1016/j.redox.2020.101734 [Crossref]
14. The fatty acid lipid metabolism nexus in COVID-19. Viruses 2021; 13(1):90. doi: 10.3390/v13010090 [Crossref]
15. An overview of NO signaling pathways in aging. Molecules 2021; 26(15):4533. doi: 10.3390/molecules26154533 [Crossref]
16. Soluble angiotensin converting enzyme 2 (ACE2) is upregulated and soluble endothelial nitric oxide synthase (eNOS) is downregulated in COVID-19-induced acute respiratory distress syndrome (ARDS). Pharmaceuticals (Basel) 2021; 14(7):695. doi: 10.3390/ph14070695 [Crossref]
17. Sigma-1 receptor activation ameliorates LPS-induced NO production and ROS formation through the Nrf2/HO-1 signaling pathway in cultured astrocytes. Neurosci Lett 2019; 711:134387. doi: 10.1016/j.neulet.2019.134387 [Crossref]
18. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat Commun 2020; 11(1):4938. doi: 10.1038/s41467-020-18764-3 [Crossref]