Subscribe to RSS
Anti-SARS-CoV-2 Action of Fluvoxamine may be Mediated by Endothelial Nitric Oxide Synthase
To the Editor
With interest we read the informative review of Khosravi M . We wish to comment on an additional mechanism that mechanistically supports Fluvoxamine’s (FLV) anti- severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) properties. As mentioned, FLV is a sigma-1 receptor (S1R) agonist and can upregulate cardiac S1R expression  . S1R-agonism reduces Interleukin (IL)-6 and increases endothelial nitric oxide (NO) synthase (eNOS) expression in the colon . Moreover, FLV-S1R stimulation activates Akt-eNOS signaling in the thoracic aorta while its vasculoprotective effect is nullified by co-administration of S1R antagonists , dramatically reducing eNOS and promoting atrial remodeling . Further, the replication of SARS-CoV has been found to be inhibited by NO through two clearly different mechanisms: (i) Decrease in the palmitoylation of nascently-expressed spike (S) protein that impacts the fusion of the S protein with its cognate receptor, angiotensin converting enzyme 2; (ii) Decline in the production of viral RNA in the very first stages of viral replication, most likely attributed to the impact on one or both of the cysteine proteases that are encoded in open reading frame 1a (Orf1a) protein of SARS-CoV . Later in the course of SARS-CoV infection, FLV-S1R-induced NO-increase may be cardio-, and renoprotective through lower oxidative stress, apoptosis, and systemic inflammatory responses, as previously demonstrated . Patients with acute respiratory distress syndrome in a moderate-sized coronavirus disease 2019 (COVID-19) cohort showed lower soluble eNOS levels, implying that greater eNOS activity and the presumed increased NO synthesis probably prevent patients from serious lung complications . These findings could provide additional insights into new therapeutic applications of FLV in COVID-19. However, further studies are needed to assess the effects of FLV in in-vitro and clinical settings.
Received: 20 August 2021
Received: 01 September 2021
Accepted: 02 September 2021
Article published online:
23 September 2021
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
- 1 Khosravi M. Candidate Psychotropics against SARS - CoV - 2: A Narrative Review. Pharmacopsychiatry 2021; DOI: 10.1055/a-1551-3756.
- 2 Tagashira H, Fukunaga K. Cardioprotective effect of fluvoxamine, sigma-1 receptor high affinity agonist. Yakugaku Zasshi 2012; 132: 167-172 DOI: 10.1248/yakushi.132.167.
- 3 Almási N, Török S, Dvorácskó S. et al. Lessons on the Sigma-1 Receptor in TNBS-Induced Rat Colitis: Modulation of the UCHL-1, IL-6 Pathway. Int J Mol Sci 2020; 21: 4046 DOI: 10.3390/ijms21114046.
- 4 Bhuiyan MS, Tagashira H, Fukunaga K. Sigma-1 receptor stimulation with fluvoxamine activates Akt-eNOS signaling in the thoracic aorta of ovariectomized rats with abdominal aortic banding. Eur J Pharmacol 2011; 650: 621-628 DOI: 10.1016/j.ejphar.2010.10.055.
- 5 Ye T, Liu X, Qu C. et al. Chronic inhibition of the sigma-1 receptor exacerbates atrial fibrillation susceptibility in rats by promoting atrial remodeling. Life Sci 2019; 235: 116837 DOI: 10.1016/j.lfs.2019.116837.
- 6 Åkerström S, Gunalan V, Keng CT. et al. Dual effect of nitric oxide on SARS-CoV replication: viral RNA production and palmitoylation of the S protein are affected. Virology 2009; 395: 1-9 DOI: 10.1016/j.virol.2009.09.007.
- 7 Pourbagher-Shahri AM, Farkhondeh T, Talebi M. et al. An Overview of NO Signaling Pathways in Aging. Molecules 2021; 26: 4533 DOI: 10.3390/molecules26154533.
- 8 Vassiliou AG, Zacharis A, Keskinidou C. et al. 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: 695 DOI: 10.3390/ph14070695.