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 [1]. 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 [1] [2]. S1R-agonism reduces Interleukin (IL)-6 and increases endothelial nitric oxide (NO) synthase (eNOS) expression in the colon [3]. Moreover, FLV-S1R stimulation activates Akt-eNOS signaling in the thoracic aorta while its vasculoprotective effect is nullified by co-administration of S1R antagonists [4], dramatically reducing eNOS and promoting atrial remodeling [5]. 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 [6]. 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 [7]. 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 [8]. 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.

Publication History

Received: 20 August 2021
Received: 01 September 2021

Accepted: 02 September 2021

Article published online:
23 September 2021

• References

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