Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model.

Abstract

The coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world's population is currently unvaccinated or incompletely vaccinated and has limited access to approved treatments against COVID-19, there is an urgent need to continue research on treatment options, especially those at low cost and which are immediately available to patients, particularly in low- and middle-income countries. Prior in vitro and observational studies have shown that fluoxetine, possibly through its inhibitory effect on the acid sphingomyelinase/ceramide system, could be a promising antiviral and anti-inflammatory treatment against COVID-19. In this report, we evaluated the potential antiviral and anti-inflammatory activities of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and against variants of concern in vitro, i.e., SARS-CoV-2 ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 and Omicron BA.5. Fluoxetine, administrated after SARS-CoV-2 infection, significantly reduced lung tissue viral titres and expression of several inflammatory markers (i.e., IL-6, TNFα, CCL2 and CXCL10). It also inhibited the replication of all variants of concern in vitro. A modulation of the ceramide system in the lung tissues, as reflected by the increase in the ratio HexCer 16:0/Cer 16:0 in fluoxetine-treated mice, may contribute to explain these effects. Our findings demonstrate the antiviral and anti-inflammatory properties of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and its in vitro antiviral activity against variants of concern, establishing fluoxetine as a very promising candidate for the prevention and treatment of SARS-CoV-2 infection and disease pathogenesis.

• Authors: David Péricat, Stephen Adonai Leon-Icaza, Marina Sanchez Rico, Christiane Mühle, Iulia Zoicas, Fabian Schumacher, Rémi Planès, Raoul Mazars, Germain Gros, Alexander Carpinteiro, Katrin Anne Becker, Jacques Izopet, Nathalie Strub-Wourgaft, Peter Sjö, Olivier Neyrolles, Burkhard Kleuser, Frédéric Limosin, Erich Gulbins, Johannes Kornhuber, Etienne Meunier, Nicolas Hoertel, Céline Cougoule
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 21 (Nov 07 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 36362409 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Antiviral Agents
• Ceramides
• Fluoxetine
• K-18 conjugate

Topics

• Animals
• Mice
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Antiviral Agents (pharmacology, therapeutic use)
• Ceramides
• Disease Models, Animal
• Fluoxetine (pharmacology, therapeutic use)
• SARS-CoV-2
• COVID-19 Drug Treatment