Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm.

Yang, Huan, George, Sam J, Thompson, Dane A, Silverman, Harold A, Tsaava, Téa, Tynan, Aisling, Pavlov, Valentin A, Chang, Eric H, Andersson, Ulf, Brines, Michael, Chavan, Sangeeta S, Tracey, Kevin J (May 2022) Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm. Molecular Medicine, 28 (1). p. 57. ISSN 1076-1551

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Abstract

BACKGROUND: Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm. METHODS: The potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes. RESULTS: Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine's mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages. CONCLUSIONS: These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.

Item Type:	Paper
Subjects:	diseases & disorders therapies diseases & disorders > viral diseases organism description > animal diseases & disorders > viral diseases > coronavirus diseases & disorders > viral diseases > coronavirus > covid 19 diseases & disorders > inflammation > cytokines therapies > famotidine diseases & disorders > inflammation organism description > animal > mammal organism description > animal > mammal > rodent > mouse organism description > animal > mammal > rodent
CSHL Authors:	Tracey, Kevin
Communities:	CSHL labs > Tracey lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	16 May 2022
Date Deposited:	31 May 2022 15:07
Last Modified:	17 Jan 2024 19:32
PMCID:	PMC9109205
URI:	https://repository.cshl.edu/id/eprint/40643

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