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 was 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 α and
interleukin-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.