Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm

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.

Cholinergic dysfunction in COVID-19: frantic search and hoping for the best

“…Vagus nerve activity is reduced in response to hyperinflammation and cytokine storm as in sepsis, systemic lupus erythematosus, and rheumatoid arthritis. Vagus nerve stimulation inhibits the release of pro-inflammatory cytokines in various inflammatory disorders (Yang et al 2022 ). Notably, H 2 -blocker famotidine, through vagus nerve stimulation, inhibits the development of pro-inflammatory cytokines.…”

“…Moreover, famotidine activates the vagus nerve leading to a significant anti-inflammatory effect in COVID-19. Yang et al ( 2022 ) illustrated that famotidine prevents the development of cytokine storm in COVID-19 via activation of the vagus nerve. Taken together, vagus nerve stimulation plays a critical role in preventing cytokine storm and coagulation disorders in COVID-19 (Yang et al 2022 ).…”

Lots of long COVID treatment leads, but few are proven

“…His group has tested famotidine and other drugs in mice experiencing an induced immune “cytokine storm” of the kind seen in severe COVID-19. They reported that famotidine improved the animals’ survival and did not work via the mast cell mechanism ( 25 ). “It was really, really surprising, but when we treated mice with famotidine, it activated their vagus nerve,” says Tracey.…”

Understanding the Pivotal Role of the Vagus Nerve in Health from Pandemics

“…As a consequence, vagus nerve stimulation is a powerful anti-inflammatory tool (see [ 54 ] for a recent review), provided the metabolic needs are met. Today, the anti-inflammatory properties of drugs are even assessed according to their vagus-nerve-dependent effects [ 55 ]. Nevertheless, upon infection, the heightened activity of the immune system requires an increased rate of metabolism and energy expenditure.…”