Famotidine exerts anti‐inflammatory effects via a vagus nerve‐dependent mechanism

Abstract

BackgroundThe COVID‐19 pandemic in the U.S. caused > 48 million infections and >500,000 deaths. Famotidine, a histamine H2 receptor antagonist widely used to treat acid reflux and gastritis, is associated with improved survival and attenuated COVID‐19 disease severity (Mather JF et al. Am J Gastroenterol. 115:1617,2020; Freedberg DE, et al. Gastroenterology 159: 1129, 2020; Janowitz T et al. Gut, 69:1592, 2020). However, the mechanism of action for these beneficial effects is unknown. As hyperactive inflammatory responses from SARS‐CoV‐2 plays a critical role in disease progression in COVID‐19, here we studied the effects of famotidine in murine models of cytokine storm.MethodsMale C57BL/6 mice were subjected to bilateral sub‐diaphragmatic vagotomy and were recovered for 7 days before experiments. Male C57BL/6 mice were given an injection of famotidine either intraperitoneally (4 mg/kg) or intracerebroventricular (0.4 mg/kg) prior to administration of LPS (7 mg/kg) given intraperitoneally. Mice were euthanized 2.5 hours after LPS administration and cytokine levels in sera were measured using ELISAs. For survival studies, male C57BL/6 mice were subjected to LPS (6 mg/kg) injected intraperitoneally followed by treatment with famotidine (intraperitoneal injection at 4 mg/kg) or vehicle (PBS) twice daily for 3 days, and survival was monitored for two weeks.ResultsFamotidine (4mg/kg, injected intraperitoneally at 30 min before LPS) significantly reduced LPS‐induced elevated serum TNF levels at 2.5 hours post‐LPS injection (serum TNF levels in LPS + vehicle = 1,491+ 129 vs. LPS + famotidine = 1,060 + 72* pg/ml, N=10 mice per group. *: P=0.001). Famotidine (4mg/kg, injected intraperitoneally, twice a day for 3 days) improved survival in endotoxemic mice (two‐week survival in famotidine group = 100% vs. 70% in the PBS‐control group, n=30/group, p=0.001). Famotidine administered intracerebroventricularly (0.4 mg/kg) also significantly reduced LPS‐induced serum TNF levels and was >10 times more potent via the intracerebroventricularly route as compared to the intraperitoneal route. Bilateral sub‐diaphragmatic vagotomy attenuated the cytokine inhibiting effects of famotidine (administered intracerebroventricularly) on LPS‐induced TNF release (serum TNF levels in LPS + vehicle = 592+ 55 vs. LPS + famotidine = 616 + 98 pg/ml, N=5 per group. P=N.S.).ConclusionsFamotidine stimulates vagus nerve’s inhibition of LPS‐induced TNF release and attenuates lethality in endotoxemic mice. These anti‐inflammatory effects require the intact vagus nerve and via a brainstem‐dependent mechanism.