Abstract | BACKGROUND: 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.
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Authors | Huan Yang, Sam J George, Dane A Thompson, Harold A Silverman, Téa Tsaava, Aisling Tynan, Valentin A Pavlov, Eric H Chang, Ulf Andersson, Michael Brines, Sangeeta S Chavan, Kevin J Tracey |
Journal | Molecular medicine (Cambridge, Mass.)
(Mol Med)
Vol. 28
Issue 1
Pg. 57
(05 16 2022)
ISSN: 1528-3658 [Electronic] England |
PMID | 35578169
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | © 2022. The Author(s). |
Chemical References |
- Anti-Inflammatory Agents
- Histamine H2 Antagonists
- Lipopolysaccharides
- alpha7 Nicotinic Acetylcholine Receptor
- Famotidine
- Histamine
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Topics |
- Animals
- Anti-Inflammatory Agents
- COVID-19
- Cytokine Release Syndrome
- Famotidine
(pharmacology)
- Histamine
- Histamine H2 Antagonists
- Lipopolysaccharides
- Mice
- Reflex
- Vagus Nerve
- alpha7 Nicotinic Acetylcholine Receptor
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