Histamine - H1 & H2 Receptors

A forum investigating the similarities between COVID-19 and fluoride poisoning, thyroid dysfunction and Gq/11 pathways.
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Histamine - H1 & H2 Receptors

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Histamine - the H1 & H2 Receptors
© 2021 PFPC


"We propose that the principal mechanism of action of famotidine for relieving COVID-19 symptoms involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release." (Malone et al., 2021)
  • Malone RW, Tisdall P, Fremont-Smith P, Liu Y, Huang XP, White KM, Miorin L, Moreno E, Alon A, Delaforge E, Hennecker CD, Wang G, Pottel J, Blair RV, Roy CJ, Smith N, Hall JM, Tomera KM, Shapiro G, Mittermaier A, Kruse AC, García-Sastre A, Roth BL, Glasspool-Malone J, Ricke DO - "COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms" Front Pharmacol 12:633680 (2021). doi: 10.3389/fphar.2021.633680

"An increase in NaF concentration resulted in increased fluoride deposition in the brain which in turn caused increase levels of epinephrine, histamine, serotonin, and glutamate and decreased levels of norepinephrine, acetylcholine, and dopamine in a dose-dependent manner." (Reddy et al., 2020)
  • Reddy YP, Tiwari S, Tomar LK, Desai N, Sharma VK - "Fluoride-Induced Expression of Neuroinflammatory Markers and Neurophysiological Regulation in the Brain of Wistar Rat Model" Biol Trace Elem Res (2020) doi: 10.1007/s12011-020-02362-x. Epub ahead of print. PMID: 32865723
Reddy YP, Tiwari SK, Shaik AP, Alsaeed A, Sultana A, Reddy PK - "Effect of sodium fluoride on neuroimmunological parameters, oxidative stress and antioxidative defenses" Toxicol Mech Methods 24(1):31-6 (2014) doi: 10.3109/15376516.2013.843224. Epub 2013 Oct 16. PMID: 24024668

Piirilä P, Espo T, Pfäffli P, Riihimäki V, Wolff H, Nordman H - "Prolonged respiratory symptoms caused by thermal degradation products of freons" Scand J Work Environ Health 29(1):71-7 (2003) doi: 10.5271/sjweh.707. PMID: 12630439

Sorgdrager B, de Looff AJ, de Monchy JG, Pal TM, Dubois AE, Rijcken B - "Occurrence of occupational asthma in aluminum potroom workers in relation to preventive measures" Int Arch Occup Environ Health 71(1):53-9 (1998)


"This study shows firstly that Sf 9 G proteins couple to mammalian histamine receptors and secondly that H1-receptors activate only Gq/11, whereas H2-receptors activate Gq/11 and G(S), but neither receptor couples to Gi/o or G12." (Leopoldt et al., 1997)
  • Leopoldt D, Harteneck C, Nürnberg B - "G proteins endogenously expressed in Sf 9 cells: interactions with mammalian histamine receptors" Naunyn Schmiedebergs Arch Pharmacol 356(2):216-24 (1997)

Gq/11 and Fluoride

"The presence of the phosphatidylinositol-specific phospholipase C (PI-PLC)-associated G protein, G alpha q/11, and the presence of mRNA for the Gq family, were ascertained by immunoblotting and Northern hybridization, respectively."
  • Li H, Choe NH, Wright DT, Adler KB - "Histamine provokes turnover of inositol phospholipids in guinea pig and human airway epithelial cells via an H1-receptor/G protein-dependent mechanism" Am J Respir Cell Mol Biol 12(4):416-24 (1995)

"Both basal and histamine, carbachol, pentagastrin stimulated-acid secretion decreased and increased in hypothyroid and hyperthyroid groups compared with control group." (Rafsanjani et al, 2003)
  • Rafsanjani FN, Z Asl S, Naseri MK, Vahedian J - "Effects of thyroid hormones on basal and stimulated gastric acid secretion due to histamine, carbachol and pentagastrin in rats" Saudi Med J 24(4):341-6 (2003)
Codolà R, García A - "Effect of thyroid state on histamine H1 receptors in adult and developing rat brain" Biochem Pharmacol 34(23):4131-6 (1985)


COVID-19, Fluoride, Thyroid & Urticaria

"Upon discontinuation of this toothpaste, the patient's episodic lip swelling and urticaria resolved. She was symptom-free for 8 weeks, when an inadvertent reexposure to the same toothpaste was associated with recurrence of urticaria and lip swelling within a few hours." Enamandram et al., 2014)
Gonzalez-Diaz SN, Sanchez-Borges M, Rangel-Gonzalez DM, Guzman-Avilan RI, Canseco-Villarreal JI, Arias-Cruz A - "Chronic urticaria and thyroid pathology" World Allergy Organ J 13(3):100101 (2020)

Pagali S, Parikh RS - "Severe urticarial rash as the initial symptom of COVID-19 infection" BMJ Case Rep 14(3):e241793 (2021)
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Doxepin - Histamine H1 receptor antagonist

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Ge S, Wang X, Hou Y, Lv Y, Wang C, He H - "Repositioning of histamine H1 receptor antagonist: Doxepin inhibits viropexis of SARS-CoV-2 Spike pseudovirus by blocking ACE2" Eur J Pharmacol 896:173897 (2021)

The spread of the corona virus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been intensifying in the past year, posing a huge threat to global health. There is an urgent need for effective drugs and vaccines to fight the COVID-19, but their advent may not be quite fast. Drug repurposing is a feasible strategy in the current situation, which could greatly shorten drug development time and help to response quickly to the novel virus outbreak. It has been reported that histamine H1 receptor antagonists have broad-spectrum antiviral effects. Therefore, in this study, we aim to screen potential drugs among histamine H1 receptor antagonists that may inhibit SARS-CoV-2 infection. Based on the model of angiotensin-converting enzyme 2 (ACE2) overexpressing HEK293T cell membrane chromatography (CMC), five FDA-approved histamine H1 receptor antagonists were found to have bioaffinity to ACE2. Then we determined the interaction between these drugs and ACE2 by frontal analysis and surface plasmon resonance (SPR), which consistently demonstrated that these hits bind to ACE2 at micromolar levels of affinity. Through the pseudovirus assay, we finally identified that doxepin could inhibit SARS-CoV-2 spike pseudovirus from entering the ACE2-expressing cell, reducing the infection rate to 25.82%. These preliminary results indicate that the histamine H1 receptor antagonist, doxepin, is a viable drug candidate for clinical trials. Therefore, we hope the work timely provides rational help for developing anti-SARS-CoV-2 drugs to control the rapid spread of SARS-CoV-2.

Fitzsimons CP, Monczor F, Fernández N, Shayo C, Davio C - "Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein" J Biol Chem 279(33):34431-9 (2004) doi: 10.1074/jbc.M400738200. Epub 2004 Jun 10. PMID: 15192105.

We found that mepyramine is able to decrease the basal constitutive activity of the guinea pig H(1) receptor, to bind with high affinity to a G(q/11) protein-coupled form of the receptor and to promote a G protein-coupled inactive state of the H(1) receptor that interferes with the G(q/11)-mediated signaling of the endogenously expressed ATP receptor, as predicted by the Cubic Ternary Complex Model of receptor occupancy. The effect of mepyramine on ATP-induced signaling was specifically neutralized by Galpha(11) overexpression, indicating that mepyramine is able to reduce G protein availability for other non-related receptors associated with the same signaling pathway. Finally, we found a loss of mepyramine efficacy in decreasing basal levels of intracellular calcium at high Galpha(11) expression levels, which can be theoretically explained in terms of high H(1) receptor constitutive activity. The whole of the present work sheds new light on H(1) receptor pharmacology and the mechanisms H(1) receptor inverse agonists could use to exert their observed negative efficacy.

Chan CK, Liao SY, Zhang YL, Xu A, Tse HF, Vanhoutte PM - "Protective effects of histamine on Gq-mediated relaxation in regenerated endothelium" Am J Physiol Heart Circ Physiol 306(2):H286-90 (2014) doi: 10.1152/ajpheart.00733.2013. Epub 2013 Nov 8. PMID: 24213613.
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