H2-receptor Blockade Research Articles

Anxiolytic- and antidepressive-like effects of harmaline in mice are mediated via histamine H3 receptor blockade

Many neuropsychiatric disorders can be caused by neurotransmitter dysfunction. Experimental studies have demonstrated that histamine and the harmaline affect physiological processes through interaction with other neurotransmitter systems. The objective of these experiments was to investigate the involvement of the histaminergic system in the effects of harmaline on anxiety- and depressive-related effects in male NMRI mice. Behavioral tests were employed to evaluate anxiety-related symptoms (elevated plus maze; EPM), depressive-like symptoms (forced swim test; FST), and cognitive decline (step-down test). The histamine H3 receptor (H3R) agonist α-methylhistamine dihydrobromide (α-MH; 5 mg/kg, i.p.) had anxiolytic- and depressive-like effects, while the H3R antagonist thioperamide (10 mg/kg, i.p.) showed an antidepressive-like property. The subthreshold dose of α-MH resulted in an increase in the tendency of mice treated with the harmaline (2.5 mg/kg) to remain in the EPM open-arms. A subthreshold dose of thioperamide (5 mg/kg) increased the time spent in the open-arms in mice treated with harmaline (2.5 and 5 mg/kg) while a high dose of harmaline decreased the immobility time. Furthermore, two higher doses of harmaline resulted in a reduction in the number of open-arm entries. Similarly, mice administered with thioperamide and a low dose of harmaline decreased locomotor activity in the EPM. Ultimately, the combined thioperamide and harmaline did not impair memory retrieval of mice. These experiments demonstrate that the histaminergic system is implicated in the anxiety- and depressive-related effects of harmaline. The combination of thioperamide and harmaline is effective in treating anxiety and depression without having an adverse effect on memory formation.

Histamine signaling in the bed nucleus of the stria terminalis modulates stress-induced anxiety

BackgroundAnxiety disorder is one of the most prevalent psychiatric disorders. Intriguingly, dysfunction of the central histaminergic system, which is recognized as a general regulator for whole-brain activity, may result in anxiety, suggesting an involvement of the central histaminergic signaling in the modulation of anxiety. However, the neural mechanisms involved have not been fully identified. MethodsHere, we examined the effect of histaminergic signaling in the bed nucleus of the stria terminalis (BNST) on anxiety-like behaviors both in normal and acute restraint stressed male rats by using anterograde tracing, immunofluorescence, qPCR, neuropharmacology, molecular manipulation and behavioral tests. ResultsWe found that histaminergic neurons in the hypothalamus send direct projections to the BNST, which forms a part of the circuitry involved in stress and anxiety. Infusion of histamine into the BNST produced anxiogenic effect. Moreover, histamine H1 and H2 receptors are expressed and distributed in the BNST neurons. Blockade of histamine H1 or H2 receptors in the BNST did not affect anxiety-like behaviors in normal rats, but ameliorated anxiogenic effect induced by acute restraint stress. Furthermore, knockdown of H1 or H2 receptors in the BNST induced anxiolytic effect in acute restraint stressed rats, which confirmed the pharmacological results. LimitationsA single dose of histamine receptor antagonist was used. ConclusionsTogether, these findings demonstrate a novel mechanism for the central histaminergic system in the regulation of anxiety, and suggest that inhibition of histamine receptors may be a useful strategy for treating anxiety disorder.

Neuroprotective effect of histamine H3 receptor blockade on methamphetamine-induced cognitive impairment in mice

ObjectiveMethamphetamine (METH) exposure is commonly believed to result in cognitive impairment. Histamine H3 receptor (H3R) antagonists reportedly have potential applications for treating cognitive impairment accompanied by various neuropsychiatric disorders. The present study aimed to investigate the effect of H3R blockade by Thioperamide (THIO) on METH-induced cognitive impairment and the underlying mechanism. MethodsIn Experiment 1, C57BL/6 mice received daily injections of saline or 5 mg/kg METH for 5 consecutive days. The Novel Object Recognition (NOR) and Morris water maze (MWM) tasks were used to assess cognitive functions of mice. H3R protein expression and apoptosis were subsequently measured in the hippocampus. In Experiment 2, HT22 cells were first treated with ddH2O or 3 mM METH. The cell survival rate and H3R protein level were subsequently assessed. In Experiment 3, the animals were first treated with saline or 20 mg/kg THIO for 7 days, followed by co-administration of either saline or 5 mg/kg METH for an additional 5 days. The remaining experiments were carried out in the same manner as Experiment 1. In Experiment 4, HT22 cells were pretreated with either ddH2O or 5 mM THIO for 2 h, followed by ddH2O or 3 mM METH treatment for an additional 12 h. The remaining experiments were carried out in the same manner as Experiment 2. In Experiment 5, the changes in MEK1/2, p-MEK1/2, ERK1/2 and p-ERK1/2 protein levels were examined in the hippocampus of all mice from Experiment 3 and HT22 cells from Experiment 4. ResultsMETH-treated mice showed significantly worsened NOR and MWM performance, along with markably hippocampal apoptosis. A significantly lower cell survival rate was observed in METH-treated HT22 cells. Increased levels of H3R protein were found in both METH-treated mice and HT22 cells. THIO significantly improved METH-induced cognitive impairment in mice and toxicity in HT22 cells. METH significantly increased the level of p-MEK1/2 and p-ERK1/2 proteins in the hippocampus of mice and HT22 cells, which was reversed by THIO pretreatment. ConclusionOur findings reveal that H3R blockade by THIO yields a neuroprotective effect against METH-induced cognitive impairment in mice and toxicity in HT22 cells via the raf-MEK-ERK signaling pathway.

Molecular dynamics and free energy calculations of clozapine bound to D2 and H1 receptors reveal a cardiometabolic mitigated derivative

Most atypical antipsychotics derive from a high dropout of drug treatments due to adverse cardiometabolic side effects. These side effects are caused, in part, by the H1 receptor blockade. The current work sought a clozapine derivative with a reduced affinity for the H1 receptor while maintaining its therapeutic effect linked to D2 receptor binding. Explicit molecular dynamics simulations and end-point free energy calculations of clozapine in complex with the D2 and H1 receptors embedded in cholesterol-rich lipid bilayers were performed to analyze the intermolecular interactions and address the relevance of clozapine-functional groups. Based on that, free energy perturbation calculations were performed to measure the change in free energy of clozapine structural modifications. Our results indicate the best clozapine derivative is the iodine atom substitution for chlorine. The latter is mainly due to electrostatic interaction loss for the H1 receptor, while the halogen orientation out of the D2 active site reduces the impact on the affinity. Communicated by Ramaswamy H. Sarma

Mechanisms of unconventional CD8 Tc2 lymphocyte induction in allergic contact dermatitis: Role of H3/H4 histamine receptors.

Histamine (HA) is a potent mediator that plays a central role in inflammation and allergy, acting through four G-protein-coupled receptors (i.e. H1–H4). HA is an accepted promoter of type 2 immunity in CD4+ T cells during hypersensitivity. Previously, we demonstrated that HA can promote antigen cross-presentation, inducing the activation of antigen-specific CD8+ T cells in an asthmatic murine model. Non-classical CD8+ T-cell profiles, such as Tc2 or Tc17, are associated with allergic disease persistence and chronicity. In this paper, we focus on the role of the H3 receptor (H3R) and the H4 receptor (H4R) in the development of allergic contact dermatitis. We were able to show that induction of the type 2 profiles associated with interleukin 13 production, both by CD4 and CD8 lymphocytes, depend on the interaction of HA with H3R and H4R. Blocking both receptors using the selective H3/H4 receptor antagonist thioperamide or the selective H4R ligand JNJ777120 reduces the inflammatory response, inducing an immunosuppressive profile associated with the increased proportion of FOXp3+ regulatory T lymphocytes and CD11b+Gr-1+ myeloid suppressor cells. Interestingly, in dendritic cells, only H4R blockade, and not H3R blockade, is capable of modulating most of the inflammatory effects observed in our model.

Cardiorespiratory Fitness Level Alters Blood Pressure Responses Induced By Histamine H1- And H2-receptor Blockade During Dynamic Exercise

INTRODUCTION: Epidemiological studies have reported that greater cardiorespiratory fitness (CRF) is associated with lower blood pressure (BP). Histamine receptor-mediated peripheral vasodilation contributes to post-exercise hypotension and lowing exercising BP responses. Previously, our laboratory found that overactive BP responses to exercise were induced by the inability of histamine receptors in individuals with prehypertension. However, it is still unknown that CRF can impact BP responses elicited by the inability of the receptors. PURPOSE: This study was to assess whether aerobic fitness is effective in lowering excessive BP responses induced by the blockade of histamine receptors METHODS: In twelve male and female subjects (6 high CRF and 6 low CRF), we examined the effects of histamine H1- and H2- receptor blockades on heart rate (HR), stroke volume (SV), cardiac output (CO), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and total peripheral resistance (TPR) at workloads corresponding to 40% and 60% workloads of VO2peak during cycling exercise. RESULTS: Our study indicated that compared to the high CRF group, changes in MAP from the baselines were higher in the low CRF group before the blockade at each workload (40%: D14±2 vs. 8±1 mmHg; 60%: D21±3 vs. 15±2 mmHg). The changes in MAP in response to the blockade during exercise were substantially lower in the high CRF group (40%: D18±2 vs. 11±1 mmHg; 60%: D29±3 vs. 19±2 mmHg). CONCLUSIONS: Our study suggests that an improvement in CRF likely reduces exaggerated BP responses elicited due to the inability of histamine receptors in pathological conditions such as prehypertension and hypertension.

Curcuminoids, a major turmeric component, have a sleep-enhancing effect by targeting the histamine H1 receptor.

Turmeric (Curcuma longa) had been considered as a universal panacea in functional foods and traditional medicines. In recent, the sedative-hypnotic effect of turmeric extract (TE) was reported. However, sleep-promoting compounds in TE have been not yet demonstrated. Curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) are the major constituents of turmeric being responsible for its various biological activities. Therefore, they can be first assumed to be sedative-hypnotic compounds of TE. In the present study, we aimed to investigate the effects and underlying mechanisms of curcuminoids and each constituent on the sleep-wake cycle of mice. Molecular docking studies, histamine H1 receptor (H1R) binding assays, and H1R knockout animal studies were used to investigate the molecular mechanisms underlying the sleep-promoting effects. Curcuminoids and their constituents reduced sleep latency and increased sleep duration in the pentobarbital-induced sleep test in mice. In addition, curcuminoids significantly increased the duration of NREMS and reduced sleep latency without altering the REMS and delta activity. Curcumin, demethoxycurcumin, and bisdemethoxycurcumin were predicted to interact with H1R in the molecular model. In the binding affinity assay, we found that curcuminoids, as well as their constituents, significantly bind to H1R with the Ki value of 1.49 μg mL-1. Furthermore, sleep latency was reduced and NREMS frequency was increased following curcuminoid administration in wild-type mice but not in H1R knockout mice. Therefore, we conclude that curcuminoids reduce sleep latency and enhance the quantity of NREMS by acting as modulators of H1R, indicating their usefulness in treating insomnia.

Влияние прометазина на амплитудно-спектральные характеристики электрокортикограмм у крыс

Pharmaco-EEG is a promising method for the study of drugs aimed at identifying their specific effect on the electrophysiological activity of the brain. This method can be used both for screening of new molecules and for detecting the still unexplored effect on the central nervous system of drugs used in clinical practice for a long time. The identification of dose-dependent effects is of particular interest in the context of studying the latter, since most of the drugs affecting the CNS can be prescribed to patients in different dosages depending on the severity or nature of the disease, which is associated either with an increase in their effectiveness or with an effect on additional targets. Since most of the psychotropic or neurotropic drugs of the first generations are non-selective and can bind to a large number of targets, a study using pharmaco-EEG can reveal both the main and side dose-dependent effects. Promethazine is a first-generation antihistamine, and in addition to the blockade of H1 receptors, its effect is also due to the blockade of M-cholinergic receptors, which is why a wide range of actions of this drug is associated. In this study, the effect of promethazine at different doses (0.5 mg/kg, 5 mg/kg and 20 mg/kg) on the amplitude-spectral characteristics of electrocorticograms in rats was evaluated, followed by analysis of the principal components. As a result, it was found that promethazine has a dose-dependent increase in the values of the main component PC1, which reflects the amplitude characteristics of electrocorticographic activity. At the same time, the effects of the drug on the spectral characteristics of the recorded signals were multidirectional and did not have statistical significance.

The type rather than the daily dose or number of antipsychotics affects the incidence of hyperglycemic progression

There have been concerns that antipsychotics increase the incidence of hyperglycemic progression. Many factors have been suggested to contribute to the risk of antipsychotic-induced hyperglycemic progression, including the type, daily dose, and number of antipsychotics; however, few studies have examined these relationships. This study aimed to examine the affect of antipsychotic treatment-associated factors on hyperglycemic progression, after adjustment for the affect of background factors suggested to be associated with hyperglycemic progression. This was a nationwide, multicenter, prospective cohort study examining the incidence of hyperglycemic progression during a 12 mo period following the initiation of newly prescribed antipsychotic medication. Demographic data, medication history, and blood test values were collected from 631 study participants with normal blood glucose levels at baseline for 12 mo. The primary endpoint (incidence of hyperglycemic progression) was defined as progression from normal to prediabetic or probable diabetic status, and was evaluated based on the Japanese monitoring guidance in patients with schizophrenia. To further examine the affect of antipsychotics on glucose metabolism over time, we examined changes in HbA1c levels 3, 6, and 12 mo after the initiation of treatment with each antipsychotic. We found that treatment with zotepine and clozapine was associated with a significantly high incidence of hyperglycemic progression. Furthermore, changes in HbA1c levels 6 mo after the initiation of zotepine treatment were significantly higher than those following blonanserin and haloperidol treatments. In contrast, there was no significant difference in the change in total cholesterol, triglycerides, HDL cholesterol, and BMI during the same period. Moreover, the “daily dose” and “number” of antipsychotics did not show an association with the incidence of hyperglycemic progression. However, in a post hoc analysis in which the antipsychotics were divided into two groups according to the strength of blockade of H1, M1, M3, and 5-HT2C receptors, the incidence of hyperglycemic progression was higher in the medium- and high-daily dose groups than in the low-daily dose group in the antipsychotic group with strong blockade of these receptors. Our study indicated that the type of antipsychotic had a greater affect on the incidence of hyperglycemic progression than the daily dose of antipsychotics or their number. Among these, zotepine was most likely to increase the incidence of hyperglycemic progression, suggesting the need for caution when these antipsychotics are prescribed.

RETRACTED: Histamine H1 receptors regulate anhedonic-like behavior in rats: Involvement of the anterior cingulate and lateral entorhinal cortices

A decreased H1 receptor activity is observed in the anterior cingulate cortex (aCgCx) of depressed patients. The role of this abnormality in the development of depression-related processes is unstudied. We examined the influence of a decreased brain H1 receptor activity on rat behavior in the sucrose preference test. The H1 receptor deficit was simulated by injection of an H1 antagonist into the aCgCx; also, two aCgCx projection areas, lateral and medial entorhinal cortices were examined. A blockade of H1-receptors in the aCgCx and lateral entorhinal cortex (LEntCx) significantly reduced sucrose preference. These findings suggest the existence of H1 receptor-mediated aCgCx-LEntCx circuitry mechanism regulating anhedonic-like behavior in rats. The presented data suggest that H1 receptor-mediated processes might be a therapeutic target in depressive disorders.

Back Cover: A Novel Potent Sleep‐Promoting Effect of Turmeric: Turmeric Increases Non‐Rapid Eye Movement Sleep in Mice Via Histamine H1Receptor Blockade

Mol. Nutr. Food Res. 2021, 65, 2100100 DOI: 10.1002/mnfr.202100100 Turmeric (Curcuma longa) has sleep-promoting effects in mice through blockade of histamine H1 receptors. This is reported by Suengmok Cho and co-workers in article number 2100100.

A Novel Potent Sleep-Promoting Effect of Turmeric: Turmeric Increases Non-Rapid Eye Movement Sleep in Mice Via Histamine H1Receptor Blockade.

Turmeric has a broad spectrum of biological properties; however, the sleep-promoting effects of turmeric have not yet been reported. Thus, this study aims to investigate the effect of turmeric on sleep and the molecular mechanism underlying this effect. Pentobarbital-induce sleep test and sleep-wake profile assessment using recorded electroencephalography are used to evaluate the hypnotic effects of the turmeric extract (TE) compared to diazepam on sleep in mice. Additionally, the molecular mechanism of TE's sleep effect is investigated using ex vivo electrophysiological recordings from brain slices in histamine H1 receptor (H1 R) knockout mice. Oral administration of TE and diazepam significantly reduce sleep latency and increase non-rapid eye movement sleep (NREMS) duration without delta activity in mice. Like doxepin, TE inhibits the H1 R agonist (2-pyridylethylamine dihydrochloride)-induced increase in action potentials in the hypothalamic neurons. In animal tests using neurotransmitter agonists or antagonists, TE effect mimick H1 R antagonistic effect of doxepin. Additionally, both reduce sleep latency and increase NREMS in wild-type mice, although these effects are not observed in H1 R knockout mice. TE has a sleep-promoting effect owing to reduction in sleep latency and enhancement of NREMS via H1 R blockade; therefore, it could be useful in insomnia.

Central histaminergic transmission modulates the expression of chronic nicotine withdrawal induced anxiety-like and somatic behavior in mice

The present study investigated the plausible modulatory role of central histaminergic transmission on the expression of nicotine withdrawal induced anxiety and somatic behavior in mice. Abrupt cessation of chronic nicotine (2 mg/kg, i.p. × 3/day) treatment for 12 days to mice, expressed increased anxiety in light & dark test and total abstinence (somatic) score at 24 h post nicotine withdrawal time. The somatic signs includes a composite score of all behaviors such as grooming, rearing, jumping, body shakes, forelimb tremors, head shakes, abdominal constrictions, scratching, empty mouth chewing or teeth chattering, genital licking, tail licking. Mice exhibited higher expression to nicotine withdrawal induced anxiety in light & dark test at 24 h post-nicotine withdrawal time on pre-treatment centrally (i.c.v) with histaminergic agents like histamine (0.1, 50 μg/mouse), histamine H3 receptor inverse agonist, thioperamide (2, 10 μg/mouse), histamine H1 receptor agonist, FMPH (2, 6.5 μg/mouse) or H2 receptor agonist amthamine (0.1, 0.5 μg/mouse) or intraperitoneally (i.p.) with histamine precursor, l-histidine (250, 500 mg/kg) as compared to control nicotine withdrawn animals. Furthermore, mice pre-treated with all these histaminergic agents except histamine H1 receptor agonist, FMPH shows exacerbated expression to post-nicotine withdrawal induced total abstinence (somatic) score in mice. On the other hand, central injection of selective histamine H1 receptor antagonist, cetirizine (0.1 μg/mouse, i.c.v.) or H2 receptor antagonist, ranitidine (50 μg/mouse, i.c.v) to mice 10 min before 24 h post-nicotine withdrawal time completely alleviated the expression of nicotine withdrawal induced anxiety and somatic behavior. Thus, it can be contemplated that the blockade of central histamine H1 or H2 receptor during the nicotine withdrawal phase could be a novel approach to mitigate the nicotine withdrawal associated anxiety-like manifestations. Contribution of endogenous histamine via H1 or H2 receptor stimulation in the nicotine withdrawal induced anxiety and somatic behavior is proposed.

Allergic rhinitis: are there any problems? Case from clinical practice

Allergic rhinitis (AR) is found in the practice of doctors of various specialties, but making the correct diagnosis and prescribing adequate therapy can take many months and sometimes years. Currently, the problem of AR remains relevant, due to the extreme prevalence of AR, late diagnosis, underestimation of the possible risks of disease progression, complications, and the addition of such a formidable pathology as bronchial asthma. The path of the patient presented in the clinical case is quite typical for many patients with AR and concomitant pathology of nose. A young patient with allergic rhinitis received conservative treatment, and was later operated, but the effect was incomplete and short-lived. Only after 4 years, the patient was first examined by an allergist. Symptoms of AR indicate that the patient has an atopic status that promotes the involvement of various organs and systems in the inflammatory process. To verify the diagnosis and clarify the entire spectrum of “guilty” allergens, a specific allergological examination was carried out, which included skin testing and determination of specific IgE antibodies. The main participants in allergic inflammation are mast cells, eosinophils, lymphocytes, epithelial and endothelial cells. The effect of mediators on vascular endothelial cells and neuroreceptors of the nasal mucosa leads to the formation of allergic inflammation and the onset of clinical symptoms of AR. One of the main mediators released upon repeated contact with an allergen in a sensitized body is histamine, therefore antihistamines are first-line drugs at any stage of AR therapy. In our clinical case, taking into account complaints, medical history, clinical manifestations, results of laboratory (specific, nonspecific) and instrumental methods, the patient needs treatment of the corresponding first stage of therapy based on symptom control. The effectiveness of 2nd generation H1-antihistamines in the management of symptoms such as pruritus, sneezing, and rhinorrhea is due to histamine-mediated development of the early phase of the allergic reaction, which in turn leads to the onset of the late phase and the chronic co Bilastine can be considered as the drug that most fully meets the requirements of ARIA experts for 2nd generation H1-antihistamines : selective blockade of H1 receptors, high antiallergic effect, rapid onset of clinical effect, duration of action 24 hours, lack of tachyphylaxis and good tolerance. The results of the studies and their analysis show that bilastine is the preferred choice for monotherapy of allergic rhinitis.urse of allergic inflammation in the nasal mucosa.

The Utility of Measuring Urinary Metabolites of Mast Cell Mediators in Systemic Mastocytosis and Mast Cell Activation Syndrome

Mast cells (MCs) leave evidence of their presence and activation. Aside from increased numbers of MCs in tissues, this evidence includes detecting elevated serum levels of tryptase and discovering increased excretion of urinary metabolites of prostaglandin (PG) D2, leukotriene (LT) C4, and/or histamine. The importance of measuring these nontryptase mediator metabolites has largely gone unnoticed. We reviewed the utility of quantitating urinary levels of MC mediator metabolites in systemic mastocytosis (SM) and MC activation disorders and summarized the relative production of these mediators by MCs and other cell types. Quantitation of urinary n-methyl histamine, 2,3-dinor-11βPGF2α, and LTE4 offers a simple, noninvasive avenue to monitor their constitutive release as well as contemporaneous discharge during MC activation as well as supporting a diagnosis of SM. These increases can occur independently of or in addition to raised levels of tryptase. Quantitation of these mediator metabolites potentially offers targets for therapeutic intervention. Synthesis of PGD2, a product nearly exclusively of MCs, can be controlled with aspirin, histamine increase by H1 and H2 receptor blockade, and LTC4 by a 5-LO inhibitor or LT receptor antagonist. Although other sources are reported, the increase in MC numbers in SM supports this cell as the predominant origin of all 3 mediators.

Effects of combined histamine H1 and H2 receptor blockade on hemodynamic responses to dynamic exercise in males with high-normal blood pressure.

While postexercise hypotension is associated with histamine H1 and H2 receptor-mediated postexercise vasodilation, effects of histaminergic vasodilation on blood pressure (BP) in response to dynamic exercise are not known. Thus, in 20 recreationally active male participants (10 normotensive and 10 with high-normal BP) we examined the effects of histamine H1 and H2 receptor blockade on cardiac output (CO), mean atrial pressure (MAP), aortic stiffness (AoStiff), and total vascular conductance (TVC) at rest and during progressive cycling exercise. Compared with the normotensive group, MAP, CO, and AoStiff were higher in the high-normal group before and after the blockade at rest, while TVC was similar. At the 40% workload, the blockade significantly increased MAP in both groups, while no difference was found in the TVC. CO was higher in the high-normal group than the normotensive group in both conditions. At the 60% workload, the blockade substantially increased MAP and decreased TVC in the normotensive group, while there were no changes in the high-normal group. A similar CO response pattern was observed at the 60% workload. These findings suggest that the mechanism eliciting an exaggerated BP response to exercise in the high-normal group may be partially due to the inability of histamine receptors. Novelty Males with high-normal BP had an exaggerated BP response to exercise. The overactive BP response is known due to an increase in peripheral vasoconstriction. Increase in peripheral vasoconstriction is partially due to inability of histamine receptors.

H1/H2 Histamine Receptor Blockade Alters the Glutathione Redox Status in Skeletal Muscle Following a Bout of Prolonged Exercise

The effects of an acute bout of prolonged exercise on muscle include increases in oxidative metabolism and altered cellular redox environment. Histamine mediates many acute exercise responses, including sustained vasodilation and associated delivery of substrates to muscle. Previously, we demonstrated that H1 and H2 histamine receptor blockade with oral antihistamines resulted in a diminished capacity for mitochondrial H2O2 emission in skeletal muscle following an acute bout of prolonged exercise. Here, we tested the hypothesis that along with diminishing mitochondrial H2O2 emission, H1 and H2 histamine receptor blockade would attenuate exercise‐induced changes in skeletal muscle glutathione redox status. Adult male Wistar rats (83 ± 5.5 days old; 440.04 ± 40.70 g) were assigned to one of four groups (n = 12/group): exercise, in the form of one hour of continuous treadmill running at 20 cm/sec (Group 1); mass‐specific oral gavage with H1 antagonist fexofenadine (7.11 mg/kg) and H2 antagonist ranitidine (3.95 mg/kg) one hour prior to the same exercise protocol (Group 2); a group receiving oral H1 and H2 antagonists, but not exercised (Group 3); and a control group, which received neither antihistamines nor exercise (Group 4). An hour post‐exercise, total, reduced (GSH) and oxidized glutathione (GSSG) were assessed in red gastrocnemius (mixed fiber types) and soleus (oxidative) skeletal muscles. Redox status was expressed as GSH/GSSG. While no changes were observed in total glutathione for any treatment in either muscle, in soleus, antihistamine treatment, but not exercise decreased GSH/GSSG (main effect; p < 0.05). In red gastrocnemius, exercise, but not antihistamine treatment decreased GSH/GSSH (main effect; p < 0.05). These observations trend with those of a blunted capacity for mitochondrial H2O2 emission in skeletal muscle with antihistamine treatment and suggest an altered redox response to exercise following H1/H2 histamine receptor blockade in soleus. Given the widespread and routine use of antihistamines, further research into the effects of these antagonists on redox status in muscle is warranted.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada, Nova Scotia Health Research Foundation, Canada Foundation for Innovation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Evaluation of antihistaminic activity of quercetin by using histamine induced bronchospasm and clonidine induced catalepsy models

Background: Histamine is an important mediator of allergic reactions. Even though presently available antihistaminics are effective in treatment of allergic reactions, still there is scope for better new drugs. Quercetin has been used as a nutritional supplement and may be beneficial against a variety of diseases. Some of the beneficial effects include anticancer, antitumor, anti-ulcer, anti-allergy and anti-inflammatory effects. As quercetin is used in traditional system of medicine for treatment of allergies, this study was undertaken to evaluate antihistaminic activity of quercetin.Methods: In histamine induced bronchospasm model, 18 guinea pigs were divided into 3 groups. Control group received normal saline, standard control group received Chlorpheniramine and test group received Quercetin. All drugs were given once daily for 5 days. Preconvulsive dyspnoea was calculated on day 0 and day 5 for all guinea pigs after administration of Histamine aerosol. In clonidine induced catalepsy model, 18 albino mice were divided into 3 groups. Control group, standard control group and test group received normal saline, Chlorpheniramine and Quercetin respectively. One hour after administration of drugs the mice were given clonidine and catalepsy was measured at 30, 60, 90, 120 and 150 min.Results: In histamine induced bronchospasm model, both chlorpheniramine and quercetin produced significant protection as compared to control group. In clonidine induced catalepsy model the effect of quercetin was comparable to chlorpheniramine.Conclusions: Quercetin has significant antihistaminic activity. It appears to be due to H1 receptor blockade, contrary to the belief that it inhibits release of histamine from mast cells.

Potassium-competitive acid blockers - are they the next generation of proton pump inhibitors?

The modern lifestyle caters to an increase in the incidence of peptic ulcer disease, gastroesophageal reflux disease and several other acid-related conditions of the gut. The drugs to prevent these conditions work either through H2 receptor blockade or inhibition of the H+, K+ ATPase enzyme. Although proton pump inhibitors have been proven to be efficacious, they have a slow onset of action with limited resolution of symptoms in most patients. Potassium-competitive acid blockers (P-CABs) are novel drugs that bind reversibly to K+ ions and block the H+, K+ ATPase enzyme, thus preventing acid production. P-CABs have a fast onset of action and have dose-dependent effects on acid production. Animal studies exist that differentiate the better results of P-CABs from proton pump inhibitors; further human trials will give a comprehensive picture of the results and will help to elucidate the therapeutic benefits of this new group of drugs.

Effects of H1/H2 histamine receptor blockade on mitochondrial function in rodent brain following prolonged exercise

Exercise has been shown to stimulate histamine release, which mediates vasodilation in exercising tissue and is sustained post‐exercise. Blockade of H1 and H2 receptors with antihistamine drugs attenuates this effect in skeletal muscle. Research examining the effects of exercise‐related histamine action on cellular level processes is relatively sparse. There also remains limited understanding of the impacts of histamine receptor blockade on non‐exercising tissue, such as the brain. To this end, 36 adult male Wistar rats (75–94 days old, 441.2 ± 39.5 g body wt) were randomly assigned to three groups: (1) given H1 and H2 receptor antagonists fexofenadine (7.11 mg/kg) and ranitidine (3.95 mg/kg) via oral gavage 1 hr prior to treadmill exercise (1 hr, 20 cm/s); (2) completed the exercise without drug, and (3) control. All groups received body mass‐proportional oral gavage volumes (water or antihistamines). One hour post‐exercise, mitochondrial function was assessed in saponin‐permeabilized prefrontal cortex and dorsal hippocampus brain sub‐regions. There was no effect of exercise or drug treatment on mitochondrial substrate‐dependent oxygen consumption (JO2; high‐resolution respirometry), or in mitochondrial hydrogen peroxide emission (mH2O2; fluorometric monitoring of Amplex Red oxidation) in permeabilized prefrontal cortex or the dorsal hippocampus. These results suggest negligible effects of oral H1/H2 antagonists on mitochondrial metabolism in brain following exercise. This supports prior evidence suggesting the effects of H1/H2 inhibition remain localized in exercising muscle. Other studies report systemic increases in histamine levels following exercise, however, which suggests further research may reveal a relationship between histamine receptor blockade and cellular processes in non‐exercising tissues.Support or Funding InformationThe Natural Sciences and Engineering Research Council of Canada (NSERC), The Nova Scotia Health Research Foundation (NSHRF), and Canada Foundation for Innovation (CFI)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.