Infusion Of Histamine Research Articles

Recombinant Human Diamine Oxidase Against Histamine Induced Shock - Implications for Mast Cell Activation Syndrome

Background and Objective:Mastocytosis patients suffer from a clonal increase in mast cells which produce and release excessive amounts of histamine even under stable conditions (Keyzer et al. 1983). Unfortunately, symptom control with new kinase inhibitors is variable and modest at best. Mast cell activation syndrome may further enhance histamine release which can result in recurrent shocks (Böhm et al. 2019), or severe, protracted anaphylaxis refractory to epinephrine (Grafeneder et al. 2022). Previously we demonstrated that recombinant human diamine oxidase (rhDAO) fully degrades 100-fold elevated histamine concentrations in plasma samples from mastocytosis patients. In vivo rhDAO, with a mutated heparin binding motif (mHBM), was able to digest massively increased histamine levels, thereby improving indirect measures of shock such as a temperature drop in mice (Karer et al. 2022). As mice are insensitive to histamine (intravenous LD50 of 385mg/kg in mice compared with 0.18mg/kg in guinea pigs), this unfortunately limits their translational value. To assess the therapeutic potential of rhDAO_mHBM, we tested its efficacy for the prevention and treatment of histamine induced shock in guinea pigs, the only histamine sensitive rodent species. Methods:Guinea pigs received continuous intravenous infusions of 8 µg/kg/min histamine to model its release from activated circulating basophils or subcutaneous injections of 1mg/kg histamine to mimic peripheral histamine release by mast cells. We used intramuscular injections of 5µg/kg adrenaline as a benchmark, because it is recommended in guidelines for the treatment of anaphylaxis, although its efficacy had never been proven. Infusions of rhDAO_mHBM were given either prophylactically before- or therapeutically after - symptom onset. Mean arterial pressure was measured intra-arterially and rhDAO_mHBM levels were quantified by enzyme immunoassay and histamine concentrations by a liquid chromatography -tandem mass spectrometry (LC-MS/MS) method. The primary outcome variable was prevention of shock as defined by a >=30% drop in mean arterial blood pressure. Results:Guinea pigs pretreated with 4 mg/kg rhDAO_mHBM showed lower mean heart rate (p<0.01) and higher body core temperatures at the end of the intravenous histamine infusions compared to controls (p<0.05). Histamine infusions increased median urinary excretion of histamine and N-methyl-histamine 8.6- and 4.0-fold (p<0.05), respectively. Pretreatment with 4 mg/kg rhDAO_mHBM reduced urinary histamine (p<0.01) and N-methyl-histamine (p<0.01) concentrations compared with controls. Subcutaneous injections of 1 mg/kg histamine induced shock within 20 minutes in all control animals, and the experiments had to be terminated prematurely in several animals. Intramuscular injection of 5mcg/kg adrenaline (similar to human adrenaline auto-injector doses) after symptom onset was unable to prevent shock, confirming its lack of efficacy demonstrated previously in an anaphylaxis model in dogs (Mink et al. 2004). In contrast, prophylactic infusions of 4-8mg/kg rhDAO_mHBM prevented hypotensive shock in all treated animals (p<0.01). After an initial histamine induced drop in blood pressure, 8mg/kg rhDAO_mHBM restored blood pressure and prevented shock in all animals when injected at the time of symptom occurrence (p<0.01 Chi2 test). Figure 1 demonstrates the median drop in blood pressure and development of shock (indicated by the dashed line) by subcutaneous injection of 1mg/kg histamine (black squares), and the prevention of shock by rhDAO-mHBM given before (blue up triangles) or after (red circles) histamine injections. Conclusion: This is the first demonstration of the beneficial effects of rhDAO_mHBM in a histamine-sensitive species. rhDAO_mHBM is a novel therapeutic approach targeting histamine excess which effectively prevented shock, in contrast to intramuscular epinephrine. As the mechanism of action is not species specific, these findings can be translated from guinea pigs to humans: it will help to select optimal dosing of rhDAO_mHBM during clinical development for the prophylaxis in - and treatment of - mastocytosis patients suffering from histamine induced symptoms or mast cell activation syndrome, or patients with anaphylaxis induced by asparaginase, plasma products or other medications.

Recombinant human diamine oxidase prevents hemodynamic effects of continuous histamine infusion in guinea pigs

ObjectiveTo test whether recombinant human diamine oxidase (rhDAO) with a mutated heparin-binding motif (mHBM), which shows an increased alpha-distribution half-life, prevents histamine-induced hemodynamic effects.MaterialThirty-eight female guinea pigs were either pretreated with rhDOA_mHBM or buffer.Treatment and methodsGuinea pigs received a continuous infusion of histamine. Heart rate (HR), body core temperature and mean arterial pressure (MAP) were measured and blood was collected.ResultsContinuous intravenous infusion of 8 µg/kg/min histamine increased mean peak plasma histamine levels from 5 (± 0.3 SEM) to 28 ng/mL (± 4.9 SEM) after 30 min but had no effect on oxygen saturation. Guinea pigs pretreated with 4 mg/kg rhDAO_mHBM showed lower mean HR (p = 0.008), histamine plasma concentrations (p = 0.002), and higher body core temperatures at the end of the histamine challenge (p = 0.02) compared to controls. Cessation of histamine infusion led to a rebound increase in MAP, but this hemodynamic instability was prevented by rhDAO_mHBM. Pretreatment with 4 mg/kg rhDAO_mHBM reduced urinary histamine (p = 0.004) and 1-Methylhistamine (p < 0.0001) concentrations compared to controls.ConclusionsProphylactic infusion of rhDAO_mHBM prevents hemodynamic effects in a guinea pig model of continuous histamine infusion. These findings might help in the translation from animals to humans and in the selection of the optimal dosing of rhDAO_mHBM during human histamine challenge studies.

Additive effect of histamine and muscimol upon induction of antinociceptive and antidepressant effects in mice.

We investigated the effects of histamine and GABA A receptor agents on pain and depression-like behaviors and their interaction using a tail-flick test and the forced swimming test (FST) in male mice. Our data revealed that intraperitoneal administration of muscimol (0.12 and 0.25 mg/kg) increased the percentage of maximum possible effect (%MPE) and area under the curve (AUC) of %MPE, indicating an antinociceptive response. Intraperitoneal injection of bicuculline (0.5 and 1 mg/kg) decreased %MPE and AUC of %MPE, suggesting hyperalgesia. Moreover, muscimol by reducing the immobility time of the FST elicited an antidepressant-like response but bicuculline by enhancing the immobility time of the FST caused a depressant-like response. Intracerebroventricular (i.c.v.) microinjection of histamine (5 µg/mouse) enhanced %MPE and AUC of %MPE. i.c.v. infusion of histamine (2.5 and 5 µg/mouse) decreased immobility time in the FST. Co-administration of different doses of histamine along with a sub-threshold dose of muscimol potentiated antinociceptive and antidepressant-like responses produced by histamine. Cotreatment of different doses of histamine plus a noneffective dose of bicuculline reversed antinociception and antidepressant-like effects elicited by histamine. Cotreatment of histamine, muscimol, and bicuculline reversed antinociceptive and antidepressant-like behaviors induced by the drugs. The results demonstrated additive antinociceptive and antidepressant-like effects between histamine and muscimol in mice. In conclusion, our results indicated an interaction between the histaminergic and GABAergic systems in the modulation of pain and depression-like behaviors.

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.

Ticagrelor prevents infective endocarditis by mitigating Staphylococcus aureus virulence

Infective endocarditis (IE) is a deadly disease mainly caused by the gram-positive and highly virulent bacteria Staphylococcus aureus (SA). Due to lack of efficacy of current antibiotic therapy, there is an urgent need to discover new strategies that could prevent this disease. To assess the ability of the antiplatelet drug ticagrelor, which also displays antibacterial activity against gram-positive bacteria, to prevent SAIE. We used a mouse model of infective endocarditis induced by a SAIE clinical isolate. Ticagrelor was administered orally at a conventional dosage (3 mg/kg, single dose) prior to infection and local histamine infusion on the aortic valve. Infected vegetation presence was determined by Gram staining on heart sections after three days. Antibacterial effect of ticagrelor at dosages equivalent to plasma levels achieved in patients (0.75–1.25 μg/mL) was assessed in vitro in human blood. Ticagrelor significantly prevented the formation of infected vegetation, with IE in only 14.3% of ticagrelor-treated mice ( n = 21) compared to 52.3% of vehicle-treated mice ( n = 37). Ex vivo ADP-induced platelet aggregation assays confirmed rapid reversibility of antiplatelet activity (4 hours), which made it unlikely that solely the antiplatelet effect would explain IE prevention by ticagrelor. Bacterial survival in blood was not diminished three days post-infection. We therefore assessed whether ticagrelor could affect bacterial virulence. We found that growing SA in the presence of 1.25 μg/mL ticagrelor inhibited a-toxin RNA expression and protein secretion, which was corroborated with drastically reduced hemolysis and platelet aggregation induced by bacterial supernatants. Ticagrelor-treated bacteria could no longer adhered to fibrinogen, and in whole blood perfusion experiments, flow-dependent bacterial adhesion on activated endothelial cells was severely impaired. Our study demonstrates the unprecedented ability of ticagrelor to prevent IE by a novel mechanism of directly mitigating bacterial virulence. Hence, clinical trials using ticagrelor as adjunct therapy to antibiotics in patients at risk for IE are warranted.

Source of dopamine in gastric juice and luminal dopamine-induced duodenal bicarbonate secretion via apical dopamine D2 receptors.

Dopamine protects the duodenal mucosa. Here we have investigated the source of dopamine in gastric juice and the mechanism underlying the effects of luminal dopamine on duodenal bicarbonate secretion (DBS) in rodents. Immunofluorescence, UPLC-MS/MS, gastric incubation and perfusion were used to detect gastric-derived dopamine. Immunofluorescence and RT-PCR were used to examine the expression of dopamine receptors in the duodenal mucosa. Real-time pH titration and pHi measurement were performed to investigate DBS. H+ -K+ -ATPase was co-localized with tyrosine hydroxylase and dopamine transporters in gastric parietal cells. Dopamine was increased in in vivo gastric perfusate after intravenous infusion of histamine and in gastric mucosa incubated, in vitro, with bethanechol chloride or tyrosine. D2 receptors were the most abundant dopamine receptors in rat duodenum, mainly distributed on the apical membrane of epithelial cells. Luminal dopamine increased DBS in a concentration-dependent manner, an effect mimicked by a D2 receptor agonist quinpirole and inhibited by the D2 receptor antagonist L741,626, in vivo D2 receptor siRNA and in D2 receptor -/- mice. Dopamine and quinpirole raised the duodenal enterocyte pHi . Quinpirole-evoked DBS and PI3K/Akt activity were inhibited by calcium chelator BAPTA-AM or in D2 receptor-/- mice. Dopamine in the gastric juice is derived from parietal cells and is secreted along with gastric acid. On arrival in the duodenal lumen, dopamine increased DBS via an apical D2 receptor- and calcium-dependent pathway. Our data provide novel insights into the protective effects of dopamine on the duodenal mucosa.

Not Itself Histamine, but H3R Antagonists/Inverse Agonist Thioperamide Enhances Long-term Potentiation in the Dentate Gyrus of Urethane- Anesthetized Rats

Purpose: Although the histamine receptor antagonists have been reported to enhance consolidation of memory in diverse disease states of the central nervous system, their contribution to the long-term potentiation (LTP), a cellular form of learning and memory, remains unknown. Herein, we evaluate the effect of H3 receptor (H3R) antagonist thioperamide (inverse agonist) on the LTP in healthy rats and compare the effect with that of histamine as an agonist, and pyrilamine, as a H2R antagonist. Methods: LTP was induced in the dentate gyrus, where field potentials were recorded during infusions of saline, histamine, thioperamide or pyrilamine alone by application of high- frequency stimulation protocols. Results: The short-term and long-temp potentiation of EPSP, not of PS, in the thioperamide group were significantly higher in comparison with controls, indicating that induction and maintenance of synaptic, not somatic, LTP further enhanced by H3R antagonism. There were also significant differences in short-term and long-term potentiation of PS between the histamine and pyrilamine groups, indicating H1R-mediated dyssynchrony in granule cell of the dentate gyrus. Conclusion: Histamine seems not to play a significant functional role in the perforant pathway- dentate gyrus synapses, but the antagonism of H3R should be considered in treatment of cognitive dysfunctions, although other forms of synaptic plasticity such as longterm depression and depotentiation of LTP are needed.

Histamine modulation of the basal ganglia circuitry in the development of pathological grooming

Aberrant histaminergic function has been proposed as a cause of tic disorders. A rare mutation in the enzyme that produces histamine (HA), histidine decarboxylase (HDC), has been identified in patients with Tourette syndrome (TS). Hdc knockout mice exhibit repetitive behavioral pathology and neurochemical characteristics of TS, establishing them as a plausible model of tic pathophysiology. Where, when, and how HA deficiency produces these effects has remained unclear: whether the contribution of HA deficiency to pathogenesis is acute or developmental, and where in the brain the relevant consequences of HA deficiency occur. Here, we address these key pathophysiological questions, using anatomically and cellularly targeted manipulations in mice. We report that specific ablation or chemogenetic silencing of histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus leads to markedly elevated grooming, a form of repetitive behavioral pathology, and to elevated markers of neuronal activity in both dorsal striatum and medial prefrontal cortex. Infusion of HA directly into the striatum reverses this behavioral pathology, confirming that acute HA deficiency mediates the effect. Bidirectional chemogenetic regulation reveals that dorsal striatum neurons activated after TMN silencing are both sufficient to produce repetitive behavioral pathology and necessary for the full expression of the effect. Chemogenetic activation of TMN-regulated medial prefrontal cortex neurons, in contrast, increases locomotion and not grooming. These data confirm the centrality of striatal regulation by neurotransmitter HA in the adult in the production of pathological grooming.

Memory retrieval of inhibitory avoidance requires histamine H1 receptor activation in the hippocampus

Retrieval represents a dynamic process that may require neuromodulatory signaling. Here, we report that the integrity of the brain histaminergic system is necessary for retrieval of inhibitory avoidance (IA) memory, because rats depleted of histamine through lateral ventricle injections of α-fluoromethylhistidine (a-FMHis), a suicide inhibitor of histidine decarboxylase, displayed impaired IA memory when tested 2 d after training. a-FMHis was administered 24 h after training, when IA memory trace was already formed. Infusion of histamine in hippocampal CA1 of brain histamine-depleted rats (hence, amnesic) 10 min before the retention test restored IA memory but was ineffective when given in the basolateral amygdala (BLA) or the ventral medial prefrontal cortex (vmPFC). Intra-CA1 injections of selective H1 and H2 receptor agonists showed that histamine exerted its effect by activating the H1 receptor. Noteworthy, the H1 receptor antagonist pyrilamine disrupted IA memory retrieval in rats, thus strongly supporting an active involvement of endogenous histamine; 90 min after the retention test, c-Fos-positive neurons were significantly fewer in the CA1s of a-FMHis-treated rats that displayed amnesia compared with in the control group. We also found reduced levels of phosphorylated cAMP-responsive element binding protein (pCREB) in the CA1s of a-FMHis-treated animals compared with in controls. Increases in pCREB levels are associated with retrieval of associated memories. Targeting the histaminergic system may modify the retrieval of emotional memory; hence, histaminergic ligands might reduce dysfunctional aversive memories and improve the efficacy of exposure psychotherapies.

Ventral hippocampal histamine increases the frequency of evoked theta rhythm but produces anxiolytic-like effects in the elevated plus maze

The neurobiological underpinnings of anxiety are of paramount importance to the development of effective therapeutic treatments. To date, there is considerable pharmacological evidence suggesting that the suppression of hippocampal theta frequency is a robust and predictive assay of anxiolytic drug action. Recently, this idea has been challenged using histamine (2-(4-imidazolyl)ethanamine), an endogenous neurotransmitter involved in a number of brain and behavioral functions. Here, we systematically evaluate the effects of dorsal and ventral hippocampal histamine infusions on evoked theta frequency and behavioral anxiety. Given the complex pharmacological profile of histamine and its receptors in the hippocampus, we reasoned that local intra-hippocampal infusions would be a powerful test of the theta suppression model. While dorsal hippocampal infusions of histamine produced neither significant changes in anxious-like behavior in the elevated plus maze nor changes of evoked theta, ventral infusions of histamine produced potent behavioral anxiolysis which corresponded to an increase, and not a decrease, in evoked theta frequency. As a positive neurophysiological control, we demonstrated that diazepam, a proven anxiolytic drug, decreased the frequency of hippocampal theta following both dorsal and ventral hippocampal infusions. Our results further challenge the hippocampal theta frequency suppression model as a measure of anxiolytic drug action.This article is part of the Special Issue entitled ‘Histamine Receptors’.

Effect of rebamipide on gastric bleeding and ulcerogenic responses induced by aspirin plus clopidogrel under stimulation of acid secretion in rats.

We examined the prophylactic effect of rebamipide on gastric bleeding induced by the perfusion of aspirin (acetylsalicylic acid [ASA]) plus clopidogrel under the stimulation of acid secretion in rats. Under urethane anesthesia, acid secretion was stimulated by the i.v. infusion of histamine (8 mg/kg/h), and the stomach was perfused with 25 mmol/L ASA at a rate of 0.4 mL/min. Gastric bleeding was evaluated as the concentration of hemoglobin in the perfusate. Clopidogrel (30 mg/kg) was given p.o. 24 h before the perfusion. Rebamipide (3-30 mg/kg) or other antiulcer drugs were given i.d. before the ASA perfusion. Slight gastric bleeding or damage was observed with the perfusion of ASA under the stimulation of acid secretion, whereas these responses were significantly increased in the presence of clopidogrel. Both omeprazole and famotidine inhibited acid secretion and prevented these responses to ASA plus clopidogrel. Rebamipide had no effect on acid secretion, but dose-dependently prevented gastric bleeding in response to ASA plus clopidogrel, with the degree of inhibition being almost equivalent to that of the antisecretory drugs, and the same effects were obtained with the gastroprotective drugs, irsogladine and teprenone. These agents also reduced the severity of gastric lesions, although the effects were less than those of the antisecretory drugs. These results suggest that the antiplatelet drug, clopidogrel, increases gastric bleeding induced by ASA under the stimulation of acid secretion, and the gastroprotective drug, rebamipide, is effective in preventing the gastric bleeding induced under such conditions, similar to antisecretory drugs.

Hippocampal α-adrenoceptors involve in the effect of histamine on spatial learning

Spatial learning is a model of higher human cognitive functions which is used for studying animal behavior. Histaminergic and noradrenergic systems play a modulatory role in learning and memory. The present study aimed to test the effects of α-adrenoceptor agonist/antagonist microinjection into the CA1 region of dorsal hippocampus on histamine-induced spatial learning facilitation in the water maze task. Pre-training intra-CA1 microinjection of α1- or α2-adrenergic agonist, phenylephrine (0.0025μg/rat) or clonidine (0.05μg/rat) decreased traveled distance and escape latency at the start of the training phase, suggesting a spatial learning facilitation; while the higher dose of the drugs (phenylephrine 0.005μg/rat, clonidine 0.2 and 0.5μg/rat) increased the performance level at the end of the training phase, indicating a water maze spatial acquisition impairment. However, α1-receptor antagonist, prazosin (1μg/rat) impaired spatial learning; α2-receptor antagonist, yohimbine (0.25μg/rat) facilitated spatial acquisition. Moreover, pre-training intra-CA1 microinjection of a subthreshold dose of phenylephrine (0.001μg/rat) reversed histamine response, while ineffective dose co-administration of clonidine (0.1μg/rat) potentiated histamine (0.01μg/rat) response. Subthreshold dose of prazosin or yohimbine did not alter histamine response. Bilateral infusion of histamine (0.05μg/rat) facilitated spatial learning by itself. Furthermore, the drug's injections had no effect on swimming speed on the training days of MWM. These results suggest that α-adrenergic receptors of the dorsal hippocampal CA1 regions may play an important role in histamine-induced facilitation of spatial acquisition.

Animal Models of Gastric Bleeding Induced by Dual Antiplatelet Therapy Using Aspirin and Clopidogrel - Prophylactic Effect of Antiulcer Drugs

We set up two models of gastric bleeding in rats using low-dose aspirin (ASA) and the antiplatelet drug clopidogrel, a P2Y₁₂ receptor antagonist, and examined the effect of antiulcer drugs on gastric bleeding and ulcerogenic responses under such conditions. Under urethane anesthesia, two catheters were inserted into the rat stomach, one from the esophagus and another through the pylorus via an incision in the duodenum. In the first model, the stomach was perfused with 25 mM ASA dissolved in 50 mM HCl using an infusion pump, and gastric bleeding was measured as the hemoglobin concentration in perfusate collected every 15 min. In the second model, the stomach was perfused with ASA under stimulation of acid secretion by a continuous i.v. infusion of histamine (8 mg/kg/hr). Clopidogrel (30 mg/kg) was given p.o. 24 h before the ASA perfusion, while antiulcer drugs were given i.d. or i.v. 30 min before. Perfusion of the stomach with acidified ASA or ASA under histamine-stimulated acid secretion caused minimal bleeding in the stomach with few lesions. The ulcerogenic and bleeding responses to ASA under these conditions were markedly aggravated by pretreatment with clopidogrel, which by itself provoked neither bleeding nor damage. Antiulcer drugs, such as prostaglandin E₂, irsogladine, rebamipide and teprenone, reduced the severity of gastric bleeding and damage in response to ASA plus clopidogrel in the presence of both exogenous and endogenous acid. In contrast, antisecretory drugs such as a proton pump inhibitor and histamine H₂ receptor antagonists markedly suppressed the gastric bleeding and lesion responses to ASA plus clopidogrel under histamine-stimulated acid secretion, but had no effect on the responses to acidified ASA plus clopidogrel. These results suggest that clopidogrel increases gastric bleeding induced by ASA and that antiulcer drugs are useful for preventing gastric bleeding caused by the dual antiplatelet therapy.

Behavioral anxiolysis without reduction of hippocampal theta frequency after histamine application in the lateral septum of rats

Hippocampal theta activity is linked to various processes, including locomotion, learning and memory, and defense and affect (i.e., fear and anxiety). Interestingly, all classes of clinically effective anxiolytics, as well as experimental compounds that decrease anxiety in pre-clinical animal models of anxiety, reduce the frequency of hippocampal theta activity elicited by stimulation of the reticular formation in freely behaving or anesthetized animals. In the present experiments, we found that bilateral histamine infusions (0.5 µg/hemisphere) into the lateral septum (LS) of rats decreased anxiety-like responses in two models of anxiety, the elevated plus maze and novelty-induced suppression of feeding test. Surprisingly, these same infusions significantly increased hippocampal theta frequency elicited by reticular stimulation in urethane-anesthetized rats. In contrast to these findings, additional experiments showed that the clinically effective anxiolytic buspirone (40 mg/kg, i.p.) reduced theta frequency, confirming previous observations. Taken together, the dissociation of behavioral anxiolysis and theta frequency reduction noted here suggest that hippocampal theta frequency is not a direct index of anxiety levels in rodents. Further, the mechanisms underlying the behavioral and physiological effects elicited by histamine in the LS require further study.

Histidine Decarboxylase Deficiency Causes Tourette Syndrome: Parallel Findings in Humans and Mice

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.

Histamine‐induced vasodilatation in the human forearm vasculature

To investigate the mechanism of action of intra-arterial histamine in the human forearm vasculature. Three studies were conducted to assess changes in forearm blood flow (FBF) using venous occlusion plethysmography in response to intra-brachial histamine. First, the dose-response was investigated by assessing FBF throughout a dose-escalating histamine infusion. Next, histamine was infused at a constant dose to assess acute tolerance. Finally, a four way, double-blind, randomized, placebo-controlled crossover study was conducted to assess FBF response to histamine in the presence of H1 - and H2 -receptor antagonists. Flare and itch were assessed in all studies. Histamine caused a dose-dependent increase in FBF, greatest with the highest dose (30 nmol min(-1) ) infused [mean (SEM) infused arm vs. control: 26.8 (5.3) vs. 2.6 ml min(-1) 100 ml(-1) ; P < 0.0001]. Dose-dependent flare and itch were demonstrated. Acute tolerance was not observed, with an increased FBF persisting throughout the infusion period. H2 -receptor antagonism significantly reduced FBF (mean (95% CI) difference from placebo at 30 nmol min(-1) histamine: -11.9 ml min(-1) 100 ml(-1) (-4.0, -19.8), P < 0.0001) and flare (mean (95% CI) difference from placebo: -403.7 cm(2) (-231.4, 576.0), P < 0.0001). No reduction in FBF or flare was observed in response to the H1 -receptor antagonist. Itch was unaffected by the treatments. Histamine did not stimulate vascular release of tissue plasminogen activator or von Willebrand factor. Histamine causes dose-dependent vasodilatation, flare and itch in the human forearm. H2 -receptors are important in this process. Our results support further exploration of combined H1 - and H2 -receptor antagonist therapy in acute allergic syndromes.

The histaminergic H1, H2, and H3 receptors of the lateral septum differentially mediate the anxiolytic-like effects of histamine on rats' defensive behaviors in the elevated plus maze and novelty-induced suppression of feeding paradigm

The neural histaminergic system is involved in a wide range of physiological processes, including anxiety. Histaminergic neurons are localized in the tuberomammillary nucleus of the posterior hypothalamus and share bidirectional connections with the lateral septum, an area well implicated in anxiety. The current study examined whether the histaminergic system of the lateral septum regulates rats' defensive behaviors in two animal models of anxiety, the elevated plus maze (EPM) and novelty-induced suppression of feeding paradigm (NISF). We found that bilateral infusions of histamine (1.0μg and 5.0μg) into the lateral septum selectively decreased rats' defensive behaviors in the EPM (both doses) and NISF (1.0μg only). Follow-up studies found that pre-infusions of the H1 and H2 antagonists, pyrilamine (20μg) and ranitidine (20μg) respectively, reversed the anxiolytic-like effects of intra-LS histamine (1.0μg) in the NISF but not in the EPM, while pre-infusions of the H3 antagonist ciproxifan (200pg) attenuated the anxiolytic-like effects of intra-LS histamine in the EPM but not in the NISF. This double dissociation suggests that H1 and H2 receptors in the lateral septum, likely via a post-synaptic mechanism, mediate the anxiolytic-like effects of histamine in the NISF but not in the EPM. In contrast, lateral septal H3 receptors mediate, likely pre-synaptically, the anxiolytic-like effects of histamine in the EPM but not in the NISF. Our findings indicate that these receptors differentially contribute to rats' specific defensive behaviors in the EPM and NISF, that is, avoidance of open spaces and neophagia respectively.

Involvement of the dorsal hippocampal GABA-A receptors in histamine-induced facilitation of memory in the Morris water maze

Several types of learning and memory processes are regulated by the hippocampus which is an important subcortical structure in the mammalians' brain. Previous investigations have shown that different receptor systems in the CA1 region of hippocampus are involved in learning and memory functions. Investigating the possible influence of dorsal hippocampal GABA-A receptors on histamine-induced spatial facilitation in adult male Wistar rats was the focus of the current study. Rats were bilaterally implanted with dorsal hippocampal (CA1) cannulae, recovered from surgery and then trained in Morris water maze (MWM) for 4 consecutive days. A block of four trials was given each day. All drugs were injected into CA1 regions, 5min before training. Pre-training intra-CA1 microinjection of muscimol, a GABA-A receptor agonist, at the dose of 0.01 or 0.02μg/rat, increased the traveled distance or the escape latency and traveled distance to the hidden platform, respectively, indicating a water maze spatial acquisition impairment. Intra-CA1 administration of bicuculline, a GABA-A receptor antagonist however, significantly decreased the escape latency and traveled distance to the hidden platform, suggesting a spatial learning facilitation. On the other hand, pre-training intra-CA1 microinjection of the subthreshold dose of muscimol plus different doses of histamine (0.025, 0.05 and 0.1μg/rat) did not alter the histamine response. Meanwhile, the co-administration of the ineffective dose of bicuculline together with histamine potentiated the spatial learning. Moreover, bilateral infusion of histamine (0.025, 0.05 and 0.1μg/rat) by itself, facilitated the spatial learning. Notably, the drug injections had no effect on swimming speed during the MWM training sessions. Our results suggest that the dorsal hippocampal (CA1) GABA-A mechanism(s) may influence the histamine-induced facilitation of spatial acquisition.

Effects of IY-81149, a newly developed proton pump inhibitor, on gastric acid secretion in vitro and in vivo.

The inhibitory effects of IY-81149 (2-[[(4-methoxy-3-methyl)-2- pyridinyl]methyl-sulfinyl]-5-(1H-pyrol-1-yl)-1H-benzimidazole, CAS 172152-36-2), a newly developed proton pump inhibitor (PPI) on gastric acid secretion were investigated in vitro and in vivo. In rabbit parietal cell preparation, IY-81149 irreversibly inhibited H+/K(+)-ATPase in dose-dependent manner with an IC50 of pump inhibitory activity of 6.0 x 10(-6) mol/l and that of omeprazole (CAS 73590-58-6) was 1 x 10(-4) mol/l at pH 7.4. On cumulation of 14C-aminopyrine in histamine stimulated parietal cells, the IC50 of IY-81149 was 9.0 x 10(-9) mol/l and that of omeprazole was 1.9 x 10(-8) mol/l. The inhibition rates of IY-81149 and omeprazole at a concentration of 1 x 10(-9) mol/l in human parietal cells were 137% and 64%, respectively. In pylorus-ligated rats, IY-81149 showed a 2-3 times stronger inhibitory activity than omeprazole against gastric acid secretion. The ED50 of IY-81149 and omeprazole administered intraduodenally was 1.6 mg/kg and 3.8 mg/kg. In the case of oral administration, the ED50 of IY-81149 and omeprazole was 1.94 mg/kg and 5.64 mg/kg, respectively. But after 24 h administration, the anti-secretory activity of IY-81149 was lower than that of omeprazole at all doses tested. In anesthetized rats, IY-81149 dose-dependently increased gastric pH which was lowered by histamine infusion. In the case of i.v. injection, the ED50 of IY-81149 and omeprazole was 1.2 and 1.4 mg/kg and in the case of i.d. administration, the ED50 of IY-81149 and omeprazole was 3.9 and 4.1 mg/kg, respectively. IY-81149 also significantly inhibited pentagastrin-stimulated gastric secretion. Its ED50 was 2.1 mg/kg and that of omeprazole was 3.5 mg/kg with i.d. administration. In the case of i.v. injection, IY-81149 was equipotent to omeprazole. IY-81149 also inhibited gastric acid secretion strongly in fistular rats. The ED50 of IY-81149 administered intraduodenally was 0.43 mg/kg and that of omeprazole was 0.68 mg/kg. In Heidenhain pouch dogs, the acid output was completely blocked at 0.3 mg/kg, 135 min after i.v. administration. Omeprazole showed a similar effect as IY-81149. The histamine induced increase of acid output in the Heidenhain pouch dog was blocked by 71% 150 min after oral administration of enteric-coated IY-81149 at a dose of 3 mg/kg, and omeprazole showed similar effects. In conclusion, IY-81149 revealed the characteristics as a strong proton pump inhibitor, and its potency against gastric acid secretion was superior to that of the reference drug, omeprazole.

An investigation of the mechanisms responsible for a reduction in capillary filtration coefficient in the innervated cat jejunum on intravenous infusion of histamine.

An investigation of the mechanisms responsible for a reduction in capillary filtration coefficient in the innervated cat jejunum on intravenous infusion of histamine.