Effects Of Histamine Research Articles

Novel insights on the biology and immunologic effects of histamine: Aroad map for allergists and mast cell biologists.

Histamine (C5H9N3, molecular weight 111.15 g/mol) is a well-studied endogenous biogenic amine composed of an imidazole ring attached to an ethylamine side chain. It has a limited half-life of a few minutes within tissues and in circulation. Several cell types including mast cells (MCs), basophils, platelets, histaminergic neurons, and enterochromaffin cells produce varying amounts of histamine using histidine decarboxylase. However, only MCs and basophils have complex mechanisms to pack and store histamine in granules along with other mediators using serglycin and its carried glycosaminoglycan side chains. Relatively low granule pH (∼5.5) supports the binding of stored histamine to heparin, whereas exposure to neutral pH after degranulation weakens the binding and histamine becomes liberated. Histamine exerts multifaceted regulatory biofunctions by engaging its 4 types of heptahelical G protein-coupled receptors (H1R-H4R), which have different expression profiles and functions. MCs express H1R, H2R, and H4R, which gives them a dual role in histamine biology as producers and responsive target cells. Histamine plays a role in a variety of physiologic and pathologic processes such as cell proliferation, differentiation, hematopoiesis, vascular permeability, embryogenesis, tissue regeneration, and wound healing. The emergence of histamine receptor-deficient mouse models and the development of multiple histamine receptor agonists and antagonists have helped researchers better understand these physiologic and pathogenic functions of histamine. We review the biology of histamine with a focus on immunologic aspects and the role of histamine in allergy and MC biology.

Біометричний аналіз показників прооксидантно-антиоксидантного стану плазми крові щурів за дії гістаміну і кверцетину

The regularities of the effect of histamine in concentrations of 0.01; 0.1; 1; 10 μM were studied and quercetin in concentrations of 0.1; 0.3; 0.5; 1; 3; 5 mM, as well as their combined effect on the prooxidant-antioxidant state of blood plasma of rats, using cluster and factor biometric analyses. It was established that the experimental groups according to the investigated indicators (TBА-positive products, lipid hydroperoxides, carbonyl groups of neutral and basic proteins, superoxide anion radical, superoxide dismutase, catalase, reduced glutathione, ATP) were distributed among 13 clusters (according to cluster analysis). In one group of similarities, the effect of histamine in concentrations of 0.01 µM and 1 µM was revealed. Quercetin at a concentration of 0.5 mM and histamine at a concentration of 0.1 µM have a similar effect on the indicators of the prоoxidant-antioxidant state of the blood plasma. Combined addition to the blood of histamine at a concentration of 10 μM and quercetin at a concentration of 0.1; 0.5; 3 mM lead to the same changes in the indicated studied indicators. Cluster analysis also combined the combined effects of 0.01 μM histamine and 0.1 and 3 mM quercetin. It is important to note that a decrease in the content of carbonyl groups of proteins was found in those classers whose experimental blood groups were added to histamine and quercetin, which indicates a decrease in protein damage due to free radical oxidation processes. Using factor analysis, it was established the presence of three hidden factors that affect the processes of free radical oxidation of blood under the action of histamine and quercetin. A high correlation of factor I with protein carbonyl groups, reduced glutathione, superoxide anion radical was revealed. Factor II is most correlated with ATP, superoxide dismutase, lipid hydroperoxides. There is a close relationship between factor III and TBА-positive products and catalase. Taking into account the closeness of the relationship, factor I was given the name “factor of action on proteins”, factor II – “factor of action on bioenergetics and initiator of lipid peroxidation processes”, factor III – “factor of enhancement of lipid peroxidation processes”. It was established that quercetin activates factor I (influence on proteins, causing their oxidation) and factor III (intensification of lipid peroxidation processes) depending on the concentration of the drug. Quercetin in a concentration of 1 mM has the property of both factors (I and III).

Evaluation of potential punishing effects of 2,5-dimethoxy-4-methylamphetamine (DOM) in rhesus monkeys responding under a choice procedure.

There has been substantial and growing interest in the therapeutic utility of drugs acting at serotonin 2A subtype (5-HT 2A ) receptors, increasing the need for characterization of potential beneficial and adverse effects of such compounds. Although numerous studies have evaluated the possible rewarding and reinforcing effects of 5-HT 2A receptor agonists, there have been relatively few studies on potential aversive effects. The current study investigated punishing effects of 2,5-dimethoxy-4-methylamphetamine (DOM) in four rhesus monkeys responding under a choice procedure in which responding on one lever delivered a sucrose pellet alone and responding on the other lever delivered a sucrose pellet plus an intravenous infusion of a range of doses of fentanyl (0.1-3.2 µg/kg/infusion), histamine (3.2-100 µg/kg/infusion), or DOM (3.2-100 µg/kg/infusion). When fentanyl was available, responding for a pellet plus an infusion increased dose dependently in all subjects, indicating a positive reinforcing effect of fentanyl. When histamine was available, responding for a pellet plus an infusion decreased in three of four subjects, indicating a punishing effect of histamine. Whether available before or after histamine, DOM did not systematically alter choice across the range of doses tested. These results suggest that the 5-HT 2A receptor agonist DOM has neither positive reinforcing nor punishing effects under a choice procedure that is sensitive to both processes.

Histamine H1-receptor-mediated modulation of NMDA receptors signaling responses.

This study attempted to clarify the role of histamine H1 receptors in epilepsy by exploring the effects of agonists and inverse agonists on the rundown of the current induced by iterative applications of NMDA or GABA in primary neuronal culture. Mepyramine, a classical H1-receptor antagonist/inverse agonist, increased the NMDA current by about 40% during the first minutes of recording. This effect was concentration-dependent, maximal at 10 nM, and mimicked by triprolidine, another antagonist/inverse agonist. No endogenous histamine was detected in the cultures by a selective immunoassay; both compounds were acting as inverse agonists. Indicating a high constitutive activity of the H1 receptor in this system, histamine did not affect the NMDA rundown, including its settlement, but significantly reversed the effect of mepyramine. A similar pattern was obtained with 2,3 bromophenyl histamine, a selective H1-receptor agonist. The initial increase induced by the two inverse agonists was followed by the same rundown as in controls. H1- and NMDA receptors are colocalized in most cultured neuronal cells. Mepyramine and histamine did not affect the GABA rundown. Our findings suggest an interaction between H1- and NMDA receptors. Inactivation of the H1-receptor by its inverse agonists delays the settlement of the NMDA rundown, which may underlie their proconvulsant effect reported in clinics. Therefore, H1-receptor constitutive activity and the effect of histamine revealed in its absence, tend to facilitate the initiation of the rundown, which is consistent with the anticonvulsant properties of histamine via activation of H1-receptors reported in many studies.

Histamine synthesis and transport are coupled in axon terminals via a dual quality control system

Monoamine neurotransmitters generated by de novo synthesis are rapidly transported and stored into synaptic vesicles at axon terminals. This transport is essential both for sustaining synaptic transmission and for limiting the toxic effects of monoamines. Here, synthesis of the monoamine histamine by histidine decarboxylase (HDC) and subsequent loading of histamine into synaptic vesicles are shown to be physically and functionally coupled within Drosophila photoreceptor terminals. This process requires HDC anchoring to synaptic vesicles via interactions with N-ethylmaleimide-sensitive fusion protein 1 (NSF1). Disassociating HDC from synaptic vesicles disrupts visual synaptic transmission and causes somatic accumulation of histamine, which leads to retinal degeneration. We further identified a proteasome degradation system mediated by the E3 ubiquitin ligase, purity of essence (POE), which clears mislocalized HDC from the soma, thus eliminating the cytotoxic effects of histamine. Taken together, our results reveal a dual mechanism for translocation and degradation of HDC that ensures restriction of histamine synthesis to axonal terminals and at the same time rapid loading into synaptic vesicles. This is crucial for sustaining neurotransmission and protecting against cytotoxic monoamines.

Suppression of excitatory synaptic transmission in the centrolateral amygdala via presynaptic histamine H3 heteroreceptors.

The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.

Immunological disturbance effect of exogenous histamine towards key immune cells

Histamine in food has attracted widespread attention due to the potential toxicity and associated health risk. However, its influences on immunological components, especially the function of key immune cells, are still poorly known. In this work, we explored the effects of exogenous histamine on the function of key immune cells such as intestinal epithelial cells, dendritic cells, and T cells. The results showed that histamine could affect the expression of allergy-related genes in CMT93 cells at a high dose of histamine. Moreover, it’s found that histamine could cause an imbalance in the levels of relevant immune factors secreted by dendritic cells and T cells, especially those related to allergy. At the same time, the proportion of MHC class II-positive dendritic cells and the proportion of T helper 2 (Th2) cells in CD4+ T cells increased after histamine stimulation. We concluded that the presence of a certain level of histamine in food may affect the expression of allergy-related cytokines, disrupt the balance of the immune homeostasis, and potentially lead to adverse immune reactions. This work demonstrated the importance of including the estimation of histamine's immune safety in aquatic products rather than merely considering the potential risk of food poisoning.

Sexual dimorphism in histamine regulation of striatal dopamine.

Many neuropsychiatric disorders show sex differences in prevalence and presentation. For example, Tourette's Syndrome (TS) is diagnosed 3-5 times more often in males. Dopamine modulation of the basal ganglia is implicated in numerous neuropsychiatric conditions, including TS. Motivated by an unexpected genetic finding in a family with TS, we previously characterized the modulation of striatal dopamine by histamine. We used microdialysis to analyze striatal dopamine response to the targeted infusion of histamine and histamine agonists. siRNA knockdown of histamine receptors was used to identify the cellular mediators of observed effects. Intracerebroventricular histamine reduced striatal dopamine in male mice, replicating previous work. Unexpectedly, histamine increased striatal dopamine in females. Targeted infusion of selected agonists revealed that the effect in males depends on H2R receptors in the substantia nigra pars compacta (SNc). Knockdown of H2R in SNc GABAergic neurons abrogated the effect, identifying these cells as a key locus of histamine's regulation of dopamine in males. In females, in contrast, H2R had no role; instead, H3R agonists in the striatum increased striatal dopamine. Strikingly, the effect of histamine on dopamine in females was modulated by the estrous cycle, appearing in estrus/proestrus but not in metestrus/diestrus. These findings confirm the regulation of striatal dopamine by histamine but identify marked sexual dimorphism in and estrous modulation of this effect. These findings may shed light on the mechanistic underpinnings of other sex differences in the striatal circuitry, perhaps including the marked sex differences seen in TS and related neuropsychiatric conditions.

Effects of systemic inflammation on the network oscillation in the anterior cingulate cortex and cognitive behavior.

Network oscillation in the anterior cingulate cortex (ACC) plays a key role in attention, novelty detection and anxiety; however, its involvement in cognitive impairment caused by acute systemic inflammation is unclear. To investigate the acute effects of systemic inflammation on ACC network oscillation and cognitive function, we analyzed cytokine level and cognitive performance as well as network oscillation in the mouse ACC Cg1 region, within 4 hours after lipopolysaccharide (LPS, 30 μg/kg) administration. While the interleukin-6 concentration in the serum was evidently higher in LPS-treated mice, the increases in the cerebral cortex interleukin-6 did not reach statistical significance. The power of kainic acid (KA)-induced network oscillation in the ACC Cg1 region slice preparation increased in LPS-treated mice. Notably, histamine, which was added in vitro, increased the oscillation power in the brain slices from LPS-untreated mice; for the LPS-treated mice, however, the effect of histamine was suppressive. In the open field test, frequency of entries into the center area showed a negative correlation with the power of network oscillation (0.3 μM of KA, theta band (3-8 Hz); 3.0 μM of KA, high-gamma band (50-80 Hz)). These results suggest that LPS-induced systemic inflammation results in increased network oscillation and a drastic change in histamine sensitivity in the ACC, accompanied by the robust production of systemic pro-inflammatory cytokines in the periphery, and that these alterations in the network oscillation and animal behavior as an acute phase reaction relate with each other. We suggest that our experimental setting has a distinct advantage in obtaining mechanistic insights into inflammatory cognitive impairment through comprehensive analyses of hormonal molecules and neuronal functions.

Mast cell degranulation is greater when exposed to dialysate collected from exercising skeletal muscle

The effect of histamine is multifaceted and potentially triggers a broad range of cellular adaptations contributing to vascular function, cellular maintenance, metabolism, and inflammation. During exercise, histamine is released from skeletal muscle. This response and the subsequent actions of histamine appear important in obtaining many of the beneficial adaptations to exercise. Increases in exercising skeletal muscle histamine release, in part, occur due to mast cell degranulation. However, the direct effect of exercise on mast cell degranulation has yet to be elucidated. To that end, this preliminary study aimed to quantify in vitro mast cell degranulation when cells are exposed to dialysate taken from exercising and non-exercising skeletal muscle. We hypothesized that greater mast cell degranulation would occur when exposed to dialysate collected from exercising skeletal muscle compared to dialysate collected from non-exercising muscle. Ten subjects (5M/5F, age 26 ± 5 years, weight 76 ± 17 kg, height 168 ± 12 cm) completed 60 minutes of single-leg dynamic knee extension exercise. Prior to exercise, a microdialysis probe was inserted into the vastus lateralis of the exercising and non-exercising legs and perfused with saline at a rate of 5 uL/min. Dialysate was collected before and every 20 minutes during exercise and the subsequent one-hour recovery period. In the exercising skeletal muscle, mast cell degranulation (quantified via b-hexosaminidase release) was greater when exposed to dialysate during exercise versus dialysate collected pre-exercise (P < 0.05). Compared to non-exercising leg dialysate, degranulation was greater for exercising leg dialysate taken between minutes 20 and 40 into exercise (20.6 ± 2.7% vs 15.8 ± 2.0%, P < 0.05) and 40 and 60 into exercise (24.0 ± 2.6 % vs 15.0 ± 2.7 %, P < 0.001) and remained greater for dialysate taken in the first 20 minutes of recovery (21.4 ± 2.8% vs 15.2 ± 3.0%, P < 0.05). These data suggest that there is a soluble factor released from exercising skeletal muscle that causes mast cell degranulation in vitro. These preliminary findings establish a bioassay for further exploration of the identity of the soluble factor released from exercising skeletal muscle, which is responsible for mast cell degranulation in vivo. This research was supported in part by National Institutes of Health Grants AG072805 and HL115027. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Role of Histamine in the Regulation of Calcium and Actin Dynamics in Collecting Duct Cells

Background. Histamine is a nitrogen-based molecule that has established involvement in allergic reactions and immune responses. The levels of histamine are increased in renal pathologies, such as nephrotic syndrome, diabetic nephropathy, acute renal failure, and end stage kidney disease. We have previously shown that all 4 histamine receptors (HR1 to HR4) are abundant in the kidney, and histamine exposure can affect levels of intracellular Ca2+ in the collecting ducts. Calcium signaling is an important regulator of actin cytoskeleton dynamics in these cells, and thus, affects their structure and integrity; however, there is a gap in knowledge regarding the role that histamine may play in this mechanism. In this study, we hypothesized that histamine exposure induces Ca2+ release and leads to reorganization of F-actin cytoskeleton in the cortical collecting duct cells. Methods. Immunofluorescent staining of cultured cells, in combination with the Western blotting, were utilized to characterize the renal expression of HRs and enzymes of the histaminergic system (HiS). The effects of histamine were tested in cultured mouse cortical collecting duct cells (mpkCCD). Functional live confocal imaging was used to detect changes in intracellular Ca2+ level (Fluo 8, 490/525 nm). Actin cytoskeleton rearrangements were assessed by F-actin staining with rhodamine-phalloidin. Images were analyzed in FIJI (NIH). Differences between the groups were assessed with 1-way ANOVA; p < 0.05 was considered significant. Results. IHC and Western blotting showed that all four HRs as well as HiS components are expressed in the mpkCCD cells. Acute application of histamine (100 uM) led to an increase in intracellular Ca2+ level which was predominantly regulated by extracellular influx, with a minor component of intracellular store release. Next, we blocked HR1, HR2, HR3, HR4 with loratadine (5uM), ranitidine (10 uM), iodophenpropit (500 nM), and A943931 (100 nM), respectively, to discern the involvement of specific HRs. We demonstrated that HR1, HR3, HR4 but not HR2 are involved in mediating the influx of Ca2+ in response to histamine. When mpkCCD cells were incubated with 100 uM histamine for 4 hours, we observed formation of the F-actin stress-fibers in the submembrane space. Conclusions. We have shown that collecting duct cells express HRs as well as HiS enzymes, indicating presence of a fully functional HiS. Our data revealed that histamine exposure leads to an influx of Ca2+ in these cells, which is mediated via H1R, H3R, and H4R. Additionally, histamine induced actin cytoskeleton rearrangements, suggesting its role in maintenance of renal epithelial cell structure. Our findings highlight the relationship between histamine, calcium regulation, and actin cytoskeleton dynamics in the renal epithelial cells, offering insights into future therapeutic strategies. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Insights on molecular modeling and supramolecular arrangement of bilastine polymorphs.

The advancement in the development of second-generation drugs in the field of antihistamines represents a significant milestone in the management of allergic diseases, targeting the effects of histamine. The efficacy of bilastine in treating allergic disorders has sparked interest in investigating its polymorphism, a crucial property that impacts quality, safety, and effectiveness as per regulatory guidelines. This study examines the polymorphism of bilastine, focusing on two crystalline forms labeled as Form I and Form II. Utilizing advanced analytical techniques, the research explores the structural characteristics and molecular interactions within these forms. Geometric parameters, such as bond lengths, bond angles, and torsion angles, are examined to comprehend molecular conformations and crystal packing arrangements. Hydrogen bonding, covalent bonds, and van der Waals forces contribute to the unique supramolecular arrangements in these forms.This study provides a significant contribution to understanding bilastine's polymorphism, offering critical insights to researchers and regulatory bodies to ensure the quality, efficacy, and safety of antihistamine products. The molecular conformation of two bilastine forms was obtained through DFT with the exchange-correlation functional M06-2X and the 6-311 + + G(d,p) basis set, and the results were compared with the experimental X-ray. The atomic coordinates were obtained directly from the crystalline structures, and charge transfer was also investigated using frontier molecular orbitals (HOMO and LUMO), and MEP map in order to evaluate the energies associated with charge transfers and regions of high electron affinity. The geometric and topological parameters and intermolecular interactions in the crystals were analyzed using Hirshfeld Surface.

Histamine- and pruritogen-induced itch is inhibited byaTRPM8 agonist: a randomized vehicle-controlled human trial.

Allergies often present challenges in managing itch and the effects of histamine. Cooling agents that act via transient receptor potential melastatin 8 (TRPM8) agonism have shown potential in itch management. However, animal studies on itch have limitations, as animals cannot communicate subjective events and their fur-coated skin differs from that of humans. Human studies offer more direct and reliable information. To investigate the effects of a specific TRPM8 agonist gel (cryosim-1) on itch induced by various pruritogens in human skin. Calcium imaging experiments determined the binding of cryosim-1 and histamine to their respective receptors. Thirty healthy volunteers underwent skin prick tests with pruritogens and a control vehicle. Itch and pain intensity were measured using a numerical rating scale (NRS) across 10 min. Participants were randomly assigned to pretreatments with vehicle or TRPM8 agonist gel. Tests were repeated at a later date, and skin moisture, transepidermal water loss and mechanical sensitivity were measured. The in vitro study confirmed that histamine is not a TRPM8 agonist and cryosim-1 does not act as an agonist or antagonist on the human histamine 1 receptor. The TRPM8 agonist gel significantly reduced the itch intensity for all pruritogens compared with the vehicle-only gel. It also reduced itch NRS and the integrated itch score. Mechanical sensitivity was also reduced. The specific TRPM8 agonist gel effectively suppressed human skin itch induced by various pruritogens. These versatile actions suggest that cooling agents may be promising treatments for multiple forms of itch stimuli.

Nasal hyperreactivity in allergic rhinitis and chronic rhinosinusitis with polyps: a role for neuronal pathways.

Nasal hyperreactivity (NHR) is prevalent in all chronic upper airway inflammatory phenotypes, including allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP). Although NHR in patients with non-allergic rhinitis is mediated by neuronal pathways, AR and CRSwNP are mainly characterized by type 2 inflammation. Eighteen healthy controls and 45 patients with symptomatic AR/CRSwNP underwent a cold, dry air (CDA) provocation test for objective diagnosis of NHR. Before and after, questionnaires were filled out and nasal secretions and biopsies were collected. Markers for neurogenic inflammation (substance P, calcitonin gene-related peptide, neurokinin A), epithelial activation (IL-33), and histamine were measured in secretions by ELISA; and expression of neuronal markers PGP9.5, TRPV1, and TRPM8 was studied in biopsies by RT-q-PCR. Effects of histamine on TRPV1/A1 were studied with Ca2+-imaging using murine trigeminal neurons. CDA-provocation reduced peak nasal inspiratory flow (PNIF) of patients with subjective NHR but not of non-NHR controls/patients CDA-provocation reduced peak nasal inspiratory flow (PNIF) of patients with subjective NHR but not of non-NHR controls/patients. Subjective (subjectively reported effect of CDA) and objective (decrease in PNIF) effects of CDA were significantly correlated. Levels of neuropeptides and histamine in nasal secretions and mRNA expression of PGP9.5, TRPV1, and TRPM8 correlated with CDA-induced PNIF-reduction. CDA-provocation induced an increase in IL-33-levels. Both TRPV1 and TRPA1 expressed on afferent neurons were sensitized by exposure to histamine. NHR is not an on/off phenomenon but spans a continuous spectrum of reactivity. A neurogenic inflammatory background and increased histamine-levels are risk factors for NHR in AR/CRSwNP.

The effect of histidine, histamine, and imidazole on electrochemical properties of Cu(II) complexes of Aβ peptides containing His-2 and His-3 motifs.

The N-truncation of amyloid beta (Aβ) peptides could lead to peptide sequences with the histidine residue at the second and third positions, creating His-2 and His-3 motifs, known as high-affinity Cu(II) binding sites. In such complexes, the Cu(II) ion is arrested in a rigid structure of a square-planar arrangement of nitrogen donors, which highly limits its susceptibility to Cu(II) reduction. Cu(II) reduction fuels the Cu(II)/Cu(I) redox cycle, which is engaged in the production of reactive oxygen species (ROS). Employing electrochemical techniques, cyclic voltammetry (CV) and differential pulse voltammetry (DPV), together with UV-vis spectroscopy, we showed that low-molecular-weight (LMW) substances, such as imidazole, histamine, and histidine, could enhance the redox activity of Cu(II) complexes of three models of N-truncated Aβ peptides, Aβ4-9, Aβ5-9, and Aβ12-16, identifying three main mechanisms. LMW compounds could effectively compete with Aβ peptides for Cu(II) ions, forming Cu(II)/LMW species, which are more prone to Cu(II) reduction. LMW substances could also shift the equilibrium between the Cu(II)/Aβ species towards the species with higher susceptibility to Cu(II) reduction. Finally, the presence of LMW molecules could promote Cu(I) reoxidation in ternary Cu(II)/Aβ/LMW systems. The obtained results raise further questions regarding the Cu(II) redox activity in Alzheimer's disease.

Cutaneous anaphylactoid reaction to polyoxyethylene hydrogenated castor oil in dogs.

Polyoxyethylene hydrogenated castor oil (HCO ethoxylates) is a nonionic surfactant used as an excipient for ointments and injections in human and veterinary drugs. Several polyethylene glycol (PEG) derivatives can be obtained depending on the number of moles of ethylene oxide (EO). HCO ethoxylates have the potential to cause anaphylactoid reactions. There is little published information about these types of reactions in dogs. To determine the potential for HCO-ethoxylate-containing drugs to cause anaphylactoid reactions in dogs, employing intradermal testing (IDT) with various concentrations of HCO ethoxylates (HCO-25, -40, -60 and -80). Four healthy male laboratory dogs. We performed IDT with drugs containing HCO ethoxylates and HCO ethoxylates alone to determine threshold concentrations. The IDT scores and threshold concentrations were compared. Analysis of skin biopsies from IDT sites was used to measure the percentage of degranulated mast cells. The effect of histamine at IDT sites was investigated by pre-treatment with an antihistamine. All HCO-ethoxylate-containing drugs caused a wheal-and-flare reaction. The threshold concentrations (0.001% and 0.00001%) of each HCO-ethoxylate depended on the number of moles of EO (p < 0.05). Mast cell degranulation was enhanced by all HCO ethoxylates. The HCO-60-induced reaction was suppressed by an oral antihistamine. The threshold concentration can serve as a consideration for developing safe new drug formulations and for clinical decision-making around using drugs containing PEG derivatives. IDT is useful to predict the risk of adverse effects. Antihistamines could demonstrate a prophylactic effect.

Co‐created in vivo pharmacology practical classes using the novel organism Lumbriculus variegatus

AbstractCo‐creation within higher education emphasizes learner empowerment to promote collaboration between the students and staff, enabling students to become active participants in their learning process and the construction of resources with academic staff. Concurrently, a diminishing number of higher education institutions offer in vivo practical classes, resulting in an in vivo skills shortage. To address this, and to actively engage students in their own learning, we describe the co‐creation of a student‐led drug trial using Lumbriculus variegatus. Under blinded conditions, final‐year undergraduate biomedical science students, under the tutelage of academic staff and fellow students, were involved in the co‐creation of an in vivo practical class to determine the effects of histamine and histamine receptor inverse agonists mepyramine and loratadine. Throughout this process, undergraduate‐ and masters‐level students played key roles in every aspect of practical delivery and data analysis. Herein, students demonstrated the test compounds, both in isolation and in combination, resulted in reduced stereotypical movements of L. variegatus (p &lt; .05, n ≥ 6). 15% of students in the class responded to a feedback survey (n = 8) after the class. Students reported the class provided “real life” insights into in vivo research and enabled the development of hands‐on skills which would be useful in applying in their future careers. All students reported that they enjoyed the class with 25% (n = 2) reporting concerns about animal use in research, enabling useful discussions about animals in research. Moreover, these student‐led in vivo trials add to the pharmacological knowledge of L. variegatus promoting education‐led research.

Exogenous histamine and H 2 receptor activation and H 3 receptor inhibition in nucleus accumbens modulate formalin-induced orofacial nociception through opioid receptors.

It has been demonstrated that the nucleus accumbens (NAc) plays an important role in modulation of nociception due to its extensive connections with different regions of the brain. In addition, this nucleus receives histaminergic projections from tuberomammillary nucleus. Considering the role of the central histaminergic system in nociception, the effect of histamine and its H 2 and H 3 receptors agonist and antagonist microinjections into the NAc on orofacial formalin nociception was investigated. In male Wistar rats, using stereotaxic surgery, two guide cannulas were bilaterally implanted into the right and left sides of the NAc. Diluted formalin solution (1.5%, 50 µl) injection into the vibrissa pad led to orofacial nociception. Immediately after injection, face rubbing was observed at 3-min blocks for 45 min. Orofacial formalin nociception was characterized by a biphasic nociceptive response (first phase: 0-3 min and second phase: 15-33 min). Microinjections of histamine (0.5 and 1 μg/site), dimaprit (1 μg/site, H 2 receptor agonist) and thioperamide (2 μg/site, H 3 receptor antagonist) attenuated both phases of formalin orofacial nociception. Prior microinjection of famotidine (2 μg/site) inhibited the antinociceptive effects of dimaprit (1 μg/site). Furthermore, comicroinjection of thioperamide (2 μg/site) and immepip (1 μg/site) prevented thioperamide (2 μg/site)-induced antinociception. Naloxone (2 μg/site) also prevented histamine, dimaprit- and thioperamide-induced antinociception. The results of this study demonstrate that at the level of the NAc, histamine and its H 2 and H 3 receptors are probably involved in the modulation of orofacial nociception with an opioid system-dependent mechanism.

Current perspectives and future directions in the management of chronic spontaneous urticaria and their link to disease pathogenesis and biomarkers.

Chronic spontaneous urticaria (CSU) is a relatively common, persistent, debilitating inflammatory skin disorder, having a global point prevalence ~0.5-1%. This disorder considerably worsens the patient's quality of life, and also poses a burden for the society. It is primarily an IgE mediated mast cell disorder, histamine being the principal mediator. So, the current treatment recommendations are aimed at antagonizing the effect of histamine, block mast cell activation by reducing IgE, or immunomodulate the inflammatory response. However, almost one in five CSU patients remain uncontrolled with the current safe treatments comprising antihistamines and add-on anti-IgE omalizumab. Thus, newer and more targeted therapeutic strategies are needed to overcome this unmet need, based on the various interlinked ligands and receptors involved in disease pathogenesis. Considerable progress has been made in understanding the pathogenesis of CSU, beyond the IgE-FceR1-mast cell axis, which has enabled the development of newer and more targeted promising therapeutic strategies. Several biomarkers are also being evaluated which would better define the disease characteristics and foretell treatment outcome even before its initiation. This would enable specific and targeted precision therapy based on disease characteristics, with better effectiveness-safety ratio. The present article discusses the current understanding about CSU, and recent up-to-date perspectives pertaining to disease pathogenesis, emerging treatments, and their link to biomarkers. These authors hope that the article would be helpful for all specialists and CSU treating physicians, in providing optimum care to their patients, based on latest evidence and concepts.

Ingested histamine and serotonin interact to alter Anopheles stephensi feeding and flight behavior and infection with Plasmodium parasites.

Blood levels of histamine and serotonin (5-HT) are altered in human malaria, and, at these levels, we have shown they have broad, independent effects on Anopheles stephensi following ingestion by this invasive mosquito. Given that histamine and 5-HT are ingested together under natural conditions and that histaminergic and serotonergic signaling are networked in other organisms, we examined effects of combinations of these biogenic amines provisioned to A. stephensi at healthy human levels (high 5-HT, low histamine) or levels associated with severe malaria (low 5-HT, high histamine). Treatments were delivered in water (priming) before feeding A. stephensi on Plasmodium yoelii-infected mice or via artificial blood meal. Relative to effects of histamine and 5-HT alone, effects of biogenic amine combinations were complex. Biogenic amine treatments had the greatest impact on the first oviposition cycle, with high histamine moderating low 5-HT effects in combination. In contrast, clutch sizes were similar across combination and individual treatments. While high histamine alone increased uninfected A. stephensi weekly lifetime blood feeding, neither combination altered this tendency relative to controls. The tendency to re-feed 2weeks after the first blood meal was altered by combination treatments, but this depended on mode of delivery. For blood delivery, malaria-associated treatments yielded higher percentages of fed females relative to healthy-associated treatments, but the converse was true for priming. Female mosquitoes treated with the malaria-associated combination exhibited enhanced flight behavior and object inspection relative to controls and healthy combination treatment. Mosquitoes primed with the malaria-associated combination exhibited higher mean oocysts and sporozoite infection prevalence relative to the healthy combination, with high histamine having a dominant effect on these patterns. Compared with uninfected A. stephensi, the tendency of infected mosquitoes to take a second blood meal revealed an interaction of biogenic amines with infection. We used a mathematical model to project the impacts of different levels of biogenic amines and associated changes on outbreaks in human populations. While not all outbreak parameters were impacted the same, the sum of effects suggests that histamine and 5-HT alter the likelihood of transmission by mosquitoes that feed on hosts with symptomatic malaria versus a healthy host.