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.

Histamine in cancer immunology and immunotherapy. Current status and new perspectives.

Cancer is the second leading cause of death globally and its incidence and mortality are rapidly increasing worldwide. The dynamic interaction of immune cells and tumor cells determines the clinical outcome of cancer. Immunotherapy comes to the forefront of cancer treatments, resulting in impressive and durable responses but only in a fraction of patients. Thus, understanding the characteristics and profiles of immune cells in the tumor microenvironment (TME) is a necessary step to move forward in the design of new immunomodulatory strategies that can boost the immune system to fight cancer. Histamine produces a complex and fine-tuned regulation of the phenotype and functions of the different immune cells, participating in multiple regulatory responses of the innate and adaptive immunity. Considering the important actions of histamine-producing immune cells in the TME, in this review we first address the most important immunomodulatory roles of histamine and histamine receptors in the context of cancer development and progression. In addition, this review highlights the current progress and foundational developments in the field of cancer immunotherapy in combination with histamine and pharmacological compounds targeting histamine receptors.

Nootkatone Inhibits Acute and Chronic Inflammatory Responses in Mice.

Nootkatone (NTK) is a sesquiterpenoid found in essential oils of many species of Citrus (Rutaceae). Considering previous reports demonstrating that NTK inhibited inflammatory signaling pathways, this study aimed to investigate the effects of this compound in mice models of acute and chronic inflammation. Murine models of paw edema induced by carrageenan, dextran, histamine, and arachidonic acid, as well as carrageenan-induced peritonitis and pleurisy, were used to evaluate the effects of NTK on acute inflammation. A murine model of granuloma induced by cotton pellets was used to access the impact of NTK treatment on chronic inflammation. In the acute inflammation models, NTK demonstrated antiedematogenic effects and inhibited leukocyte recruitment, which was associated with decreased vascular permeability, inhibition of myeloperoxidase (MPO), interleukin (IL)1-ß, and tumor necrosis factor (TNF)-α production. In silico analysis suggest that NTZ anti-inflammatory effects may also occur due to inhibition of cyclooxygenase (COX)-2 activity and antagonism of the histamine receptor type 1 (H1). These mechanisms might have contributed to the reduction of granuloma weight and protein concentration in the homogenates, observed in the chronic inflammation model. In conclusion, NTK exerted anti-inflammatory effects that are associated with inhibition of IL1-ß and TNF-α production, possibly due to inhibition of COX-2 activity and antagonism of the H1 receptor. However, further studies are required to characterize the effects of this compound on chronic inflammation.

Intra-articular injection of 2-pyridylethylamine produces spinal NPY-mediated antinociception in the formalin-induced rat knee-joint pain model.

Low doses of histamine or H1R agonist 2-pyridylethylamine (2-PEA) into the knee-joint were found to decrease formalin-induced articular nociception in rats. In this study, we evaluated the participation of spinal NPY in the antinociceptive effect produced by 2-PEA. Injection of formalin (1.5%) into one of the knee-joints causes the limping of the respective limb due to nociception, which was registered each 5 min over 60 min. Neuropeptide Y1 receptor (Y1R) content in the spinal cord was evaluated by western-blotting. Intrathecal (i.t.) injection of Y1R agonist Leu31, Pro34-NPY (0.7-7 µmol) decreased nociception, while injection of the antagonist BIBO 3304 (4 µmol), increased nociception. Antinociception produced by 2-PEA was reversed by a sub-effective i.t. dose of the Y1R antagonist. Similarly, this antinociceptive effect was prevented by i.t. pretreatment with the neurotoxin NPY-saporin (750 ng), which also reduced immunoblotting for Y1R in spinal cord homogenates. These data support the idea that antinociception induced by H1R agonists in the knee-joint of rats may be mediated by the spinal release of NPY, and this peptide seems to be acting via Y1R.

Histamine receptors and cancer pharmacology: an update.

In the present review, we will discuss the recent advances in the understanding of the role of histamine and histamine receptors in cancer biology. The controversial role of the histaminergic system in different neoplasias including gastric, colorectal, oesophageal, oral, pancreatic, liver, lung, skin, blood and breast cancers will be reviewed. The expression of histamine receptor subtypes, with special emphasis on the histamine H4 receptor, in different cell lines and human tumours, the signal transduction pathways and the associated biological responses as well as the in vivo treatment of experimental tumours with pharmacological ligands will be described. The presented evidence demonstrates that histamine regulates cancer-associated biological processes during cancer development in multiple cell types, including neoplastic cells and cells in the tumour micro-environment. The outcome will depend on tumour cell type, the level of expression of histamine receptors, signal transduction associated with these receptors, tumour micro-environment and histamine metabolism, reinforcing the complexity of cancer disease. Findings show the pivotal role of H4 receptors in the development and progression of many types of cancers, and considering its immunomodulatory properties, the H4 receptor appears to be the most promising molecular therapeutic target for cancer treatment within the histamine receptor family. Furthermore, the H4 receptor is differentially expressed in tumours compared with normal tissues, and in most cancer types in which data are available, H4 receptor expression is associated with clinicopathological characteristics, suggesting that H4 receptors might represent a novel cancer biomarker. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.

Proinflammatory profile of neonatal monocytes induced by microbial ligands is downmodulated by histamine.

Although the neonatal period is characterized by relative immunological immaturity, an inflammatory response due to Toll-like receptor (TLR) activation is observed. Histamine may be one of the factors playing a role in restraining inflammation during the early stages of life. Therefore, we evaluated the responsiveness of human cord blood cells to TLR4 agonists and the immunomodulatory function of histamine in the inflammatory response. Compared with adults, mononuclear cells (MNCs) from newborns (NBs) exhibit impaired production of IFN-γ-inducible chemokines, such as CXCL10 and CXCL9, upon lipopolysaccharide (LPS) stimulation. Notably, LPS induced a 5-fold increase in CCL2 secretion in NBs. Evaluation of the effect of histamine on LPS-induced CCL2 secretion showed an inhibitory effect in the majority of adults, whereas this effect was detectable in all NBs. Histamine receptor (HR) blockage revealed partial involvement of H1R, H2R and H4R in LPS-induced CCL2 inhibition in MNCs from both NBs and adults. As monocytes are the main type of mononuclear cell that produces CCL2, we evaluated genes related to TLR signaling upon LPS stimulation. Monocytes from NBs showed up-regulation of genes associated with JAK/STAT/NF-κB and IFN signaling. Some differentially expressed genes encoding proinflammatory factors were preferentially detected in LPS-activated monocytes from NBs, and markedly down-regulated by histamine. The immunomodulatory role of histamine on CCL2 and CXCL8 was detected at the transcript and protein levels. Our findings show that NBs have enhanced CCL2 responsiveness to LPS, and that histamine acts in immune homeostasis during the neonatal period to counterbalance the robustness of TLR stimulation.

Role of Histamine in Modulating the Immune Response and Inflammation.

Inflammatory mediators, including cytokines, histamine, bradykinin, prostaglandins, and leukotrienes, impact the immune system, usually as proinflammatory factors. Other mediators act as regulatory components to establish homeostasis after injury or prevent the inflammatory process. Histamine, a biogenic vasoactive amine, causes symptoms such as allergies and has a pleiotropic effect that is dependent on its interaction with its four histamine receptors. In this review, we discuss the dualistic effects of histamine: how histamine affects inflammation of the immune system through the activation of intracellular pathways that induce the production of inflammatory mediators and cytokines in different immune cells and how histamine exerts regulatory functions in innate and adaptive immune responses. We also evaluate the interactions between these effects.

Intracerebellar microinjection of histaminergic compounds on locomotor and exploratory behaviors in mice.

The neural histaminergic system innervates the cerebellum, with a high density of fibers in the vermis and flocculus. The cerebellum participates in motor functions, but the role of the histaminergic system in this function is unclear. In the present study, we investigated the effects of intracerebellar histamine injections and H1, H2 and H3 receptor antagonist injections (chlorpheniramine, ranitidine, and thioperamide, respectively) and H4 receptor agonist (VUF-8430) on locomotor and exploratory behaviors in mice. The cerebellar vermis of male mice was implanted with guide cannula. After three days of recovery,the animals received microinjections of saline or histamine (experiment1), saline or chlorpheniramine (experiment 2), saline or ranitidine(experiment 3), saline or thioperamide (experiment 4), and saline or VUF-8430 (experiment 5) in different concentrations. Five minutes postinjection,the open field test was performed. The data were analyzed using one-way ANOVA and Duncan's post hoc test. The microinjections of histamine, ranitidine or thioperamide did not lead any behavioral effects at the used doses. In contrast, animals that received chlorpheniramine at the highest dose (0.16 nmol) and VUF-8430 at the highest dose (1.48 nmol)were more active in the open field apparatus, with an increase in the number of crossed quadrants, number of rearings and time spent in the central area of the arena, suggesting that chlorpheniramine and VUF-8430 modulates locomotor and exploratory behaviors in mice.

1-[(2,3-Dihydro-1-benzofuran-2-yl) methyl]piperazines as novel anti-inflammatory compounds: Synthesis and evaluation on H3 R/H4 R.

The histamine receptors (HRs) are members of G-protein-coupled receptor superfamily and traditional targets of huge therapeutic interests. Recently, H3 R and H4 R have been explored as targets for drug discovery, including in the search for dual-acting H3 R/H4 R ligands. The H4 R, the most recent histamine receptor, is a promising target for novel anti-inflammatory agents in several conditions such as asthma and other chronic inflammatory diseases. Due to similarity with previously reported ligands of HRs, a set of 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines were synthesized and evaluated in competitive binding assays as H3 R/H4 R ligands herein. The results showed the compounds presented affinity (Ki ) for H3 R/H4 R in micromolar range, and they are more selective to H3 R. All the compounds showed no important cytotoxicity to mammalian cells. The phenyl-substituted compound LINS01005 has shown the higher affinity of the set for H4 R, but no considerable selectivity toward this receptor over H3 R. LINS01005 showed interesting anti-inflammatory activity in murine asthma model, reducing the eosinophil counts in bronchoalveolar lavage fluid, as well as the COX-2 expression. The presented compounds are valuable prototypes for further improvements to achieve better anti-inflammatory agents.

Effect of perinatal asphyxia on tuberomammillary nucleus neuronal density and object recognition memory: A possible role for histamine?

Perinatal asphyxia (PA) is associated with long-term neuronal damage and cognitive deficits in adulthood, such as learning and memory disabilities. After PA, specific brain regions are compromised, including neocortex, hippocampus, basal ganglia, and ascending neuromodulatory pathways, such as dopamine system, explaining some of the cognitive disabilities. We hypothesize that other neuromodulatory systems, such as histamine system from the tuberomammillary nucleus (TMN), which widely project to telencephalon, shown to be relevant for learning and memory, may be compromised by PA. We investigated here the effect of PA on (i) Density and neuronal activity of TMN neurons by double immunoreactivity for adenosine deaminase (ADA) and c-Fos, as marker for histaminergic neurons and neuronal activity respectively. (ii) Expression of the histamine-synthesizing enzyme, histidine decarboxylase (HDC) by western blot and (iii) thioperamide an H3 histamine receptor antagonist, on an object recognition memory task. Asphyxia-exposed rats showed a decrease of ADA density and c-Fos activity in TMN, and decrease of HDC expression in hypothalamus. Asphyxia-exposed rats also showed a low performance in object recognition memory compared to caesarean-delivered controls, which was reverted in a dose-dependent manner by the H3 antagonist thioperamide (5-10mg/kg, i.p.). The present results show that the histaminergic neuronal system of the TMN is involved in the long-term effects induced by PA, affecting learning and memory.

Pharmacological targeting of histamine H4 receptor in periodontal disease.

OBJECTIVE: The objective of this study was to investigate whether histamine H4 receptor (H4 R) antagonists could prevent experimental periodontitis (EP)-induced histological, functional and inflammatory alterations in submandibular gland (SMG), periodontal bone and gingiva. METHODS: Bilateral EP was induced for 2 weeks in anaesthetized male rats. The effect of systemic and local administration of H4 R antagonists (JNJ7777120, JNJ10191584) on histopathology and functionality of SMG, bone loss and gingival inflammation was evaluated. RESULTS: The subcutaneous administration of JNJ7777120 prevented periodontitis-induced SMG histological injury, reducing vacuolization and apoptosis and additionally reversed the increased prostaglandin E2 (PGE2) levels in SMG while it partially reversed the methacholine-induced salivation reduction produced by periodontitis. JNJ7777120 attenuated bone loss and the increased PGE2 levels and inflammatory infiltration in gingival tissue of rats with periodontitis. Finally, local administration of JNJ7777120 and JNJ10191584 was also beneficial for improving periodontal parameters. CONCLUSIONS: H4 receptor antagonists are able to ameliorate periodontitis-induced injury on SMG, gingival tissue and bone structure, suggesting that pharmacological targeting of H4 R could be an attractive strategy to improve periodontal health.

Histamine H4 receptor ligands: future applications and state of art.

Histamine is a chemical transmitter found practically in whole organism and exerts its effects through the interaction with H1 to H4 histaminergic receptors. Specifically, H4 receptors are found mainly in immune cells and blood-forming tissues, thus are involved in inflammatory and immune processes, as well as some actions in central nervous system. Therefore, H4 receptor ligands can have applications in the treatment of chronic inflammatory and immune diseases and may be novel therapeutic option in these conditions. Several H4 receptor ligands have been described from early 2000's until nowadays, being imidazole, indolecarboxamide, 2-aminopyrimidine, quinazoline, and quinoxaline scaffolds the most explored and discussed in this review. Moreover, several studies of molecular modeling using homology models of H4 receptor and QSAR data of the ligands are summarized. The increasing and promising therapeutic applications are leading these compounds to clinical trials, which probably will be part of the next generation of blockbuster drugs.

A comparison of histamine effects on the sympathetic neurotransmission of testicular capsule and rat vas deferens.

Histamine is an important modulatory agent of the sympathetic neurotransmission, but its exact action on the testicular capsule or rat vas deferens is not fully understood. The present study sought to further investigate the functional effects of histamine on the neuronal and exogenous noradrenaline-induced contraction of the testicular capsule and rat vas deferens as well as to evaluate the contractile properties of this drug. The testicular capsule or vas deferens from Wistar rats, 3-4 months old, weighing 300-400 g, was isolated and mounted in organ baths for functional experiments. The results indicated that the neuronally evoked contraction of the testicular capsule was affected by histamine (10(-10) to 10(-8) M) with participation of inhibitory (H3 receptors) and excitatory (H1 receptors) receptors. Histamine (10(-7) to 10(-4) M) modulated the field-stimulated vas deferens by excitatory (H2 receptors) and inhibitory (H1 receptors) receptors. Histamine was able to decrease the tonic response for noradrenaline-induced contractions with participation of H1 receptors (testicular capsule) and H3 receptors (vas deferens) followed by nitric oxide generation. At high concentration, histamine exerts contractile effects in both tissues. In the testicular capsule, the histamine-induced contractions were related to H1 receptor activation followed by release of prostaglandins. In contrast, the contractile effects of histamine in the vas deferens were related to H2 receptor activation followed by release of catecholamines from sympathetic nerve endings. Therefore, our results indicate that histamine induced several effects on the sympathetic neurotransmission of rat testicular capsule and vas deferens. These effects are dependent on the concentration used and with participation of multiple histamine receptors.

Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma.

BACKGROUND: Functional presence of histamine H4 receptor (H4R) was demonstrated in human melanoma cell lines and biopsies. OBJECTIVE: The purposes of this work were to investigate signal transduction pathways and biological responses triggered by the activation of H4R in human primary (WM35) and metastatic (M1/15) melanoma cell lines and to evaluate the in vivo antitumor activity of histamine (HA) and clozapine (CLZ) on human M1/15 melanoma xenografts. METHODS: Clonogenic assay, incorporation of BrdU, cell cycle distribution, phosphorylation levels of ERK1/2 and cAMP production were evaluated in vitro. An experimental human melanoma model was developed into athymic nude mice. Tumor growth, survival and histochemical studies were performed in order to investigate the expression levels of H4R, HA, PCNA, mitotic index (MI), and angiogenesis. RESULTS: The results indicate that H4R agonists inhibited forskolin-induced cAMP levels only in M1/15 cells while increased phosphorylation levels of ERK1/2 and decreased proliferation in both cell types. In vivo studies show that HA and CLZ (1mgkg(-1), sc) significantly increased median survival and decreased tumor volume. These effects were associated to a reduction in MI, in the expression of proliferation marker and in intratumoral neovascularization. CONCLUSIONS: We conclude that HA and CLZ exhibit an antitumoral effect in vitro and in vivo on human melanoma, suggesting the therapeutic potential of these compounds for the treatment of malignant melanoma.

Protection of radiation-induced damage to the hematopoietic system, small intestine and salivary glands in rats by JNJ7777120 compound, a histamine H4 ligand.

Based on previous data on the histamine radioprotective effect on highly radiosensitive tissues, in the present work we aimed at investigating the radioprotective potential of the H4R ligand, JNJ7777120, on ionizing radiation-induced injury and genotoxic damage in small intestine, salivary glands and hematopoietic tissue. For that purpose, rats were divided into 4 groups. JNJ7777120 and JNJ7777120-irradiated groups received a daily subcutaneous JNJ7777120 injection (10 mg/kg) starting 24 h before irradiation. Irradiated groups received a single dose of 5 Gy on whole-body using Cesium-137 source and were sacrificed 3 or 30 days after irradiation. Tissues were removed, fixed, stained with hematoxylin and eosin or PAS staining and histological characteristics were evaluated. Proliferative and apoptotic markers were studied by immunohistochemistry, while micronucleus assay was performed to evaluate DNA damage. Submandibular gland (SMG) function was evaluated by methacholine-induced salivation. Results indicate that JNJ7777120 treatment diminished mucosal atrophy and preserved villi and the number of crypts after radiation exposure (240±8 vs. 165±10, P<0.01). This effect was associated to a reduced apoptosis and DNA damage in intestinal crypts. JNJ7777120 reduced radiation-induced aplasia, preserving medullar components and reducing formation of micronucleus and also it accelerated bone marrow repopulation. Furthermore, it reduced micronucleus frequency in peripheral blood (27±8 vs. 149±22, in 1,000 erythrocytes, P<0.01). JNJ7777120 completely reversed radiation-induced reduced salivation, conserving glandular mass with normal histological appearance and reducing apoptosis and atrophy of SMG. JNJ7777120 exhibits radioprotective effects against radiation-induced cytotoxic and genotoxic damages in small intestine, SMG and hematopoietic tissues and, thus, could be of clinical value for patients undergoing radiotherapy.

Antihistaminergics and inverse agonism: potential therapeutic applications.

The accurate characterization of the molecular mechanisms involved in the action of receptor ligands is important for their appropriate therapeutic use and safety. It is well established that ligands acting at the histamine system currently used in the clinic exert their actions by specifically antagonizing G-protein coupled H1 and H2 receptors. However, most of these ligands, assumed to be neutral antagonists, behave as inverse agonists displaying negative efficacy in experimental systems. This suggests that their therapeutic actions may involve not only receptor blockade, but also the decrease of spontaneous receptor activity. The mechanisms whereby inverse agonists achieve negative efficacy are diverse. Theoretical models predict at least three possible mechanisms, all of which are supported by experimental observations. Depending on the mechanism of action engaged, the inverse agonist could interfere specifically with signaling events triggered by unrelated receptors. This possibility opens up new venues to explain the therapeutic actions of inverse agonists of the histamine receptor and perhaps new therapeutic applications.

The role of histamine receptors in the consolidation of object recognition memory.

Findings have shown that histamine receptors in the hippocampus modulate the acquisition and extinction of fear motivated learning. In order to determine the role of hippocampal histaminergic receptors on recognition memory, adult male Wistar rats with indwelling infusion cannulae stereotaxically placed in the CA1 region of dorsal hippocampus were trained in an object recognition learning task involving exposure to two different stimulus objects in an enclosed environment. In the test session, one of the objects presented during training was replaced by a novel one. Recognition memory retention was assessed 24 h after training by comparing the time spent in exploration (sniffing and touching) of the known object with that of the novel one. When infused in the CA1 region immediately, 30, 120 or 360 min posttraining, the H1-receptor antagonist, pyrilamine, the H2-receptor antagonist, ranitidine, and the H3-receptor agonist, imetit, blocked long-term memory retention in a time dependent manner (30-120 min) without affecting general exploratory behavior, anxiety state or hippocampal function. Our data indicate that histaminergic system modulates consolidation of object recognition memory through H1, H2 and H3 receptors.

Therapeutic potential of histamine H4 receptor agonists in triple-negative human breast cancer experimental model.

BACKGROUND AND PURPOSE: The presence of the histamine H4 receptor (H4R) was previously reported in benign and malignant lesions and cell lines derived from the human mammary gland. The aim of this work was to evaluate the effects of H4R ligands on the survival, tumour growth rate and metastatic capacity of breast cancer in an experimental model. EXPERIMENTAL APPROACH: Xenograft tumours of the highly invasive human breast cancer cell line MDA-MB-231 were established in immune deficient nude mice. The following H4R agonists were employed: histamine (5 mg kg⁻¹), clozapine (1 mg kg⁻¹) and the experimental compound JNJ28610244 (10 mg kg⁻¹). RESULTS: Data indicate that developed tumours were highly undifferentiated, expressed H4R and exhibited high levels of histamine content and proliferation marker (PCNA) while displaying low apoptosis. Mice of the untreated group displayed a median survival of 60 days and a tumour doubling time of 7.4 ± 0.6 days. A significant decrease in tumour growth evidenced by an augment of the tumour doubling time was observed in the H4R agonist groups (13.1 ± 1.2, P < 0.01 in histamine group; 15.1 ± 1.1, P < 0.001 in clozapine group; 10.8 ± 0.7, P < 0.01 in JNJ28610244 group). This effect was associated with a decrease in the PCNA expression levels, and also reduced intratumoural vessels in histamine and clozapine treated mice. Histamine significantly increased median survival (78 days; Log rank Mantel-Cox Test, P = 0.0025; Gehan-Breslow-Wilcoxon Test, P = 0.0158) and tumoural apoptosis. CONCLUSIONS AND IMPLICATIONS: Histamine through the H4R exhibits a crucial role in tumour progression. Therefore, H4R ligands offer a novel therapeutic potential as adjuvants for breast cancer treatment.

Antihistamínicos Parte 1 - Historia y características de los receptores histaminérgicos / Antihistamines. Part 1 - History and characteristics of histaminergic receptors

Los antihistamínicos han sido usados durante los últimos 50 años y se han convertido en los medicamentos de mayor prescripción en el mundo. En este artículo se revisa el desarrollo de nuestro conocimiento referente a la histamina en el transcurso del siglo, como mediador biológico almacenado y liberado mayormente por los basófilos y mastocitos; mediador biológico situado en diferentes tejidos corporales, y otras células, con un papel fisiológico fundamental en el control de la secreción de ácido gástrico y un papel fisiopatológico en una gama de trastornos alérgicos. La síntesis y estudios farmacológicos de agonistas y antagonistas selectivos han establecido la existencia de cuatro tipos de receptores de histamina y antagonistas de ellos, que han encontrado muy importantes aplicaciones terapéuticas. Debido al aumento de la prevalencia de las enfermedades alérgicas según el Libro Blanco de Alergia (WAO), se deben crear normas que promuevan el uso de los antihistamínicos de manera adecuada y racional. De esta manera, la correcta elección debe ser realizada de acuerdo a su eficacia, tolerabilidad, seguridad, grupo etario, situaciones y precauciones particulares en pacientes con algún riesgo incrementado. El crear normas que promuevan una práctica terapéutica óptima o uso racional de dichos medicamentos. Elegirlos de acuerdo a su eficacia, tolerabilidad, seguridad, grupo etario, situaciones y precauciones especiales en pacientes portadores de ciertas enfermedades de riesgo a utilizarlos.(AU)

Antihistamines have been used for the last 50 years and have become the most prescribed medications in the world. In this article we review the development of our knowledge regarding histamine in the course of the century, as a biological mediator stored and released mostly by basophils and mast cells; biological mediator located in different body tissues, and other cells, with a fundamental physiological role in the control of gastric acid secretion and a physiopathological role in a range of disorders allergic The synthesis and pharmacological studies of selective agonists and antagonists have established the existence of four types of histamine receptors and antagonists of them, who have found very important therapeutic applications. Due to the increased prevalence of allergic diseases according to the White Paper on Allergy (WAO), standards should be created that promote the use of antihistamines in an adequate and rational way. In this way, the correct choice must be made in accordance to its efficacy, tolerability, safety, age group, situations and special precautions in patients with an increased risk. The creation of norms that promote an optimal therapeutic practice or rational use of said medications. Choose them according to their effectiveness, tolerability, safety, age group, situations and special precautions in patients with certain risk diseases to use them.

Toll-like receptor 3 activation promotes desensitization of histamine response in human gingival fibroblasts: Poly (I:C) induces histamine receptor desensitization in human gingival fibroblasts.

Viruses are associated with the development of periodontal disease, particularly during periods of suppressed cellular immunity. For this reason, we evaluated the hypothesis that viral components regulate the actions of histamine, an important mediator of immune responses. We assessed the effect of Poly (I:C) on histamine-mediated intracellular calcium mobilization in human gingival fibroblasts. Our results show that histamine induces an increase in intracellular calcium concentrations in a dose-dependent manner. This response was blocked when cells were incubated in the presence of Poly (I:C). In addition, phorbol esters, a diacylglycerol analog, mimics the inhibitory actions of Poly (I:C) in response to histamine. The effect of Poly (I:C) was reversed by Stuarosporine (1 µM), GÖ6983 (7 µM), Bisindolylmaleimide (1 µM) [a protein inhibitor (PKC)], and SB 203580 (3 µM) (a p38-MAPK inhibitor). These findings suggest that Poly (I:C) regulates histamine-induced calcium mobilization through activation of PKC and p38.