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Sample records for cerebral histamine receptor

  1. Characterization of histamine receptors in isolated human cerebral arteries.

    OpenAIRE

    Ottosson, A; Jansen, I.; Edvinsson, L.

    1988-01-01

    1. The subtypes of histamine-receptors which mediate dilatation of small human cerebral arteries have been characterized in vitro using 'selective' agonists and antagonists. 2. Dilator responses were studied after preconstriction with prostaglandin F2 alpha, since contraction was not seen with histamine concentrations up to 10(-4) M. Histamine caused a concentration-related relaxation of cerebral vessels with an IC50 value of 5.2 +/- 1.6 x 10(-8) M. 3. Mepyramine caused a parallel shift to th...

  2. Characterization of histamine receptors mediating the stimulation of cyclic AMP accumulation in rabbit cerebral cortical slices.

    OpenAIRE

    Al-Gadi, M.; Hill, S. J.

    1985-01-01

    The characteristics of histamine-stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation in slices of rabbit cerebral cortex have been investigated. The selective H2-receptor antagonists, cimetidine, tiotidine, metiamide and ranitidine appeared to antagonize the stimulation of cyclic AMP accumulation elicited by histamine in a competitive manner consistent with an interaction with histamine H2-receptors. The H1-receptor antagonist mepyramine (0.8 microM) produced only a weak...

  3. Histamine H(3 receptor-mediated signaling protects mice from cerebral malaria.

    Directory of Open Access Journals (Sweden)

    Walid Beghdadi

    Full Text Available BACKGROUND: Histamine is a biogenic amine that has been shown to contribute to several pathological conditions, such as allergic conditions, experimental encephalomyelitis, and malaria. In humans, as well as in murine models of malaria, increased plasma levels of histamine are associated with severity of infection. We reported recently that histamine plays a critical role in the pathogenesis of experimental cerebral malaria (CM in mice infected with Plasmodium berghei ANKA. Histamine exerts its biological effects through four different receptors designated H1R, H2R, H3R, and H4R. PRINCIPAL FINDINGS: In the present work, we explored the role of histamine signaling via the histamine H3 receptor (H3R in the pathogenesis of murine CM. We observed that the lack of H3R expression (H3R(-/- mice accelerates the onset of CM and this was correlated with enhanced brain pathology and earlier and more pronounced loss of blood brain barrier integrity than in wild type mice. Additionally tele-methylhistamine, the major histamine metabolite in the brain, that was initially present at a higher level in the brain of H3R(-/- mice was depleted more quickly post-infection in H3R(-/- mice as compared to wild-type counterparts. CONCLUSIONS: Our data suggest that histamine regulation through the H3R in the brain suppresses the development of CM. Thus modulating histamine signaling in the central nervous system, in combination with standard therapies, may represent a novel strategy to reduce the risk of progression to cerebral malaria.

  4. Lack of histamine synthesis and down-regulation of H1 and H2 receptor mRNA levels by dexamethasone in cerebral endothelial cells.

    Science.gov (United States)

    Karlstedt, K; Sallmén, T; Eriksson, K S; Lintunen, M; Couraud, P O; Joó, F; Panula, P

    1999-03-01

    The purpose of this work was to determine whether cerebral endothelial cells have the capacity to synthesize histamine or to express mRNA of receptors that specifically respond to available free histamine. The histamine concentrations and the expression of L-histidine decarboxylase (HDC) and histamine H1 and H2 receptor mRNA, both in adult rat brain and in cultured immortalized RBE4 cerebral endothelial cells, were investigated. In this study endothelial cells were devoid of any kind of detectable histamine production, both in vivo and in the immortalized RBE4 cells in culture. Both the immunostainings for histamine and the in situ hybridizations for HDC were negative, as well as histamine determinations by HPLC, indicating that endothelial cells do not possess the capacity to produce histamine. Also, glucocorticoid (dexamethasone) treatment failed to induce histamine production in the cultured cells. Although the cerebral endothelial cells lack histamine production, a nonsaturable uptake in RBE4 cells is demonstrated. The internalized histamine is detected both in the cytoplasm and in the nucleus, which could indicate a role for histamine as an intracellular messenger. Histamine H1 and H2 receptor mRNA was expressed in RBE4 cells, and glucocorticoid treatment down-regulated the mRNA levels of both H1 and H2 receptors. This mechanism may be involved in glucocorticoid-mediated effects on cerebrovascular permeability and brain edema. PMID:10078884

  5. Postischemic regulation of central histamine receptors.

    Science.gov (United States)

    Lozada, A; Munyao, N; Sallmen, T; Lintunen, M; Leurs, R; Lindsberg, P J; Panula, P

    2005-01-01

    This study characterizes changes occurring in the central histaminergic system associated with ischemia-reperfusion pathology in the rat. Specifically, after a postocclusion time period of 48 h, we have analyzed histamine H(1) receptor mRNA expression, histamine H(2) receptor protein amount and binding densities, and histamine H(3) receptor mRNA expression and binding densities in brain regions that have been suggested to be selectively vulnerable to transient global ischemia, i.e. hippocampus, thalamus, caudate-putamen, and cerebral cortex. We found an increase in H(1) receptor mRNA expression in the caudate-putamen: given that ischemia reduces glucose uptake and H(1) receptor activation has been shown to decrease this effect, an increase of expression levels may result in mitigating tissue damage due to energy failure observed in ischemia. A decrease in H(2) receptor binding densities in the caudate-putamen was also observed; the ischemia-induced decrease in H(2) receptor protein was also detectable by Western blot analysis. This phenomenon may underlie the previously reported ischemia induced striatal dopamine release. H(3) receptor mRNA expression was increased in the caudate putamen of the postischemic brain but was decreased in the globus pallidus and the thalamus; in association with this, H(3) receptor binding densities were increased in the cortex, caudate-putamen, globus pallidus, and hippocampus. The upregulation of H(3) receptor ligand binding may be involved in the previously reported continuous neuronal histamine release. Our data suggest that central histamine receptor expression and ligand binding are altered in brain ischemia in distinct areas, and may participate in neuroprotection and/or ischemia-associated neuronal damage. PMID:16181737

  6. Pharmacological characterization of histamine receptors in the human temporal artery.

    OpenAIRE

    Ottosson, A; Jansen, I.; Edvinsson, L.

    1989-01-01

    1. The subtypes of histamine-receptors which mediate dilatation of small human temporal arteries have been characterized in vitro using 'selective' agonists and antagonists. 2. Dilatory responses were studied after preconstriction with prostaglandin F2 alpha since contraction was not seen at histamine concentrations up to 10(-4) M. Histamine caused a concentration-related relaxation of cerebral vessels with an IC50 value of 2.8 +/- 0.6 X 10(-7) M. 3. Cimetidine caused a parallel shift to the ...

  7. Histamine-2 Receptor Antagonists and Semen Quality.

    Science.gov (United States)

    Banihani, Saleem A

    2016-01-01

    Histamine-2 receptor antagonists are a class of drugs used to treat the acid-related gastrointestinal diseases such as ulcer and gastro-oesophageal reflux disease. Although such drugs, especially ranitidine and famotidine, are still widely used, their effects on semen quality, and hence on male infertility, is still unclear. This MiniReview systematically addresses and summarizes the effect of histamine-2 receptor antagonists (cimetidine, ranitidine, nizatidine and famotidine) on semen quality, particularly, on sperm function. Cimetidine appears to have adverse effects on semen quality. While the effects of ranitidine and nizatidine on semen quality are still controversial, famotidine does not appear to change semen quality. Therefore, additional studies will be required to clarify whether histamine-2 receptor-independent effects of these drugs play a role in semen quality as well as further clinical studies including direct comparison of the histamine-2 receptor antagonists. PMID:26176290

  8. The new biology of histamine receptors.

    Science.gov (United States)

    Huang, Jing-Feng; Thurmond, Robin L

    2008-03-01

    The physiologic functions of histamine have been recognized for more than 100 years, yet new roles are still being uncovered. Most importantly, a newly discovered receptor of the amine has helped refine our understanding of histamine. This new receptor, the histamine H4 receptor (H4R), has a higher affinity for histamine compared with the histamine H1 receptor and appears to be more selectively expressed, found mainly on hematopoietic cells. H4R is involved in chemotaxis and inflammatory mediator release by eosinophils, mast cells, monocytes, dendritic cells, and T cells. Studies in animal models using selective antagonists or H4R-deficient mice have shown a role for the receptor in inflammation in vivo. In particular, H4R antagonists have shown promise in experimental models of asthma and pruritus, two conditions where currently marketed antihistamines targeting the histamine H1 receptor are not optimally effective in humans. Thus, a new class of H4R-specific antihistamines may be distinctively effective in treating allergic diseases associated with chronic pruritus and asthma. PMID:18377770

  9. Effects of multivalent histamine supported on gold nanoparticles: activation of histamine receptors by derivatized histamine at subnanomolar concentrations.

    Science.gov (United States)

    Gasiorek, Friederike; Pouokam, Ervice; Diener, Martin; Schlecht, Sabine; Wickleder, Mathias S

    2015-10-21

    Colloidal gold nanoparticles with a functionalized ligand shell were synthesized and used as new histamine receptor agonists. Mercaptoundecanoic acid moieties were attached to the surface of the nanoparticles and derivatized with native histamine. The multivalent presentation of the immobilized ligands carried by the gold nanoparticles resulted in extremely low activation concentrations for histamine receptors on rat colonic epithelium. As a functional read-out system, chloride secretion resulting from stimulation of neuronal and epithelial histamine H1 and H2 receptors was measured in Ussing chamber experiments. These responses were strictly attributed to the histamine entities as histamine-free particles Au-MUDOLS or the monovalent ligand AcS-MUDA-HA proved to be ineffective. The vitality of the tissues used was not impaired by the nanoparticles. PMID:26289108

  10. Autoregulation of enterochromaffin-like cell histamine secretion via the histamine 3 receptor subtype.

    OpenAIRE

    Kidd, M.; Tang, L. H.; Miu, K.; Lawton, G. P.; Sandor, A.; Modlin, I. M.

    1996-01-01

    INTRODUCTION: The neuroendocrine histamine-secreting cell of the gastric fundus, the enferochromaffin-like cell, is the principal regulator of parietal cell acid secretion. We have proposed that histamine may regulate its own synthesis and release via an autocrine mechanism. The purpose of this study was to evaluate the role of the histamine receptor subtypes H1, H2 and H3 in the regulation of this phenomenon. METHODS: Purified ECL cells were isolated by pronase digestion and EDTA exposure of...

  11. Histamine-2 receptor antagonists as immunomodulators: new therapeutic views?

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1996-01-01

    from such studies are currently accumulating and suggest that the histamine-2 receptor antagonists have potential beneficial effects in the treatment of certain malignant, autoimmune and skin diseases, either alone or in combination with other drugs. The beneficial effect of histamine-2 receptor......Considerable evidence has emerged to suggest that histamine participates in the regulation of the inflammatory response, immune reaction, coagulation cascade, and cardiovascular function. Furthermore, histamine may play a major role in the growth of normal and malignant tissue as a regulator of...... proliferation and angiogenesis. Specific histamine receptors have been identified on the surface of bone marrow cells, immune competent cells, endothelial cells, fibroblasts, and also on malignant cells. This has prompted research in regulation by specific histamine receptor agonists and antagonists. Results...

  12. Development of a homogeneous binding assay for histamine receptors.

    Science.gov (United States)

    Crane, Kathy; Shih, Daw-Tsun

    2004-12-01

    Histamine is critically involved in a wide range of physiological and pathological processes through its actions at different receptors. Thus, histamine receptors have been actively pursued as therapeutic targets in the pharmaceutical industry for the treatment of a variety of diseases. There are currently four histamine receptors that have been cloned, all of which are G protein-coupled receptors. Studies from both academia and pharmaceutical companies have identified compounds that modulate the function of specific histamine receptors. These efforts led to the successful introduction of histamine H(1) and H(2) receptor antagonists for the treatment of allergy and excess gastric acid secretion, respectively. Histamine H(3) receptor ligands are currently under investigation for the treatment of obesity and neurological disorders. The recently identified histamine H(4) receptor is preferentially expressed in the immune tissues, suggesting a potential role in normal immune functions and possibly in the pathogenesis of inflammatory diseases. Even with the long history of histamine research and the important applications of histamine receptor ligands, assays to measure the affinity of compounds binding to histamine receptors are still routinely analyzed using a filtration assay, a very low-throughput assay involving washing and filtration steps. This article describes a simple, robust, and homogeneous binding assay based on the scintillation proximity assay (SPA) technology that provides results equivalent to those obtained using the more complex filtration assay. The SPA format is easily adapted to high-throughput screening because it is amenable to automation. In summary, this technique allows high-throughput screening of compounds against multiple histamine receptors and, thus, facilitates drug discovery efforts. PMID:15519569

  13. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Mohammad eKhanfar

    2016-05-01

    Full Text Available With the very recent market approval of pitolisant (Wakix®, the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

  14. Histamine and histamine type-2 receptor antagonists in psoriasis. Mechanisms and speculations

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1991-01-01

    pathogenesis. This is supported by the findings that CsA and methotrexate (Mxt) reduce formation and release of histamine. However, the well known side-effects of CsA and Mxt may argue potential use of other agents acting on formation and action of histamine. Such agents may be the histamine-2 receptor......The findings that the immunosuppressant cyclosporine A (CsA) improves psoriasis raise the possibility that cellular immune processes may play a major role in the pathogenesis of this disease. It is broadly agreed that histamine released by mast cells is one of the molecules involved in the...... antagonists, previously reported to have a clinical effect on psoriasis. But randomised short-term studies have disclosed that these drugs have no beneficial or even an aggravating effect on the disease. This article reports on recent findings of improvement in psoriasis using high doses of the histamine-2...

  15. Histamine and histamine type-2 receptor antagonists in psoriasis. Mechanisms and speculations

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1991-01-01

    pathogenesis. This is supported by the findings that CsA and methotrexate (Mxt) reduce formation and release of histamine. However, the well known side-effects of CsA and Mxt may argue potential use of other agents acting on formation and action of histamine. Such agents may be the histamine-2 receptor...... antagonists, previously reported to have a clinical effect on psoriasis. But randomised short-term studies have disclosed that these drugs have no beneficial or even an aggravating effect on the disease. This article reports on recent findings of improvement in psoriasis using high doses of the histamine-2......The findings that the immunosuppressant cyclosporine A (CsA) improves psoriasis raise the possibility that cellular immune processes may play a major role in the pathogenesis of this disease. It is broadly agreed that histamine released by mast cells is one of the molecules involved in the...

  16. Azines as histamine H4 receptor antagonists.

    Science.gov (United States)

    Lazewska, Dorota; Kiec-Kononowicz, Katarzyna

    2012-01-01

    Since 2000, when the histamine H4 receptor (H4R) was cloned, it has constituted an interesting target for drug development. Pharmacological studies suggest the potential utility of histamine H4R antagonists/inverse agonists in the treatment of inflammatory diseases, e.g. allergic rhinitis, asthma, atopic dermatitis, colitis, or pruritus. The first H4R ligands were non-selective compounds, but intensive chemical and pharmacological work has led to the discovery of highly potent and selective H4R antagonists (e.g. JNJ7777120, CZC-13788, PF-2988403, A-940894, A-987306). The first compound (UR-63325) has finally entered into clinical studies for the treatment of allergic respiratory diseases (completing the phase I ascending dose trial) and has been found to be safe and well tolerated. The number of scientific publications and patent applications in the H4 field is increasing annually. Among the diverse chemical structures of the H4R antagonists described a 2-aminopyrimidine scaffold is repeatedly found. This review looked at recent advances in the search for H4R antagonists as reflected in patent applications/patents and peer-reviewed publications over the last two years. The work concerns azines (mono-, di-, triazines) and their fused analogues. The chemistry and pharmacology has been described. PMID:22202103

  17. Functional Profiling of 2-Aminopyrimidine Histamine H4 Receptor Modulators.

    Science.gov (United States)

    Tichenor, Mark S; Thurmond, Robin L; Venable, Jennifer D; Savall, Brad M

    2015-09-24

    Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis. PMID:25993395

  18. Brain histamine H1- and H2-receptors and histamine-sensitive adenylate cyclase: effects of antipsychotics and antidepressants

    International Nuclear Information System (INIS)

    Several classes of psychoactive compounds have been investigated for their effects on histamine-sensitive adenylate cyclase in cell-free preparations from the guinea-pig cerebral cortex. Their inhibitory actions on this enzyme system have been compared with their abilities to displace [3H]pyrilamine and [3H]cimetidine from histamine H1- and H2-receptor sites, respectively. The results of these studies show that compounds which inhibited the histamine-sensitive cyclase were also displacers of either [3H]pyrilamine or [3H]cimetidine or both 3H-ligands from their binding sites. In spite of the lack of a correlation between binding and cyclase antagonism it was observed that compounds that displace both ligands showed greater inhibition of the cyclase than those that have affinities for sites labeled by one or the other ligand. It was concluded that antihistamines, the antipsychotics and the antidepressants share a common property through their antagonism of H1-receptors and that may be responsible for their sedative side effect. (Auth.)

  19. Histamine H2 receptor - Involvement in gastric ulceration

    Science.gov (United States)

    Brown, P. A.; Vernikos-Danellis, J.; Brown, T. H.

    1976-01-01

    The involvement of the H1 and H2 receptors for histamine in the pathogenesis of gastric ulcers was investigated in rats. Metiamide, an H2 receptor antagonist, reliably reduced ulceration produced by stress alone or by a combination of stress and aspirin. In contrast, pyrilamine, which blocks only the H1 receptor, was without effect under these same conditions. The results support the hypothesis that histamine mediates both stress and stress plus aspirin induced ulceration by a mechanism involving the H2 receptor.

  20. The histamine H4 receptor: from orphan to the clinic.

    Science.gov (United States)

    Thurmond, Robin L

    2015-01-01

    The histamine H4 receptor (H4R) was first noted as a sequence in genomic databases that had features of a class A G-protein coupled receptor. This putative receptor was found to bind histamine consistent with its homology to other histamine receptors and thus became the fourth member of the histamine receptor family. Due to the previous success of drugs that target the H1 and H2 receptors, an effort was made to understand the function of this new receptor and determine if it represented a viable drug target. Taking advantage of the vast literature on the function of histamine, a search for histamine activity that did not appear to be mediated by the other three histamine receptors was undertaken. From this asthma and pruritus emerged as areas of particular interest. Histamine has long been suspected to play a role in the pathogenesis of asthma, but antihistamines that target the H1 and H2 receptors have not been shown to be effective for this condition. The use of selective ligands in animal models of asthma has now potentially filled this gap by showing a role for the H4R in mediating lung function and inflammation. A similar story exists for chronic pruritus associated with conditions such as atopic dermatitis. Antihistamines that target the H1 receptor are effective in reducing acute pruritus, but are ineffective in pruritus experienced by patients with atopic dermatitis. As for asthma, animal models have now suggested a role for the H4R in mediating pruritic responses, with antagonists of the H4R reducing pruritus in a number of different conditions. The anti-pruritic effect of H4R antagonists has recently been shown in human clinical studies, validating the preclinical findings in the animal models. A selective H4R antagonist inhibited histamine-induced pruritus in health volunteers and reduced pruritus in patients with atopic dermatitis. The history to date of the H4R provides an excellent example of the deorphanization of a novel receptor and the translation

  1. The Histamine H4 Receptor: From Orphan to the Clinic

    Directory of Open Access Journals (Sweden)

    Robin L. Thurmond

    2015-03-01

    Full Text Available The histamine H4 receptor (H4R was first noted as a sequence in genomic databases that had features of a G-protein coupled receptor. This putative receptor was found to bind histamine consistent with its homology to other histamine receptors and thus became the fourth member of the histamine receptor family. Due to the previous success of drugs that target the H1 and H2 receptors, an effort was made to understand the function of this receptor and determine if it represented a drug target. Taking advantage of the vast literature on histamine, a search for histamine activity that did not appear to be mediated by the other three histamine receptors was undertaken. From this asthma and pruritus emerged as areas of particular interest. Histamine has long been suspected to play a role in the pathogenesis of asthma, but antihistamines that target the H1 and H2 receptors have not been shown to be effective for this condition. The use of selective ligands in animal models of asthma has now potentially filled this gap by showing a role for the H4R in mediating lung function and inflammation. A similar story exists for chronic pruritus associated with conditions such as atopic dermatitis. Antihistamines that target the H1 receptor are effective in reducing acute pruritus, but are ineffective in pruritus experienced by patients with atopic dermatitis. As for asthma, animal models have now suggested a role for the H4R in mediating pruritic responses, with antagonists to the H4R reducing pruritus in a number of different conditions. The anti-pruritic effect of H4R antagonists has recently been shown in human clinical studies, validating the preclinical findings in the animal models. A selective H4R antagonist inhibited histamine-induced pruritus in health volunteers and reduced pruritus in patients with atopic dermatitis. The history to date of the H4R provides an excellent example of the deorphanization of a novel receptor and the translation of this into

  2. In vitro study of histamine and histamine receptor ligands influence on the adhesion of purified human eosinophils to endothelium.

    Science.gov (United States)

    Grosicki, Marek; Wójcik, Tomasz; Chlopicki, Stefan; Kieć-Kononowicz, Katarzyna

    2016-04-15

    It is a well-known fact that histamine is involved in eosinophil-dependent inflammatory responses including cellular chemotaxis and migration. Nevertheless, the relative role of histamine receptors in the mechanisms of eosinophils adhesion to endothelial cells is not known. Therefore the aim of presented study was to examine the effect of selective histamine receptors ligands on eosinophils adhesion to endothelium. For that purpose the highly purified human eosinophils have been isolated from the peripheral blood. The viability and functional integrity of isolated eosinophils have been validated in several tests. Histamine as well as 4-methylhistamine (selective H4 agonist) in concentration-dependent manner significantly increased number of eosinophils that adhere to endothelium. Among the selective histamine receptors antagonist or H1 inverse agonist only JNJ7777120 (histamine H4 antagonist) and thioperamide (dual histamine H3/H4 antagonist) had direct effect on eosinophils adhesion to endothelial cells. Antagonists of H1 (diphenhydramine, mepyramine) H2 (ranitidine and famotidine) and H3 (pitolisant) histamine receptors were ineffective. To the best of our knowledge, this is the first study to demonstrate that histamine receptor H4 plays a dominant role in histamine-induced eosinophils adhesion to endothelium. PMID:26939881

  3. Histamine modulates multiple functional activities of monocyte-derived dendritic cell subsets via histamine receptor 2.

    Science.gov (United States)

    Simon, Tünde; Gogolák, Péter; Kis-Tóth, Katalin; Jelinek, Ivett; László, Valéria; Rajnavölgyi, Eva

    2012-02-01

    Expression of CD1a proteins in human monocyte-derived dendritic cells (DCs) specifies functionally distinct subsets with different inflammatory properties. Histamine is recognized as an inflammatory mediator released by various cell types including DCs. The diverse biological effects of histamine are mediated by G-protein-coupled histamine receptors (HRs), which are able to modulate the functional activities of DC subsets. The goal of the present study was to compare the expression and activity of HRs in the CD1a(-) and CD1a(+) monocyte-derived DC subsets and to test the effects of histamine on the differentiation, activation and functional activities of these subsets. We show that H2R is present at high levels in both DC subsets, whereas H1R and H4R are expressed in a subset-specific manner. Histamine shifts DC differentiation to the development of CD1a(-) DCs and modulates DC activation through its inhibitory effect on CD1a(+) DC differentiation. Histamine-induced reduction of CD1a(+) DCs is associated with increased secretion of IL-6 and IL-10, up-regulation of a typical combination of chemokines, expression C5aR1 by the CD1a(-) DC subset and enhanced migration of both activated DC subsets supported by the production of MMP-9 and MMP-12 enzymes. All these effects were shown to be mediated in a H2R-specific manner as revealed by the specific antagonist of the receptor. As H2R is expressed at high levels in both DC subsets, we propose that it may dominate the regulation of multiple DC functions. In contrast, H1R and H4R with opposing subset-related expression may have a regulatory or fine-tuning role in histamine-induced functional activities. PMID:22232416

  4. Histamine and histamine receptors in Tourette syndrome and other neuropsychiatric conditions.

    Science.gov (United States)

    Rapanelli, Maximiliano; Pittenger, Christopher

    2016-07-01

    The potential contributions of dysregulation of the brain's histaminergic modulatory system to neuropsychiatric disease, and the potential of histamine-targeting medications as therapeutic agents, are gradually coming into focus. The H3R receptor, which is expressed primarily in the central nervous system, is a promising pharmacotherapeutic target. Recent evidence for a contribution of histamine dysregulation to Tourette syndrome and tic disorders is particularly strong; although specific mutations in histamine-associated genes are rare, they have led to informative studies in animal models that may pave the way for therapeutic advances. A controlled study of an H3R antagonist in Tourette syndrome is ongoing. Preclinical studies of H3R antagonists in schizophrenia, attention deficit disorder, and narcolepsy have all shown promise. Recently reported controlled studies have been disappointing in schizophrenia and attention deficit disorder, but the H3R antagonist pitolisant shows promise in the treatment of narcolepsy and excessive daytime sleepiness and is currently under regulatory review for these conditions. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID:26282120

  5. The therapeutic potential of histamine receptor ligands in inflammatory bowel disease.

    Science.gov (United States)

    Neumann, Detlef; Seifert, Roland

    2014-09-01

    In the intestine of patients suffering from inflammatory bowel disease concentrations of histamine are increased compared to healthy controls. Genetic ablation of histamine production in mice ameliorates the course of experimentally induced colitis. These observations and first pharmacological studies indicate a function of histamine in the pathogenesis of inflammatory bowel disease. However, a closer examination reveals that available data are highly heterogeneous, limiting the rational design of strategies addressing specific histamine receptor subtypes as possible target for pharmacological interaction. However, very recently first clinical data indicate that antagonism at the histamine receptor subtype H4 provides a beneficial effect in at least the skin. Here, we discuss the available data on histamine effects and histamine receptor subtype functions in inflammatory bowel disease with a special emphasis on the histamine H4-receptor. PMID:24929116

  6. Human eosinophils - potential pharmacological model applied in human histamine H4 receptor research.

    Science.gov (United States)

    Grosicki, Marek; Kieć-Kononowicz, Katarzyna

    2015-01-01

    Histamine and histamine receptors are well known for their immunomodulatory role in inflammation. In this review we describe the role of histamine and histamine H4 receptor on human eosinophils. In the first part of article we provide short summary of histamine and histamine receptors role in physiology and histamine related therapeutics used in clinics. We briefly describe the human histamine receptor H4 and its ligands, as well as human eosinophils. In the second part of the review we provide detailed description of known histamine effects on eosinophils including: intracellular calcium concentration flux, actin polymerization, cellular shape change, upregulation of adhesion proteins and cellular chemotaxis. We provide proofs that these effects are mainly connected with the activation of histamine H4 receptor. When examining experimental data we discuss the controversial results and limitations of the studies performed on isolated eosinophils. In conclusion we believe that studies on histamine H4 receptor on human eosinophils can provide interesting new biomarkers that can be used in clinical studies of histamine receptors, that in future might result in the development of new strategies in the treatment of chronic inflammatory conditions like asthma or allergy, in which eosinophils are involved. PMID:25760088

  7. Histamine H₄ Receptor Antagonists: A New Approach for Tinnitus Treatment?

    Science.gov (United States)

    Hagenow, Jens; Stark, Holger

    2015-01-01

    Tinnitus, a disorder with disruptive sound perception in the head without an external source, affects around 15 % of the worldwide adult population. Since there is no approved drug for the treatment for this symptom, novel strategies need to be developed to provide relief for the patient. A patent from the small French start-up company Sensorion suggests the use of histamine H4 receptor (H4R) inhibitors as potential treatment. Since histamine and its receptor subtypes are strongly involved in neuronal and inflammatory processes in vestibular areas, targeting the H4R could be a novel way to gain a treatment for tinnitus. Although mRNA and protein levels of H4R have been demonstrated on isolated spiral ganglion neurons from mice, the methods of receptor detection as well as the species relevance of the data are under discussion and require considerable further verification, especially on a disease with a high medical need like tinnitus. PMID:25909438

  8. Histamine delays gastric emptying of solid food in man through histamine, receptors

    International Nuclear Information System (INIS)

    The authors have shown that histamine (H) contracts the cat pylorus and duodenum through H/sub 1/ receptor mechanisms. The authors investigated the effect of H infusion on gastric emptying (GE) and the role of H/sub 1/ and H/sub 2/ receptor blockade in healthy volunteers. Radionuclide GE studies were performed using chicken liver labeled in vivo with /sup 99m/Technetium-sulfur colloid as a marker of solid food. Study days were as follows: a baseline GE study (Day 1); H infused continuously IV at a rate of 40 μg/kg/hr during the GE study (Day 2); an IV bolus of 50 mg of diphenhydramine (Day 3), or 300 mg cimetidine (Day 4) given just prior to the continuous infusion of H; a final day when cimetidine was given alone (Day 5). GE was monitored for 2 hours on each day. The results of days 1, 2 and 3 are summarized below (+p<0.05 vs baseline or Day 1). Pretreatment with cimetidine (Day 4) augmented the delay in GE induced by H infusion, while cimetidine without H (Day 5) had no effect on GE. The authors conclude that: 1) H given at a dose which elicits maximal acid secretory response in man significantly delays GE; and 2) H/sub 1/ receptor blockade but not H/sub 2/ blockade prevented this effect. Histamine may play a modulatory role in human gastric emptying through an H/sub 1/ receptor mechanism

  9. Histamine H3 receptor in primary mouse microglia inhibits chemotaxis, phagocytosis, and cytokine secretion.

    Science.gov (United States)

    Iida, Tomomitsu; Yoshikawa, Takeo; Matsuzawa, Takuro; Naganuma, Fumito; Nakamura, Tadaho; Miura, Yamato; Mohsen, Attayeb S; Harada, Ryuichi; Iwata, Ren; Yanai, Kazuhiko

    2015-07-01

    Histamine is a physiological amine which initiates a multitude of physiological responses by binding to four known G-protein coupled histamine receptor subtypes as follows: histamine H1 receptor (H1 R), H2 R, H3 R, and H4 R. Brain histamine elicits neuronal excitation and regulates a variety of physiological processes such as learning and memory, sleep-awake cycle and appetite regulation. Microglia, the resident macrophages in the brain, express histamine receptors; however, the effects of histamine on critical microglial functions such as chemotaxis, phagocytosis, and cytokine secretion have not been examined in primary cells. We demonstrated that mouse primary microglia express H2 R, H3 R, histidine decarboxylase, a histamine synthase, and histamine N-methyltransferase, a histamine metabolizing enzyme. Both forskolin-induced cAMP accumulation and ATP-induced intracellular Ca(2+) transients were reduced by the H3 R agonist imetit but not the H2 R agonist amthamine. H3 R activation on two ubiquitous second messenger signalling pathways suggests that H3 R can regulate various microglial functions. In fact, histamine and imetit dose-dependently inhibited microglial chemotaxis, phagocytosis, and lipopolysaccharide (LPS)-induced cytokine production. Furthermore, we confirmed that microglia produced histamine in the presence of LPS, suggesting that H3 R activation regulate microglial function by autocrine and/or paracrine signalling. In conclusion, we demonstrate the involvement of histamine in primary microglial functions, providing the novel insight into physiological roles of brain histamine. PMID:25754956

  10. Histamine induces NF-κB controlled cytokine secretion by orbital fibroblasts via histamine receptor type-1.

    Science.gov (United States)

    Virakul, Sita; Phetsuksiri, Tanachaporn; van Holten-Neelen, Conny; Schrijver, Benjamin; van Steensel, Leendert; Dalm, Virgil A S H; Paridaens, Dion; van den Bosch, Willem A; van Hagen, P Martin; Dik, Willem A

    2016-06-01

    Mast cells and their products are likely to be involved in regulating orbital fibroblast activity in Graves' Ophthalmopathy (GO). Histamine is abundantly present in granules of mast cells and is released upon mast cell activation. However, the effect of histamine on orbital fibroblasts has not been examined so far. Orbital tissues from GO patients and controls were analyzed for the presence of mast cells using toluidine blue staining and immunohistochemical detection of CD117 (stem cell factor receptor). Orbital fibroblasts were cultured from GO patients and healthy controls, stimulated with histamine and cytokines (IL-6, IL-8, CCL2, CCL5, CCL7, CXCL10 and CXCL11) were measured in culture supernatants. Also hyaluronan levels were measured in culture supernatants and hyaluronan synthase (HAS) and hyaluronidase (HYAL) gene expression levels were determined. In addition, histamine receptor subtype gene expression levels were examined as well as the effect of the histamine receptor-1 (HRH1) antagonist loratadine and NF-κB inhibitor SC-514 on histamine-induced cytokine production. Mast cell numbers were increased in GO orbital tissues. Histamine stimulated the production of IL-6, IL-8 and CCL2 by orbital fibroblasts, while it had no effect on the production of CCL5, CCL7, CXCL10, CXCL11 and hyaluronan. Orbital fibroblasts expressed HRH1 and loratadine and SC-514 both blocked histamine-induced IL-6, IL-8 and CCL2 production by orbital fibroblasts. In conclusion, this study demonstrates that histamine can induce the production of NF-κB controlled-cytokines by orbital fibroblasts, which supports a role for mast cells in GO. PMID:27170049

  11. Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists clobenpropit and iodophenpropit as subunit-selective N-methyl-D-aspartate receptor antagonists

    DEFF Research Database (Denmark)

    Hansen, Kasper Bø; Mullasseril, Praseeda; Dawit, Sara; Kurtkaya, Natalie L; Yuan, Hongjie; Vance, Katie M; Orr, Anna G; Kvist, Trine; Ogden, Kevin K; Le, Phuong; Vellano, Kimberly M; Lewis, Iestyn; Kurtkaya, Serdar; Du, Yuhong; Qui, Min; Murphy, T J; Snyder, James P; Bräuner-Osborne, Hans; Traynelis, Stephen F

    2010-01-01

    NMDA receptor function, including the histamine H3 receptor antagonists clobenpropit and iodophenpropit, as well as the vanilloid receptor transient receptor potential cation channel, subfamily V, member 1 (TRPV1) antagonist capsazepine. These compounds are noncompetitive antagonists and the histamine...

  12. H2 receptor blockade and bronchial hyperreactivity to histamine in asthma.

    OpenAIRE

    Nogrady, S G; Bevan, C

    1981-01-01

    The role of histamine H1 and H2 receptors in the lung is not clear. H1 receptor blockade results in bronchodilatation and inhibition of histamine induced bronchoconstriction. H2 receptor blockade in vitro prevents the normal negative feedback of histamine on further mediator release in antigen challenge. Bronchospasm in guinea pigs given antigen challenge is enhanced by previous administration of metiamide or burimamide but not of cimetidine. These findings suggest the possible deleterious ef...

  13. Cherry-picked ligands at histamine receptor subtypes.

    Science.gov (United States)

    Sadek, Bassem; Stark, Holger

    2016-07-01

    Histamine, a biogenic amine, is considered as a principle mediator of multiple physiological effects through binding to its H1, H2, H3, and H4 receptors (H1-H4Rs). Currently, the HRs have gained attention as important targets for the treatment of several diseases and disorders ranging from allergy to Alzheimer's disease and immune deficiency. Accordingly, medicinal chemistry studies exploring histamine-like molecules and their physicochemical properties by binding and interacting with the four HRs has led to the development of a diversity of agonists and antagonists that display selectivity for each HR subtype. An overview on H1-R4Rs and developed ligands representing some key steps in development is provided here combined with a short description of structure-activity relationships for each class. Main chemical diversities, pharmacophores, and pharmacological profiles of most innovative H1-H4R agonists and antagonists are highlighted. Therefore, this overview should support the rational choice for the optimal ligand selection based on affinity, selectivity and efficacy data in biochemical and pharmacological studies. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID:26581501

  14. Inhibition of radiation-induced polyuria by histamine receptor antagonists

    International Nuclear Information System (INIS)

    In previous studies the authors have demonstrated that gamma radiation results in polyuria, which is preceded by polydypsia. This suggests that the increased thirst elicited by radiation causes increased urinary volume (UV). Histamine, which is released following radiation exposure, also elicits drinking by nonirradiated rats when administered exogenously. In this study the authors have investigated both the role of water deprivation and the effect of histamine receptor antagonists (HRA) on radiation-induced polyuria. Sprague-Dawley rats were housed individually in metabolic cages. Water was allowed ad libitum except in deprivation experiments where water was removed for 24 hr immediately following radiation. Cimetidine (CIM), an H2 HRA, and dexbromopheniramine (DXB), an H1 HRA, were administered i.p. (16 and 1 mg/kg, respectively) 30 min prior to irradiation (950 rads from a cobalt source). UV was determined at 24-hr intervals for 3 days preceding irradiation and 24 hr postirradiation. UV in DXB treated rats was significantly reduced 24 hr postirradiation (CON = 427 +/- 54%; DXB = 247 +/- 39% of preirradiated CON) compared to postirradiation control values. CIM did not affect postirradiation UV. These data suggest that radiation-induced polyuria is caused by polydypsia which is, in part, mediated by histamine induced by an H1 receptor

  15. Effect of subarachnoid hemorrhage on contractile responses and noradrenaline release evoked in cat cerebral arteries by histamine

    International Nuclear Information System (INIS)

    This study analyzes the changes induced by subarachnoid hemorrhage (SAH) on the contractile responses and the noradrenaline release evoked in cat cerebral arteries by histamine. The dose-dependent vasoconstriction induced by histamine on the cerebral arteries of normal cats was significantly reduced by diphenhydramine and phentolamine. When SAH was produced 3 and 7 days before the experiment, the histamine-induced vasoconstriction also decreased. Thereafter, a tendency to normalization in the contractile vascular responses was observed such that in 15 days after the hemorrhage it was not significantly different from that found in controls animals. The decrease in the contractile responses to histamine provoked by SAH was similar to that seen after pretreatment with intracisternal injections of 6-hydroxydopamine. The amount of radioactivity released by histamine following preincubation with 3H-noradrenaline from the cerebral arteries of cats exposed to SAH 3, 7, and 15 days before the experiment was significantly reduced when compared with controls. Moreover, the basal level of tritium release and the radioactivity retained at the end of the experiment were also decreased after SAH. Results indicate histamine releases noradrenaline from cat cerebral arteries, and SAH produce a transient denervation of the perivascular adrenergic nerve endings, which explained by the impairment of the indirect adrenergic mechanism involved in the overall contractile response elicited by this amine in cerebral arteries. Histamine does not seem to play a significant role in the production of the cerebral vasospasm occurring after SAH

  16. Identification of amino acids involved in histamine potentiation of GABA A receptors

    OpenAIRE

    Thiel, Ulrike; Platt, Sarah J.; Wolf, Steffen; Hatt, Hanns; Gisselmann, Günter

    2015-01-01

    Histamine is a neurotransmitter involved in a number of physiological and neuronal functions. In mammals, such as humans, and rodents, the histaminergic neurons found in the tuberomamillary nucleus project widely throughout the central nervous system. Histamine acts as positive modulator of GABAA receptors (GABAARs) and, in high concentrations (10 mM), as negative modulator of the strychnine-sensitive glycine receptor. However, the exact molecular mechanisms by which histamine acts on GABAARs...

  17. Expression of histamine H4 receptor in human epidermal tissues and attenuation of experimental pruritus using H4 receptor antagonist.

    Science.gov (United States)

    Yamaura, Katsunori; Oda, Manabu; Suwa, Eriko; Suzuki, Masahiko; Sato, Hiromi; Ueno, Koichi

    2009-10-01

    Many medicines exist which can cause pruritus (itching) as "serious adverse events." Many severe pruritic conditions respond poorly to histamine H1 receptor antagonists; there is no generally accepted antipruritic treatment. Recently described histamine H4 receptors are expressed in haematopoietic cells and have been linked to the pathology of allergy and asthma. We previously reported their expression in human dermal fibroblasts; in this study we have investigated H4 receptor expression in human epidermal tissue and found it to be greater in keratinocytes in the epidermal upper layer than in the lower layer. We have also investigated the effect of histamine H4 receptor antagonists on histamine H1 receptor antagonist-resistant pruritus using a mouse model. Scratching behavior was induced by histamine (300 nmol) or substance P (100 nmol) injected intradermally into the rostral part of the back of each mouse. Fexofenadine, a histamine H1 receptor antagonist, reduced scratching induced by histamine but not by substance P, whereas JNJ7777120, a histamine H4 receptor antagonist, significantly reduced both histamine- and substance P-induced scratching. These results suggest that H4 receptor antagonists may be useful for treatment of H1 receptor antagonist-resistant pruritus. PMID:19652466

  18. Diaminopyrimidines, diaminopyridines and diaminopyridazines as histamine H4 receptor modulators.

    Science.gov (United States)

    Savall, Brad M; Meduna, Steven P; Tays, Kevin; Cai, Hui; Thurmond, Robin L; McGovern, Patricia; Gaul, Michael; Zhao, Bao-Ping; Edwards, James P

    2015-02-15

    Previously disclosed H4 receptor modulators, the triamino substituted pyridines and pyrimidines, contain a free primary amino (-NH2) group. In this Letter we demonstrate that an exocyclic amine (NH2) is not needed to maintain affinity, and also show a significant divergence in the SAR of the pendant diamine component. These des-NH2 azacycles also show a distinct functional spectrum, that appears to be influenced by the diamine component; in the case of the 1,3-amino pyrimidines, the preferred diamine is the amino pyrrolidine instead of the more common piperazines. Finally, we introduce 3,5-diamino pyridazines as novel histamine H4 antagonists. PMID:25595684

  19. The interaction between histamine H1 receptor and μ- opioid receptor in scratching behavior in ICR mice.

    Science.gov (United States)

    Nakasone, Tasuku; Sugimoto, Yumi; Kamei, Chiaki

    2016-04-15

    In this study, we examined the interaction between histamine H1 receptor and μ-opioid receptor in scratching behavior in ICR mice. Both histamine and morphine caused scratching and simultaneous injection of histamine and morphine had an additive effect. Chlorpheniramine and naloxone inhibited histamine-induced scratching behavior. These two drugs also inhibited morphine-induced scratching behavior. Simultaneous injection of chlorpheniramine and naloxone caused a significant inhibition of histamine-induced scratching compared with separate injections. The same findings were also noted for morphine-induced scratching. These results strongly indicate a close relationship between histamine H1 receptor and μ-opioid receptor in scratching behavior in ICR mice. PMID:26948312

  20. Albizia lebbeck suppresses histamine signaling by the inhibition of histamine H1 receptor and histidine decarboxylase gene transcriptions.

    Science.gov (United States)

    Nurul, Islam Mohammed; Mizuguchi, Hiroyuki; Shahriar, Masum; Venkatesh, Pichairajan; Maeyama, Kazutaka; Mukherjee, Pulok K; Hattori, Masashi; Choudhuri, Mohamed Sahabuddin Kabir; Takeda, Noriaki; Fukui, Hiroyuki

    2011-11-01

    Histamine plays major roles in allergic diseases and its action is mediated mainly by histamine H(1) receptor (H1R). We have demonstrated that histamine signaling-related H1R and histidine decarboxylase (HDC) genes are allergic diseases sensitive genes and their expression level affects severity of the allergic symptoms. Therefore, compounds that suppress histamine signaling should be promising candidates as anti-allergic drugs. Here, we investigated the effect of the extract from the bark of Albizia lebbeck (AL), one of the ingredients of Ayruvedic medicines, on H1R and HDC gene expression using toluene-2,4-diisocyanate (TDI) sensitized allergy model rats and HeLa cells expressing endogenous H1R. Administration of the AL extract significantly decreased the numbers of sneezing and nasal rubbing. Pretreatment with the AL extract suppressed TDI-induced H1R and HDC mRNA elevations as well as [(3)H]mepyramine binding, HDC activity, and histamine content in the nasal mucosa. AL extract also suppressed TDI-induced up-regulation of IL-4, IL-5, and IL-13 mRNA. In HeLa cells, AL extract suppressed phorbol-12-myristate-13-acetate- or histamine-induced up-regulation of H1R mRNA. Our data suggest that AL alleviated nasal symptoms by inhibiting histamine signaling in TDI-sensitized rats through suppression of H1R and HDC gene transcriptions. Suppression of Th2-cytokine signaling by AL also suggests that it could affect the histamine-cytokine network. PMID:21782040

  1. Histamine H3 receptors regulate acetylcholine release from the guinea pig ileum myenteric plexus

    International Nuclear Information System (INIS)

    The effect of selective histamine H3-receptor agonists and antagonists on the acetylcholine release from peripheral nerves was evaluated in the guinea pig longitudinal muscle-myenteric plexus preparations, preloaded with (3H)choline. In the presence of H1 and H2 blockade, histamine and (R)-α-methylhistamine inhibited the electrically-evoked acetylcholine release, being (R)-α-methylhistamine more active than histamine, but behaving as a partial agonist. The effect of histamine was completely reversed by selective H3-blocking drugs, thioperamide and impromidine, while only submaximal doses of (R)-α-methylhistamine were antagonized. Furthermore, thioperamide and impromidine enhanced the electrically-evoked acetylcholine release. On the contrary, the new H3-blocker, HST-7, was found substantially ineffective, both as histamine antagonist and as acetylcholine overflow enhancer. These data suggest that histamine exerts an inhibitory control on the acetylcholine release from intestinal cholinergic nerves through the activation of H3 receptors

  2. Histamine suppresses gene expression and synthesis of tumor necrosis factor alpha via histamine H2 receptors

    OpenAIRE

    1991-01-01

    Histamine and tumor necrosis factor alpha (TNF-alpha) can each contribute to the pathogenesis of allergic reactions and chronic inflammatory diseases. We now report the effect of histamine on gene expression and total cellular synthesis of TNF-alpha. Lipopolysaccharide (LPS)-induced synthesis of TNF-alpha in peripheral blood mononuclear cells (PBMC) from 18 healthy donors was suppressed by histamine concentrations from 10(-6) to 10(-4) M, levels comparable with those measured in tissues after...

  3. No evidence for histamine H4 receptor in human monocytes.

    Science.gov (United States)

    Werner, Kristin; Neumann, Detlef; Buschauer, Armin; Seifert, Roland

    2014-12-01

    The histamine H4 receptor (H4R) is a classic pertussis toxin-sensitive Gi protein-coupled receptor that mediates increases in intracellular calcium concentration ([Ca(2+)]i). The presence of H4R in human eosinophils has been rigorously documented by several independent groups. It has also been suggested that H4R is expressed in human monocytes, but this suggestion hinges in part on H4R antibodies with questionable specificity. This situation prompted us to reinvestigate H4R expression in human monocytes. As positive control, we studied human embryonic kidney 293T cells stably expressing the human H4R (hH4R). In these cells, histamine (HA) and the H4R agonist UR-PI376 (2-cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[(2-phenylthio)ethyl]guanidine) induced pertussis toxin-sensitive [Ca(2+)]i increases. However, in quantitative real-time polymerase chain reaction studies we failed to detect hH4R mRNA in human monocytes and U937 promonocytes. In human monocytes, ATP and N-formyl-l-methionyl-l-leucyl-l-phenylalanine increased [Ca(2+)]i, but HA, UR-PI376, and 5-methylhistamine (a dual H4R/H2 receptor agonist) did not. In U937 promonocytes and differentiated U937 cells, HA increased [Ca(2+)]i, but this increase was mediated via HA H1 receptor. In conclusion, there is no evidence for the presence of H4R in human monocytes. PMID:25273276

  4. Analysis of histamine receptors in the central thermoregulatory mechanism of Mastomys natalensis.

    OpenAIRE

    B N Dhawan; Shukla, R.; Srimal, R. C.

    1982-01-01

    1 The effect of intracerebroventricular (i.c.v.) injection of histamine on the rectal temperature of Mastomys natalensis at ambient temperatures of 10, 24 and 33 degrees C has been studied. 2 Low doses (0.1-1.0 microgram) of histamine produced hypothermia while larger doses (5-20 micrograms) produced dose-dependent hyperthermia. The hypothermic effect was significantly antagonized by mepyramine while the hyperthermia was blocked by cimetidine. 3 Histamine H1-receptor agonists, 2-methyl-histam...

  5. Impromidine is a partial histamine H2-receptor agonist on human ventricular myocardium.

    OpenAIRE

    English, T A; Gristwood, R. W.; Owen, D A; Wallwork, J

    1986-01-01

    The inotropic effects of impromidine have been studied and compared with those of histamine on human isolated left ventricular preparations stimulated at 1 Hz. Both drugs caused concentration-related increases in force of contraction and were of similar potency, although the maximum response to impromidine was markedly and significantly less than that to histamine. The positive inotropic responses of impromidine were inhibited by cimetidine 1 X 10(-5) M, consistent with histamine H2-receptor ...

  6. The function of histamine receptor H4R in the brain revealed by interaction partners.

    Science.gov (United States)

    Moya-Garcia, Aurelio A; Rodriguez, Carlos E; Morilla, Ian; Sanchez-Jimenez, Francisca; Ranea, Juan A G

    2011-01-01

    The histamine H4 receptor is mainly expressed in haematopoietic cells, hence is linked to inflammatory and immune system conditions. It has been recently discovered that the receptor is expressed also in the mammalian central nervous system (CNS), but its role in the brain remains unclear. We address the potential functions of the histamine H4 receptor in the human brain using a 'guilty by association' logic, by close examination of protein-protein functional associations networks in the human proteome. PMID:21622255

  7. Inhibition by the tetramine disulphide, benextramine, of cardiac chronotropic histamine H2-receptor-mediated effects.

    OpenAIRE

    Belleau, B.; Benfey, B. G.; Benfey, T. J.; Melchiorre, C.

    1982-01-01

    1 Benextramine (N,N1-bis[o-methoxybenzylamino)-n-hexyl]cystamine), which irreversibly blocks alpha-adrenoceptors and does not inhibit the H1-receptor-mediated contractile effect of histamine on guinea-pig isolated ileum, also did not inhibit the H1-receptor-mediated inotropic effect of histamine on guinea-pig isolated atrium. 2 Benextramine irreversibly inhibited the H2-receptor-mediated chronotropic effect of histamine on guinea-pig isolated atrium. 3 Since its combination with the competiti...

  8. Effects of antidepressant drugs on histamine-H1 receptors in the brain

    International Nuclear Information System (INIS)

    The histamine-H1 receptor blocking properties of a number of structurally different antidepressant drugs have been evaluated using a 3H-mepyramine binding assay and a guinea-pig ileum preparation. The tricyclic antidepressants all inhibited the histamine-H1 receptor. Some newer antidepressant drugs, such as zimeldine and nomifensine were devoid of activity while others, such as iprindole and mianserin were very potent. It is concluded that antagonistic effects on the histamine-H1 receptor is not associated with the therapeutic efficacy in depression, but may contribute to the sedative effects of the antidepressant drugs

  9. The Quantum Nature of Drug-Receptor Interactions: Deuteration Changes Binding Affinities for Histamine Receptor Ligands

    Science.gov (United States)

    Repič, Matej; Zakšek, Maja; Kotnik, Kristina; Fijan, Estera; Mavri, Janez

    2016-01-01

    In this article we report a combined experimental and computational study concerning the effects of deuteration on the binding of histamine and two other histaminergic agonists to 3H-tiotidine-labeled histamine H2 receptor in neonatal rat astrocytes. Binding affinities were measured by displacing radiolabeled tiotidine from H2 receptor binding sites present on cultured neonatal rat astrocytes. Quantum-chemical calculations were performed by employing the empirical quantization of nuclear motion within a cluster model of the receptor binding site extracted from the homology model of the entire H2 receptor. Structure of H2 receptor built by homology modelling is attached in the supporting information (S1 Table) Experiments clearly demonstrate that deuteration affects the binding by increasing the affinity for histamine and reducing it for 2-methylhistamine, while basically leaving it unchanged for 4-methylhistamine. Ab initio quantum-chemical calculations on the cluster system extracted from the homology H2 model along with the implicit quantization of the acidic N–H and O–H bonds demonstrate that these changes in the binding can be rationalized by the altered strength of the hydrogen bonding upon deuteration known as the Ubbelohde effect. Our computational analysis also reveals a new mechanism of histamine binding, which underlines an important role of Tyr250 residue. The present work is, to our best knowledge, the first study of nuclear quantum effects on ligand receptor binding. The ligand H/D substitution is relevant for therapy in the context of perdeuterated and thus more stable drugs that are expected to enter therapeutic practice in the near future. Moreover, presented approach may contribute towards understanding receptor activation, while a distant goal remains in silico discrimination between agonists and antagonists based on the receptor structure. PMID:27159606

  10. Biphasic effects of intra-accumbens histamine administration on spontaneous motor activity in the rat; a role for central histamine receptors.

    OpenAIRE

    Bristow, L. J.; Bennett, G. W.

    1988-01-01

    1. The effect of intra-accumbens injection of histamine and related compounds on the spontaneous motor activity of the rat has been investigated. 2. Microinjections of histamine (1-200 micrograms) induced dose-dependent, biphasic changes in rat activity consisting of an initial brief hypoactivity response followed by a marked hyperactivity phase. The histamine metabolite, n-tele-methylhistamine was without effect. 3. Pretreatment with the H1-receptor antagonist mepyramine (10 micrograms) bloc...

  11. Histamine receptors on adult rat cardiomyocytes: antagonism of alpha1-receptor stimulation of cAMP degradation

    International Nuclear Information System (INIS)

    Incubation of intact cardiomyocytes with the histamine antagonist [3H]mepyramine results in rapid reversible binding to a single class of high affinity sites (K/sub D/ = 1.2nM; 50,000 sites/myocyte). In membranes from purified myocytes histamine competition of [3H]mepyramine binding (K/sub D/ = 300nM) is not altered by GTP (10μM). Competition of [3H]mepyramine binding by H-receptor subtype-selective antagonists suggests the presence of a single class of H1-receptors. Incubation of intact myocytes with histamine (luM, H1 receptor activation) plus norepinephrine (NE 1uM, alpha1 + beta1 receptor activation) for 3 min leads to significantly more cAMP accumulation (36.5 pmol/106 myocytes) than NE alone (30 pmol/106 myocytes). Histamine alone does not alter basal cAMP = 10.4 pmol/106 myocytes, or beta1 stimulation (isoproternol, 1uM) = 39.6 pmol/106 myocytes. Cyclic AMP accumulation with NE plus prazosin 10nM, (alpha1 + beta1 + alpha1 blockade) is indistinguishable from NE + histamine, (alpha1 + beta1 + H1) stimulation. Histamine competition for [3H]prazosin binding suggests that histamine does not block alpha1 receptors on the myocyte. These data suggest that H1 receptor activation leads to antagonism of the alpha1 receptor mediated activation of cAMP phosphodiesterase the authors have recently described

  12. The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines.

    Science.gov (United States)

    Thurmond, Robin L; Gelfand, Erwin W; Dunford, Paul J

    2008-01-01

    Histamine has a key role in allergic inflammatory conditions. The inflammatory responses resulting from the liberation of histamine have long been thought to be mediated by the histamine H1 receptor, and H1-receptor antagonists--commonly known as antihistamines--have been used to treat allergies for many years. However, the importance of histamine in the pathology of conditions such as asthma and chronic pruritus may have been underestimated. Here, we review accumulating evidence suggesting that histamine indeed has roles in inflammation and immune function modulation in such diseases. In particular, the discovery of a fourth histamine receptor (H4) and its expression on numerous immune and inflammatory cells has prompted a re-evaluation of the actions of histamine, suggesting a new potential for H4-receptor antagonists and a possible synergy between H1 and H4-receptor antagonists in targeting various inflammatory conditions. PMID:18172439

  13. Comparative study of histamine H4 receptor expression in human dermal fibroblasts.

    Science.gov (United States)

    Ikawa, Yoshiko; Shiba, Kayoko; Ohki, Emi; Mutoh, Nanami; Suzuki, Masahiko; Sato, Hiromi; Ueno, Koichi

    2008-10-01

    The histamine H4 receptor (H4R) is the newest receptor identified of four histamine receptors. Its expression in numerous immune and inflammatory organs has been implicated in relation to immune systems and allergic diseases. In the present study, we demonstrate the expression of H4R in human dermal fibroblasts and investigate changes in its expression level when stimulated by histamine, phorbol 12-myristate 13-acetate (PMA), lipopolysaccharides (LPS), dexamethasone and indomethacin. Histamine and PMA showed no effects on H4R expression. LPS and indomethacin up-regulated H4R mRNA expression, and 20 microM dexamethasone increased H4R protein levels. These results indicate a good prospective for this new receptor in the development of effective treatments of inflammatory diseases and pruritus or for the appropriate prevention of toxicities. PMID:18827451

  14. Development of novel cellular model for affinity studies of histamine H(4) receptor ligands.

    Science.gov (United States)

    Karcz, Tadeusz; Kieć-Kononowicz, Katarzyna

    2013-01-01

    The G protein-coupled histamine H4 receptor (H4R) is the last member of histamine receptors family discovered so far. Its expression pattern, together with postulated involvement in a wide variety of immunological and inflammatory processes make histamine H4 receptor an interesting target for drug development. Potential H4R ligands may provide an innovative therapies for different immuno-based diseases, including allergy, asthma, pruritus associated with allergy or autoimmune skin conditions, rheumatoid arthritis and pain. However, none of successfully developed selective and potent histamine H4 receptor ligands have been introduced to the market up to date. For that reason there is still a strong demand for pharmacological models to be used in studies on potent H4R ligands. In current work we present the development of novel mammalian cell line, stably expressing human histamine H4 receptor, with use of retroviral transduction approach. Obtained cell line was pharmacologically characterized in radioligand binding studies and its utility for affinity testing of potent receptor ligands was confirmed in comparative studies with the use of relevant insect cells expression model. Obtained results allow for statement that developed cellular model may be successfully employed in search for new compounds active at histamine H4 receptor. PMID:24432340

  15. Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats.

    OpenAIRE

    Blandina, P.; Giorgetti, M.; L. Bartolini; M.Cecchi; Timmerman, H.; Leurs, R.; Pepeu, G; Giovannini, M. G.

    1996-01-01

    1. The effects of histamine and agents at histamine receptors on spontaneous and 100 mM K(+)-evoked release of acetylcholine, measured by microdialysis from the cortex of freely moving, rats, and on cognitive tests are described. 2. Local administration of histamine (0.1-100 microM) failed to affect spontaneous but inhibited 100 mM K(+)-stimulated release of acetylcholine up to about 50%. The H3 receptor agonists (R)-alpha-methylhistamine (RAMH) (0.1-10 microM), imetit (0.01-10 microM) and im...

  16. Involvement of the H1 histamine receptor, p38 MAP kinase, MLCK, and Rho/ROCK in histamine-induced endothelial barrier dysfunction

    Science.gov (United States)

    Adderley, Shaquria P.; Zhang, Xun E.; Breslin, Jerome W.

    2015-01-01

    Objective The mechanisms by which histamine increases microvascular permeability remain poorly understood. We tested the hypothesis that H1 receptor activation disrupts the endothelial barrier and investigated potential downstream signals. Methods We used confluent endothelial cell (EC) monolayers, assessing transendothelial electrical resistance (TER) as an index of barrier function. Human umbilical vein EC (HUVEC), cardiac microvascular EC (HCMEC), and dermal microvascular EC (HDMEC) were compared. Receptor expression was investigated using Western blotting, immunofluorescence (IF) confocal microscopy and RT-PCR. Receptor function and downstream signaling pathways were tested using pharmacologic antagonists and inhibitors, respectively. Results We identified H1-H4 receptors on all three EC types. H1 antagonists did not affect basal TER but prevented the histamine-induced decrease in TER. Blockade of H2 or H3 attenuated the histamine response only in HDMEC, while inhibition of H4 attenuated the response only in HUVEC. Combined inhibition of both PKC and PI3K caused exaggerated histamine-induced barrier dysfunction in HDMEC, whereas inhibition of p38 MAP kinase attenuated the histamine response in all three EC types. Inhibition of RhoA, ROCK, or MLCK also prevented the histamine-induced decrease in TER in HDMEC. Conclusion The data suggest that multiple signaling pathways contribute to histamine-induced endothelial barrier dysfunction via the H1 receptor. PMID:25582918

  17. Molecular cloning and pharmacology of functionally distinct isoforms of the human histamine H(3) receptor

    DEFF Research Database (Denmark)

    Wellendorph, Petrine; Goodman, M W; Burstein, E S;

    2002-01-01

    The pharmacology of histamine H(3) receptors suggests the presence of distinct receptor isoforms or subtypes. We herein describe multiple, functionally distinct, alternatively spliced isoforms of the human H(3) receptor. Combinatorial splicing at three different sites creates at least six distinc...

  18. Associations of polymorphisms in histidine decarboxylase, histamine N-methyltransferase and histamine receptor H3 genes with breast cancer.

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    Gong-Hao He

    Full Text Available We previously found that genetic polymorphisms in gene coding for histamine H4 receptors were related to the risk and malignant degree of breast cancer. The roles of polymorphisms in other histamine-related genes, such as histidine decarboxylase (HDC, histamine N-methyltransferase (HNMT and histamine H3 receptor (HRH3, remain unexplored. The aim of this study is to analyze the clinical associations of polymorphisms in HDC, HNMT and HRH3 with breast cancer. Two hundred and one unrelated Chinese Han breast cancer patients and 205 ethnicity-matched health controls were recruited for case-control investigation. Genomic DNA from the participants was extracted and 5 single nucleotide polymorphisms (SNPs in HDC, HNMT and HRH3 were genotyped. We found that polymorphisms of HNMT and HRH3 were irrelevant with breast cancer in the present study. However, the T allele of rs7164386 in HDC significantly decreased the risk of breast cancer (adjusted odds ratios [ORs], 0.387; 95% confidence intervals [CIs], 0.208-0.720; P = 0.003. Furthermore, for HDC haplotypes, the CG haplotype of rs7164386-rs7182203 was more frequent among breast cancer patients (adjusted OR, 1.828; 95% CI, 1.218-2.744; P = 0.004 while the TG haplotype was more frequent among health controls (adjusted OR, 0.351; 95% CI, 0.182-0.678; P = 0.002. These findings indicated that polymorphisms of HDC gene were significantly associated with breast cancer in Chinese Han population and may be novel diagnostic or therapeutic targets for breast cancer. Further studies with larger participants worldwide are still needed for conclusion validation.

  19. Histamine H3 and H4 receptor ligands modify vascular histamine levels in normal and arthritic large blood vessels in vivo.

    Science.gov (United States)

    Kyriakidis, Konstantinos; Zampeli, Evangelia; Palaiologou, Marina; Tiniakos, Dina; Tiligada, Ekaterini

    2015-01-01

    Growing evidence associates histamine with arthritis, but its implication in shaping vascular function in chronic inflammation remains largely elusive. This study explored the involvement of vascular histamine in the extra-articular responses in peripheral large blood vessels using a rat model of adjuvant-induced arthritis. Histamine levels were increased in the abdominal aorta and the inferior vena cava of arthritic animals. Contrary to the H1 receptor antagonist dimetindene, histamine induction was observed following administration of the H3 and H4 receptor ligands GSK334429 and JNJ7777120, respectively. In arthritis, prophylactic treatment with GSK334429 partially attenuated the clinical signs and restored basal histamine levels only in the abdominal aorta. This study is the first to implicate the H3 and H4 receptors in a concerted constitutive regulation of basal vascular histamine in the rat large blood vessels and to identify the H3 receptor as a component that may influence arterial histamine during the onset of arthritis. PMID:25359709

  20. Histamine H4 receptor: insights into a potential therapeutic target in breast cancer.

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    Martinel Lamas, Diego J; Rivera, Elena S; Medina, Vanina A

    2015-01-01

    Breast cancer is the second most common cancer worldwide, and the leading cause of cancer death in women. Several studies underlined the critical role of histamine in breast cancer development and progression. This review addresses the latest evidence regarding the involvement of histamine and histamine receptors in breast cancer, focusing particularly in the histamine H4 receptor (H4R). Histamine concentration in breast cancer tissues was found to be higher than that in normal tissues of healthy controls by means of an increase in the activity of histidine decarboxylase (HDC), the enzyme involved in histamine production. The expression of H4R in different experimental models and human biopsies, the associated biological responses, as well as the in vivo treatment of experimental tumors with H4R ligands is reviewed. Evidence demonstrates that the H4R exhibits a key role in histamine-mediated biological processes such as cell proliferation, senescence and apoptosis in breast cancer. The polymorphisms of the H4R and HDC genes and their association with breast cancer risk and malignancy reinforce the critical (patho)physiological role of H4R in breast cancer. In addition, H4R agonists display anti-tumor effects in vivo in a triple negative breast cancer model. The findings support the exploitation of the H4R as a molecular target for breast cancer drug development. PMID:25961682

  1. Major advances in the development of histamine H4 receptor ligands.

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    Smits, Rogier A; Leurs, Rob; de Esch, Iwan J P

    2009-08-01

    The search for new and potent histamine H4 receptor ligands is leading to a steadily increasing number of scientific publications and patent applications. Several interesting and structurally diverse compounds have been found, but fierce IP competition for a preferred 2-aminopyrimidine scaffold is becoming apparent. Recent investigations into the role of the histamine H(4)R in (patho)physiology and the use of H4R ligands in in vivo disease models reveal enormous potential in the field of inflammation and allergy, among others. The development of ligands that display activity at two or more histamine receptor (HR) subtypes is another clinical opportunity that is currently being explored. Taken together, the histamine H4R field is gearing up for clinical studies and has the potential to deliver another generation of blockbuster drugs. PMID:19477292

  2. Effects of high levels of dietary zinc oxide on ex vivo epithelial histamine response and investigations on histamine receptor action in the proximal colon of weaned piglets.

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    Kröger, S; Pieper, R; Aschenbach, J R; Martin, L; Liu, P; Rieger, J; Schwelberger, H G; Neumann, K; Zentek, J

    2015-11-01

    The aim of the study was to identify the effect of high dietary zinc oxide (ZnO) levels on the histamine-induced secretory-type response and histamine metabolism in the porcine proximal colon. After weaning at d 26, 3 diets with low (LZn), normal (NZn), and high (HZn) concentrations of zinc (57, 164, or 2,425 mg/kg) were fed to a total of 120 piglets. Digesta and tissue samples were taken from the ascending colon after 7 ± 1, 14 ± 1, 21 ± 1, and 28 ± 1 d. Partially stripped tissue was mounted in Ussing chambers, and histamine was applied either to the serosal or mucosal compartments. Tissue was pretreated with or without aminoguanidine and amodiaquine to block the histamine-degrading enzymes diamine oxidase (DAO) and histamine -methyltransferase (HMT), respectively. Gene expression and catalytic activity of DAO and HMT in the tissue were analyzed. The numbers of mast cells were determined in tissue samples, and histamine concentration was measured in the colon digesta. Colon tissue from another 12 piglets was used for functional studies on histamine H and H receptors by using the neuronal conduction blocker tetrodotoxin (TTX) and the H and H receptor blocker chloropyramine and famotidine, respectively. After serosal histamine application to colonic tissue in Ussing chambers, the change of short-circuit current (Δ) was not affected by pretreatment and was not different between Zn feeding groups. The Δ after mucosal histamine application was numerically lower ( = 0.168) in HZn compared to LZn and NZn pigs. Mast cell numbers increased from 32 to 46 d of life ( pig colon that are localized either on neurons or on cells that activate secretion via neurons. Luminal histamine can elicit a secretory-type response via these receptors. PMID:26641046

  3. Histamine elevates the expression of Ets-1, a protooncogen in human melanoma cell lines through H2 receptor.

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    Hegyesi, Hargita; Horváth, Barnabás; Pállinger, Eva; Pós, Zoltán; Molnár, Viktor; Falus, András

    2005-04-25

    Histamine is known to act, at least in part, as a growth factor for several cell types, and as production of this biogen amine has been found to accelerate the rate of tissue proliferation in wound repair, embryogenesis and malignant growth. Abundant experimental and clinical data suggest that histamine augments in vivo tumour cell proliferation via histamine H2 receptors (H2R). Here, we report that exogenously added histamine stimulates Ets-1 (v-ets erythroblastosis virus E26 oncogene homolog 1) synthesis in human melanoma cells. Involvement of histamine receptors in the histamine induced ets-1 expression has been also studied. Our data show that these newly recognized actions of histamine are mediated by the H2R. Modification of local protooncogen Ets-1 level is likely being involved in the regulation of melanoma growth. PMID:15848191

  4. The role of histamine H4 receptor in immune and inflammatory disorders.

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    Zampeli, E; Tiligada, E

    2009-05-01

    Since its discovery at the beginning of the 20th century, histamine has been established to play a pathophysiological regulatory role in cellular events through binding to four types of G-protein-coupled histamine receptors that are differentially expressed in various cell types. The discovery, at the turn of the millennium, that the histamine H4 receptor is largely expressed in haemopoietic cells as well as its chemotactic properties designate its regulatory role in the immune system. H4 receptors modulate eosinophil migration and selective recruitment of mast cells leading to amplification of histamine-mediated immune responses and eventually to chronic inflammation. H4 receptor involvement in dendritic cell activation and T cell differentiation documents its immunomodulatory function. The characterization of the H4 as the immune system histamine receptor directed growing attention towards its therapeutic exploitation in inflammatory disorders, such as allergy, asthma, chronic pruritus and autoimmune diseases. The efficacy of a number of H4 receptor ligands has been evaluated in in vivo and in vitro animal models of disease and in human biological samples. However, before reaching decisive conclusions on H4 receptor pathophysiological functions and therapeutic exploitation, identification of genetic polymorphisms and interspecies differences in its relative actions and pharmacological profile need to be addressed and taken into consideration. Despite certain variations in the reported findings, the available data strongly point to the H4 receptor as a novel target for the pharmacological modulation of histamine-transferred immune signals and offer an optimistic perspective for the therapeutic exploitation of this promising new drug target in inflammatory disorders. PMID:19309354

  5. Intrathecal high-dose histamine induces spinally-mediated nociceptive behavioral responses through a polyamine site of NMDA receptors.

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    Watanabe, Chizuko; Orito, Tohru; Watanabe, Hiroyuki; Mizoguchi, Hirokazu; Yonezawa, Akihiko; Yanai, Kazuhiko; Mobarakeh, Jalal Izadi; Onodera, Kenji; Sakurada, Tsukasa; Sakurada, Shinobu

    2008-02-26

    Previous research has demonstrated that a high dose of histamine (1600 pmol) injected i.t. in mice can evoke nociceptive behaviors consisting of biting/licking along with occasional scratching. The present study was undertaken to examine the involvement of spinal N-methyl-d-aspartate (NMDA) and histamine H(1) and H(2) receptors in the nociceptive behaviors evoked by high-dose histamine. Co-administration of the histamine H(1) receptor antagonists, d-chlorpheniramine and pyrilamine, or the histamine H(2) receptor antagonists, ranitidine and zolantidine, failed to suppress the histamine-evoked nociceptive behaviors. Moreover, following histamine administration, nociceptive behaviors in histamine H(1) receptor-knockout and histamine H(2) receptor-knockout mice were indistinguishable from those in wild-type mice, suggesting that histamine-induced nociceptive behaviors are not mediated through histamine H(1) and H(2) receptors in the spinal cord. The histamine-induced nociceptive behaviors were inhibited by co-administration of the competitive NMDA receptor antagonists, d-(-)-2-amino-5-phosphonovaleric acid (D-APV) and 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPPA), and the ion channel blocker, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine maleate (MK-801). Co-administration of ifenprodil, an antagonist for both the polyamine site and the NR2B subunit of NMDA receptors, also inhibited the histamine-induced nociceptive behaviors. (R-[R, S])-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidinepropanol hydrochloride (Ro25-6981), an antagonist of the NMDA receptor subtype containing the NR2B subunit, did not inhibit histamine-induced nociceptive behaviors, whereas these behaviors were attenuated by pretreatment with an antisense oligodeoxynucleotide against the mRNA for the NR1 subunit of the NMDA receptor. Moreover, agmatine and arcaine, antagonists for a polyamine site on the NMDA receptor, inhibited nociceptive

  6. A new generation of anti-histamines: Histamine H4 receptor antagonists on their way to the clinic.

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    Engelhardt, Harald; Smits, Rogier A; Leurs, Rob; Haaksma, Eric; de Esch, Iwan J P

    2009-09-01

    At the turn of the millennium, the DNA sequence encoding the histamine H4 receptor (H4R) was identified in data from human genome databases. Considering the clinical importance of H1R and H2R ligands, and the clinical trials that are ongoing for H3R ligands, the latest addition to the histamine receptor family was noted with interest by the pharmaceutical industry. Initial studies describing the expression of the H4R, and the activity of this receptor in (patho)physiology, suggested that the H4R played a role in the immune system. The introduction of the reference H4R antagonist JNJ-7777120 (Johnson & Johnson Pharmaceutical Research & Development LLC/Abbott Laboratories), and proof of the efficacy of this agent in models of asthma, allergic rhinitis and pruritus, highlighted the H4R as a novel drug target. The first clinical candidates targeting the H4R have been identified, and new H4R antagonists are expected to enter the clinic in the near future. PMID:19736622

  7. Functional characteristics of histamine receptor-bearing mononuclear cells. I. Selective production of lymphocyte chemoattractant lymphokines with histamine used as a ligand.

    Science.gov (United States)

    Center, D M; Cruikshank, W W; Berman, J S; Beer, D J

    1983-10-01

    Mitogens and antigens have been the traditional ligands for activating lymphocytes in vitro for the elaboration of lymphokines. Recently, histamine, by interaction with histamine-type 2 receptors on T lymphocytes, has been found to induce the production of one lymphokine, histamine-induced suppressor factor (HSF), that inhibits lymphocyte proliferation and lymphokine production in vitro. Because the biologic effects of HSF appear to be confined to alterations in lymphocyte function, we assessed the ability of soluble products of histamine-stimulated human blood mononuclear cells to affect another lymphocyte function, motility. Utilizing a modified Boyden chamber assay to assess lymphocyte migration, we identified chemoattractant activity for human blood and rat splenic T lymphocytes in histamine-induced mononuclear cell supernatants. No neutrophil or monocyte chemoattractant activity was present. Sephadex G-100 gel filtration of histamine-induced supernatants showed the lymphotactic activity eluted with a 56,000 m.w. This activity was cationic as determined by its elution pattern from a Sephadex QAE anion exchange matrix with a single pl of 9.0 to 9.4 determined by isoelectric focusing in sucrose. Its biologic activity is predominantly chemokinetic in nature, is stable to heating at 56 degrees C for 30 min, but is sensitive to the effects of trypsin and neuraminidase. These physicochemical and functional characteristics establish it as identical to a recently described concanavalin A-induced (Con A) lymphotactic lymphokine (LCF). Mononuclear cells that did not adhere to a histamine affinity matrix were unable to produce LCF when subsequently stimulated with histamine or Con A. Mononuclear cells incubated with histamine and diphenhydramine produced LCF; the addition of cimetidine eliminated LCF production. In fact, supernatants from cells incubated with histamine and cimetidine significantly inhibited lymphocyte migration, a phenomenon explainable by the two regions

  8. The Effects of Histamine H3 Receptors on Contractile Responses on Rat Gastric Fundus

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    Aşkın Hekimoğlu

    2006-01-01

    Full Text Available The aim of this study is to determine the effects of histamine receptors on the gastrointestinal system smooth muscle contractions and the role of histamine H3 receptors on these effects. İsolated rat gastric fundus preparations were hanged on isolated organ bath and histamine receptor agonist and anthagonists were added to the bath solution and the electrical field stimulation-induced contractile responses were evaluated. In our study groups after blocking one of the histamine receptors H1, H2,H3; contractile responses were observed. Then, other two receptors were blocked one by one or combination of them to observe the changes on the contractile responses given to the electrical stimulation .To blocke histamine receptors pyrilamine (10-6м as H1 receptor blocker, famotidine (10-6м as H2 receptor blocker and thioperamide (10-5м as H3 receptor blocker and various combination of them were used. All groups were treated with H3 receptor anthagonist thioperamide (10-5м and agonist (R-α-methylhistamine (RMHA on 10-8, 10-7, 10-6 ve 10-5 molar concentrations cumulatively to observe its mediator effects on contractile responses. We suggested that (R-α-methylhistamine mediates the inhibition on the contractile effects of rat gastric fundus. This conclusion was supported by these findings: a the selective agonists (RMHA caused a dumping of the contractile effect of acetylcholine; b the effect of (RMHA was prevented by the selective H3 receptor antagonist thioperamide.

  9. Histamine H1, H3 and H4 receptors are involved in pruritus.

    Science.gov (United States)

    Rossbach, K; Nassenstein, C; Gschwandtner, M; Schnell, D; Sander, K; Seifert, R; Stark, H; Kietzmann, M; Bäumer, W

    2011-09-01

    Histamine has long been recognised as a classical inducer of pruritus. However, the specific mechanism of histamine-induced itch has still not been fully understood. The H1 and H4 receptor appear to be key components in the induction of itch. The specific role of the H3 receptor in histamine-induced itch remains unclear. The aim of our study was to investigate the role of the four known histamine receptors (H1-4) in acute itch in mice. Intradermal injection of the selective H3R inverse agonist pitolisant induced strong itch in mice. Pitolisant (50 nmol/injection)-induced pruritus could be completely blocked by a combined treatment with the H1R antagonist cetirizine (15 mg/kg) and the H4R antagonist JNJ 7777120 (15 mg/kg), whereas the H2R antagonist ranitidine (15 mg/kg) failed to inhibit the scratch response. Next, expression and function of histamine receptors on sensory neurons isolated from dorsal root ganglia of mice were investigated. As the itch sensation results from the excitation of sensory nerves in the skin, we further focused on skin specific sensory neurons. Therefore, neurons were retrograde labelled from the skin by means of a fluorescent tracer. Expression of H1R, H3R and H4R on skin innervating sensory neurons was detected. By single-cell calcium imaging, it was demonstrated that histamine induces a calcium increase in a subset of (skin-specific) sensory neurons via activation of the H1R and H4R as well as inhibition of the H3R. It is assumed that the decreased threshold in response to H3R antagonism activates H1R and H4R on sensory neurons, which in turn results in the excitation of histamine-sensitive afferents and therefore elicits the sensation of itch. PMID:21689731

  10. Histamine H3 receptor antagonist decreases cue-induced alcohol reinstatement in mice.

    Science.gov (United States)

    Nuutinen, Saara; Mäki, Tiia; Rozov, Stanislav; Bäckström, Pia; Hyytiä, Petri; Piepponen, Petteri; Panula, Pertti

    2016-07-01

    We have earlier found that the histamine H3 receptor (H3R) antagonism diminishes motivational aspects of alcohol reinforcement in mice. Here we studied the role of H3Rs in cue-induced reinstatement of alcohol seeking in C57BL/6J mice using two different H3R antagonists. Systemic administration of H3R antagonists attenuated cue-induced alcohol seeking suggesting that H3R antagonists may reduce alcohol craving. To understand how alcohol affects dopamine and histamine release, a microdialysis study was performed on C57BL/6J mice and the levels of histamine, dopamine and dopamine metabolites were measured in the nucleus accumbens. Alcohol administration was combined with an H3R antagonist pretreatment to reveal whether modulation of H3R affects the effects of alcohol on neurotransmitter release. Alcohol significantly increased the release of dopamine in the nucleus accumbens but did not affect histamine release. Pretreatment with H3R antagonist ciproxifan did not modify the effect of alcohol on dopamine release. However, histamine release was markedly increased with ciproxifan. In conclusion, our findings demonstrate that H3R antagonism attenuates cue-induced reinstatement of alcohol seeking in mice. Alcohol alone does not affect histamine release in the nucleus accumbens but H3R antagonist instead increases histamine release significantly suggesting that the mechanism by which H3R antagonist inhibits alcohol seeking found in the present study and the decreased alcohol reinforcement, reward and consumption found earlier might include alterations in the histaminergic neurotransmission in the nucleus accumbens. These findings imply that selective antagonists of H3Rs could be a therapeutic strategy to prevent relapse and possibly diminish craving to alcohol use. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID:26107118

  11. Pharmacological profile of astemizole-derived compounds at the histamine H1 and H4 receptor--H1/H4 receptor selectivity.

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    Wagner, Eva; Wittmann, Hans-Joachim; Elz, Sigurd; Strasser, Andrea

    2014-03-01

    Astemizole, a H1R antagonist shows high affinity to the histamine H1 receptor but only a moderate affinity to the histamine H4 receptor. This study aims to modify the astemizole to keep high affinity to the histamine H1 receptor and to increase affinity to the histamine H4 receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H1 and H4 receptors. The new compounds show affinity to the histamine H1 receptor in the pK i range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H4 receptor was surprisingly rather low (pK i from 4.4 to 5.6). Three representative compounds were docked into the histamine H1 receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level. Furthermore, taking into account the binding mode of compounds with high affinity to the histamine H4 receptor, a H1/H4-pharmacophore hypothesis was developed. PMID:24241585

  12. Changes in Histamine Receptors (H1, H2, and H3 Expression in Rat Medial Vestibular Nucleus and Flocculus after Unilateral Labyrinthectomy: Histamine Receptors in Vestibular Compensation.

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    Liuqing Zhou

    Full Text Available Vestibular compensation is the process of behavioral recovery following peripheral vestibular lesion. In clinics, the histaminergic medicine is the most widely prescribed for the treatment of vertigo and motion sickness, however, the molecular mechanisms by which histamine modulates vestibular function remain unclear. During recovery from the lesion, the modulation of histamine receptors in the medial vestibular nucleus (MVN and the flocculus may play an important role. Here with the means of quantitative real-time PCR, western blotting and immunohistochemistry, we studied the expression of histamine receptors (H1, H2, and H3 in the bilateral MVN and the flocculus of rats on the 1st, 3rd, and 7th day following unilateral labyrinthectomy (UL. Our results have shown that on the ipsi-lesional flocculus the H1, H2 and H3 receptors mRNA and the protein increased significantly on the 1st and 3rd day, with compare of sham controls and as well the contralateral side of UL. However, on the 7th day after UL, this expression returned to basal levels. Furthermore, elevated mRNA and protein levels of H1, H2 and H3 receptors were observed in the ipsi-lesional MVN on the 1st day after UL compared with sham controls and as well the contralateral side of UL. However, this asymmetric expression was absent by the 3rd post-UL. Our findings suggest that the upregulation of histamine receptors in the MVN and the flocculus may contribute to rebalancing the spontaneous discharge in bilateral MVN neurons during vestibular compensation.

  13. Histamine Stimulates Ciliary Beat Frequency via the H2 Receptor in the Protochordate Botryllus schlosseri.

    Science.gov (United States)

    Cima, Francesca; Franchi, Nicola

    2016-05-01

    Histamine is a biogenic molecule that plays a role in many physiological pathways via binding to a specific receptor. Histaminergic receptors belong to the large family of seven-transmembrane α-helix domain receptors classified in mammals into four distinct classes: H1, H2, H3, and H4. Despite being widely studied in vertebrates, few data are available on the invertebrate receptors, with only predicted H1 and H2 sequences for nonchordate deuterostomes. Here, we report the first characterized transcript sequence for an H2 receptor from the colonial ascidian Botryllus schlosseri, describing the localization of both transcript and protein during blastogenic development through in situ hybridization and immunohistochemistry. Its phylogenetic relationships with deuterostome orthologous proteins are reported, its role in ciliary beat frequency (CBF) in cultured stigma cells of the branchial basket is outlined, and the effects of histamine and its receptor agonists and antagonists are analyzed. In the presence of increasing concentrations of histamine in the medium, CBF increases similarly to the selective H2 receptor agonist dimaprit. In contrast, ranitidine, which is an inhibitor of the H2 receptor, causes a significant inhibition of CBF, similar to that observed after preincubation with the specific anti-BsHRH2 or the anti-human HRH2 antibody. In cells bordering the branchial basket stigmata, both antibodies colocalize in the proximal region of the ciliary plasmalemma, and histamine is present inside vesicles of the apical region, thus supporting the hypothesis of a histamine-binding H2 receptor control of the pharyngeal mucociliary transport similar to that of the upper respiratory tract and middle ear in mammals. PMID:27139577

  14. TRPV1 and PLC Participate in Histamine H4 Receptor-Induced Itch.

    Science.gov (United States)

    Jian, Tunyu; Yang, Niuniu; Yang, Yan; Zhu, Chan; Yuan, Xiaolin; Yu, Guang; Wang, Changming; Wang, Zhongli; Shi, Hao; Tang, Min; He, Qian; Lan, Lei; Wu, Guanyi; Tang, Zongxiang

    2016-01-01

    Histamine H4 receptor has been confirmed to play a role in evoking peripheral pruritus. However, the ionic and intracellular signaling mechanism of activation of H4 receptor on the dorsal root ganglion (DRG) neurons is still unknown. By using cell culture and calcium imaging, we studied the underlying mechanism of activation of H4 receptor on the DRG neuron. Immepip dihydrobromide (immepip)-a histamine H4 receptor special agonist under cutaneous injection-obviously induced itch behavior of mice. Immepip-induced scratching behavior could be blocked by TRPV1 antagonist AMG9810 and PLC pathway inhibitor U73122. Application of immepip (8.3-50 μM) could also induce a dose-dependent increase in intracellular Ca(2+) ([Ca(2+)]i) of DRG neurons. We found that 77.8% of the immepip-sensitized DRG neurons respond to the TRPV1 selective agonist capsaicin. U73122 could inhibit immepip-induced Ca(2+) responses. In addition, immepip-induced [Ca(2+)]i increase could be blocked by ruthenium red, capsazepine, and AMG9810; however it could not be blocked by TRPA1 antagonist HC-030031. These results indicate that TRPV1 but not TRPA1 is the important ion channel to induce the DRG neurons' responses in the downstream signaling pathway of histamine H4 receptor and suggest that TRPV1 may be involved in the mechanism of histamine-induced itch response by H4 receptor activation. PMID:26819760

  15. TRPV1 and PLC Participate in Histamine H4 Receptor-Induced Itch

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    Tunyu Jian

    2016-01-01

    Full Text Available Histamine H4 receptor has been confirmed to play a role in evoking peripheral pruritus. However, the ionic and intracellular signaling mechanism of activation of H4 receptor on the dorsal root ganglion (DRG neurons is still unknown. By using cell culture and calcium imaging, we studied the underlying mechanism of activation of H4 receptor on the DRG neuron. Immepip dihydrobromide (immepip—a histamine H4 receptor special agonist under cutaneous injection—obviously induced itch behavior of mice. Immepip-induced scratching behavior could be blocked by TRPV1 antagonist AMG9810 and PLC pathway inhibitor U73122. Application of immepip (8.3–50 μM could also induce a dose-dependent increase in intracellular Ca2+ (Ca2+i of DRG neurons. We found that 77.8% of the immepip-sensitized DRG neurons respond to the TRPV1 selective agonist capsaicin. U73122 could inhibit immepip-induced Ca2+ responses. In addition, immepip-induced Ca2+i increase could be blocked by ruthenium red, capsazepine, and AMG9810; however it could not be blocked by TRPA1 antagonist HC-030031. These results indicate that TRPV1 but not TRPA1 is the important ion channel to induce the DRG neurons’ responses in the downstream signaling pathway of histamine H4 receptor and suggest that TRPV1 may be involved in the mechanism of histamine-induced itch response by H4 receptor activation.

  16. Histamine-induced end-tidal inspiratory activity and lung receptors in cats.

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    Meeseen, N E; van der Grinten, C P; Folgering, H T; Luijendijk, S C

    1995-12-01

    Hyperinflation in acute asthma has been associated with inspiratory muscle activity, which persist during expiration. The main objective of the present study was to evaluate the role of rapidly adapting receptors (RARs), slowly adapting receptors (SARs) and C-fibre endings in generating end-tidal inspiratory activity (ETIA). ETIA was induced by intravenous administration of histamine and continuous negative airway pressure (CNAP) in anaesthetized, spontaneously breathing cats. To differentiate between reflex activities from the three types of lung receptors, both vagus nerves were cooled to eight different temperatures (Tvg) between 4 and 37 degrees C. It is known that CNAP stimulates RARs and inhibits SARs. Histamine was used to stimulate RARs, and this was combined with continuous positive airway pressure (CPAP) to further stimulate SARs. ETIA was evoked in the diaphragm and in parasternal intercostal muscles by both stimuli (histamine and CNAP) in 8 out of 18 cats. After vagotomy, neither histamine nor CNAP evoked ETIA any more. At Tvg = 37 degrees C, CPAP suppressed histamine-induced ETIA; whereas, this suppression was diminished at Tvg between 14 and 8 degrees C. ETIA sharply declined for Tvg between 8 degrees and 4 degrees C, and at Tvg = 4 degrees C ETIA had virtually disappeared. At Tvg = 37 degrees and 22 degrees C values of ETIA during CNAP were larger than those in response to histamine; whereas, at Tvg = 10 degrees C comparable ETIA values were obtained. It was shown that ETIA is a vagal reflex activity in which C-fibre endings are not involved. Histamine-induced ETIA originates from stimulation of RARs, and is inhibited by stimulation of SARs. Mechanical stimulation of RARs is a forceful stimulus to induce ETIA. This suggests that hyperinflation in acute asthma might be due, at least in part, to ETIA resulting from an imbalance between SAR and RAR activity. PMID:8666106

  17. Pathogenetic and therapeutic implications of the histamine H4 receptor in inflammatory skin diseases and pruritus.

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    Gutzmer, Ralf; Gschwandtner, Maria; Rossbach, Kristine; Mommert, Susanne; Werfel, Thomas; Kietzmann, Manfred; Baeumer, Wolfgang

    2011-01-01

    Chronic inflammatory skin diseases such as atopic dermatitis (AD) are clinically characterized by erythematous and pruritic skin lesions, immunologically mediated by an inflammatory infiltrate consisting of T-cells, antigen presenting cells (APC) and eosinophilic granulocytes. Histamine levels are increased in lesions of inflammatory skin diseases. It is likely that histamine also plays a pathogenetic role since various relevant cell types such as T-cells and APC express functional histamine receptors. However, therapeutic blockade of the histamine H1 and H2 receptor is inefficient at least in the treatment of atopic dermatitis. We summarize here current data on the role of the recently described histamine H4 receptor (H4R) in chronic inflammatory skin diseases. The H4R is functionally expressed on relevant cell types such as T-cells, APC and keratinocytes. In murine models of contact hypersensitivity and pruritus, H4R blockade had significant in vivo effects. Taken together, several lines of evidence suggest a role of the H4R in chronic inflammatory skin disease and the H4R might be a therapeutic target for diseases such as AD. PMID:21622248

  18. Cardiac mast cells regulate myocyte ANP release via histamine H2 receptor in beating rabbit atria.

    Science.gov (United States)

    Li, Dan; Wen, Jin Fu; Jin, Jing Yu; Quan, He Xiu; Cho, Kyung Woo

    2009-06-01

    It has been shown that histamine inhibits atrial natriuretic peptide (ANP) release. Because cardiac mast cells are the principal source of histamine in the heart, we hypothesized that cardiac mast cells are involved in the regulation of atrial ANP release. To test the hypothesis, experiments were performed in perfused beating rabbit atria allowing atrial pacing and measurements of changes in atrial stroke volume, intraatrial pulse pressure and myocyte ANP release. Mast cell degranulation with Compound 48/80 decreased atrial myocyte ANP release, and the response was blocked by a selective histamine H(2) receptor blocker, cimetidine, indicating that histamine was responsible for the decrease in ANP release. Mast cell stabilization with cromolyn blocked the Compound 48/80-induced decrease in ANP release. These data suggest that mast cell-derived histamine is involved in the regulation of cardiac ANP release. Thus, the cardiac mast cell-cardiomyocyte communication via the histamine-ANP pathway may implicate in the cardiac disorder associated with mast cell degranulation such as in acute coronary syndrome or cardiac hypertrophy. PMID:19328828

  19. Partial involvement of NMDA receptors and glial cells in the nociceptive behaviors induced by intrathecally administered histamine.

    Science.gov (United States)

    Mizoguchi, Hirokazu; Komatsu, Takaaki; Iwata, Yoko; Watanabe, Chizuko; Watanabe, Hiroyuki; Orito, Tohru; Katsuyama, Soh; Yonezawa, Akihiko; Onodera, Kenji; Sakurada, Tsukasa; Sakurada, Shinobu

    2011-05-16

    The involvement of spinal glial cells in the nociceptive behaviors induced by 800 pmol of histamine was determined in mice. Histamine at 800 pmol injected intrathecally (i.t.) produced nociceptive behaviors, consisting of scratching, biting and licking. The nociceptive behaviors induced by histamine were significantly suppressed by i.t. co-administration with tachykinin NK(1) receptor antagonist CP99,994 or competitive antagonist for N-methyl-d-aspartate (NMDA) receptor d-(-)-2-amino-5-phosphonovaleric acid (d-APV). The i.t. pretreatment with the glial cell inhibitor dl-fluorocitric acid or minocycline failed to affect the nociceptive behaviors induced by histamine. However, in mice pretreated i.t. with dl-fluorocitric acid or minocycline, the nociceptive behaviors induced by histamine were significantly suppressed by i.t. co-administration with CP99,994 but not d-APV. In Western blot analysis using lumbar spinal cords, i.t. treatment with 800 pmol of histamine increased the phosphorylation of the NR1 subunit of NMDA receptors. The increased phosphorylation of the NR1 subunit of NMDA receptors by histamine was abolished by i.t. pretreatment with dl-fluorocitric acid or minocycline. The present results suggest that histamine at 800 pmol elicits nociceptive behaviors through activation of the neuronal NK(1) receptor and the NR1 subunit-containing NMDA receptors on glial cells in the spinal cord. PMID:21352890

  20. Calyx and dimorphic neurons of mouse Scarpa's ganglion express histamine H3 receptors

    Directory of Open Access Journals (Sweden)

    Zucca Gianpiero

    2009-06-01

    Full Text Available Abstract Background Histamine-related drugs are commonly used in the treatment of vertigo and related vestibular disorders. The site of action of these drugs however has not been elucidated yet. Recent works on amphibians showed that histamine H3 receptor antagonists, e.g. betahistine, inhibit the afferent discharge recorded from the vestibular nerve. To assess the expression of H3 histamine receptors in vestibular neurons, we performed mRNA RT-PCR and immunofluorescence experiments in mouse Scarpa's ganglia. Results RT-PCR analysis showed the presence of H3 receptor mRNA in mouse ganglia tissue. H3 protein expression was found in vestibular neurons characterized by large and roundish soma, which labeled for calretinin and calbindin. Conclusion The present results are consistent with calyx and dimorphic, but not bouton, afferent vestibular neurons expressing H3 receptors. This study provides a molecular substrate for the effects of histamine-related antivertigo drugs acting on (or binding to H3 receptors, and suggest a potential target for the treatment of vestibular disorders of peripheral origin.

  1. Characterization of histamine receptors in isolated pig basilar artery by functional and radioligand binding studies

    International Nuclear Information System (INIS)

    Histamine receptors in pig basilar arteries were investigated in vitro by radioligand binding assays and by measuring the contractile and relaxant responses to histamine. Histamine and 2-pyridyethylamine (H1-agonist) induced concentration-dependent contractions, whereas impromidine (H2-agonist) induced concentration-dependent relaxations. These responses were independent of the presence of endothelial cells. Diphenhydramine (H1-antagonist) partially reversed the histamine-induced contractions to relaxations. Cimetidine (Hα2-antagonist) potentiated the contraction in a concentration-dependent manner. In the presence of cimetidine, the pEC50 value of histamine for the contraction was 6.30, and diphenhydramine competitively antagonized the histamine-induced contractions (pA2, 7.77). In the presence of diphenhydramine, the pEC50 value of histamine for the relaxation was 5.93, and cimetidine competitively antagonized the histamine-induced relaxations (pA2, 6.62). In the binding studies, the Kd value of [3H]mepyramine was 2.1 nM and the Bmax value was 95.6 fmol/mg protein. A competition experiment with diphenhydramine showed that the pKi value (7.51) was similar to the pA2 value. The Kd value for [3H]cimetidine was 126.0 nM and the Bmax value was 459.8 fmol/mg protein. The pKd (6.90) for [3H]cimetidine was similar to the pA2 for cimetidine. The Hill coefficients for these experiments were not significantly different from unity. The present findings indicate that the number of H1-receptors, in terms of the Bmax value for [3H]mepyramine, is smaller than that of H2-receptors, in terms of the Bmax value for [3H]cimetidine. However, the contractile response to histamine is predominantly mediated through stimulation of H1-receptors on vascular smooth muscle cells in pig basilar artery

  2. Histamine-induced inhibition of leukotriene biosynthesis in human neutrophils: involvement of the H2 receptor and cAMP

    OpenAIRE

    Flamand, Nicolas; Plante, Hendrick; Picard, Serge; Laviolette, Michel; Borgeat, Pierre

    2004-01-01

    Histamine is generally regarded as a pro-inflammatory mediator in diseases such as allergy and asthma. A growing number of studies, however, suggest that this autacoid is also involved in the downregulation of human polymorphonuclear leukocyte (PMN) functions and inflammatory responses through activation of the Gs-coupled histamine H2 receptor.We report here that histamine inhibits thapsigargin- and ligand (PAF and fMLP)-induced leukotriene (LT) biosynthesis in human PMN in a dose-dependent m...

  3. Desipramine inhibits histamine H1 receptor-induced Ca2+ signaling in rat hypothalamic cells.

    Directory of Open Access Journals (Sweden)

    Ji-Ah Kang

    Full Text Available The hypothalamus in the brain is the main center for appetite control and integrates signals from adipose tissue and the gastrointestinal tract. Antidepressants are known to modulate the activities of hypothalamic neurons and affect food intake, but the cellular and molecular mechanisms by which antidepressants modulate hypothalamic function remain unclear. Here we have investigated how hypothalamic neurons respond to treatment with antidepressants, including desipramine and sibutramine. In primary cultured rat hypothalamic cells, desipramine markedly suppressed the elevation of intracellular Ca(2+ evoked by histamine H1 receptor activation. Desipramine also inhibited the histamine-induced Ca(2+ increase and the expression of corticotrophin-releasing hormone in hypothalamic GT1-1 cells. The effect of desipramine was not affected by pretreatment with prazosin or propranolol, excluding catecholamine reuptake activity of desipramine as an underlying mechanism. Sibutramine which is also an antidepressant but decreases food intake, had little effect on the histamine-induced Ca(2+ increase or AMP-activated protein kinase activity. Our results reveal that desipramine and sibutramine have different effects on histamine H1 receptor signaling in hypothalamic cells and suggest that distinct regulation of hypothalamic histamine signaling might underlie the differential regulation of food intake between antidepressants.

  4. Pharmacological Evidence that Histamine H3 Receptors Mediate Histamine-Induced Inhibition of the Vagal Bradycardic Out-flow in Pithed Rats.

    Science.gov (United States)

    García, Mónica; García-Pedraza, José Ángel; Villalón, Carlos M; Morán, Asunción

    2016-02-01

    In vivo stimulation of cardiac vagal neurons induces bradycardia by acetylcholine (ACh) release. As vagal release of ACh may be modulated by autoreceptors (muscarinic M2 ) and heteroreceptors (including serotonin 5-HT1 ), this study has analysed the pharmacological profile of the receptors involved in histamine-induced inhibition of the vagal bradycardic out-flow in pithed rats. For this purpose, 180 male Wistar rats were pithed, artificially ventilated and pre-treated (i.v.) with 1 mg/kg atenolol, followed by i.v. administration of physiological saline (1 ml/kg), histamine (10, 50, 100 and 200 μg/kg) or the selective histamine H1 (2-pyridylethylamine), H2 (dimaprit), H3 (methimepip) and H4 (VUF 8430) receptor agonists (1, 10, 50 and 100 μg/kg each). Under these conditions, electrical stimulation (3, 6 and 9 Hz; 15 ± 3 V and 1 ms) of the vagus nerve resulted in frequency-dependent bradycardic responses, which were (i) unchanged during the infusions of saline, 2-pyridylethylamine, dimaprit or VUF 8430; and (ii) dose-dependently inhibited by histamine or methimepip. Moreover, the inhibition of the bradycardia caused by 50 μg/kg of either histamine or methimepip (which failed to inhibit the bradycardic responses to i.v. bolus injections of acetylcholine; 1-10 μg/kg) was abolished by the H3 receptor antagonist JNJ 10181457 (1 mg/kg, i.v.). In conclusion, our results suggest that histamine-induced inhibition of the vagal bradycardic out-flow in pithed rats is mainly mediated by pre-junctional activation of histamine H3 receptors, as previously demonstrated for the vasopressor sympathetic out-flow and the vasodepressor sensory CGRPergic (calcitonin gene-related peptide) out-flow. PMID:26301462

  5. Histamine, histamine intoxication and intolerance.

    Science.gov (United States)

    Kovacova-Hanuskova, E; Buday, T; Gavliakova, S; Plevkova, J

    2015-01-01

    Excessive accumulation of histamine in the body leads to miscellaneous symptoms mediated by its bond to corresponding receptors (H1-H4). Increased concentration of histamine in blood can occur in healthy individuals after ingestion of foods with high contents of histamine, leading to histamine intoxication. In individuals with histamine intolerance (HIT) ingestion of food with normal contents of histamine causes histamine-mediated symptoms. HIT is a pathological process, in which the enzymatic activity of histamine-degrading enzymes is decreased or inhibited and they are insufficient to inactivate histamine from food and to prevent its passage to blood-stream. Diagnosis of HIT is difficult. Multi-faced, non-specific clinical symptoms provoked by certain kinds of foods, beverages and drugs are often attributed to different diseases, such as allergy and food intolerance, mastocytosis, psychosomatic diseases, anorexia nervosa or adverse drug reactions. Correct diagnosis of HIT followed by therapy based on histamine-free diet and supplementation of diamine oxidase can improve patient's quality of life. PMID:26242570

  6. Histamine H4 receptor antagonists for the treatment of inflammatory disorders.

    Science.gov (United States)

    Liu, Wai L

    2014-08-01

    Since its initial discovery by Sir Henry Dale and Patrick Laidlaw in 1910, the biogenic amine histamine has been one of the most widely researched molecules in science. H4R, the newest member of the histamine receptor family, was first identified at the turn of the millennium. Its predominant expression on inflammatory cells and lymphoid tissues, coupled with a key role in processes ranging from chemotaxis to cytokine release, suggests it could command an important role in immune and inflammatory responses. PMID:24859018

  7. The histamine H4 receptor is a potent inhibitor of adhesion-dependent degranulation in human neutrophils.

    Science.gov (United States)

    Dib, Karim; Perecko, Tomas; Jenei, Veronika; McFarlane, Cheryl; Comer, David; Brown, Vanessa; Katebe, Mwape; Scheithauer, Torsten; Thurmond, Robin L; Chazot, Paul L; Ennis, Madeleine

    2014-09-01

    The histamine H4 receptor regulates the inflammatory response. However, it is not known whether this receptor has a functional role in human neutrophils. We found that fMLP (1 μM), but not histamine (0.1-1 μM), induced Mac-1-dependent adhesion, polarization, and degranulation (release of lactoferrin). A pretreatment of neutrophils with histamine (0.001-1 μM) or JNJ 28610244 (0.1-10 μM), a specific H4 receptor agonist, led to inhibition of degranulation. Total inhibition of degranulation was obtained with 0.1 μM histamine and 10 μM JNJ 28610244. Furthermore, such inhibition by histamine of degranulation was reversed by JNJ 7777120 and JNJ 28307474, two selective H4 receptor antagonists. However, neither histamine nor the H4 receptor agonist JNJ 28610244 prevented fMLP-induced, Mac-1-dependent adhesion, indicating that the H4 receptor may block signals emanating from Mac-1-controlling degranulation. Likewise, engagement of the H4 receptor by the selective agonist JNJ 28610244 blocked Mac-1-dependent activation of p38 MAPK, the kinase that controls neutrophil degranulation. We also show expression of the H4 receptor at the mRNA level in ultrapure human neutrophils and myeloid leukemia PLB-985 cells. We concluded that engagement of this receptor by selective H4 receptor agonists may represent a good, therapeutic approach to accelerate resolution of inflammation. PMID:24799603

  8. Roles of histamine and its receptors in allergic and inflammatory bowel diseases

    Institute of Scientific and Technical Information of China (English)

    Hua Xie; Shao-Heng He

    2005-01-01

    Mast cell has a long history of being recognized as an important mediator-secreting cell in allergic diseases, and has been discovered to be involved in IBD in last two decades. Histamine is a major mediator in allergic diseases, and has multiple effects that are mediated by specific surface receptors on target cells. Four types of histamine receptors have now been recognized pharmacologically and the first three are located in the gut. The ability of histamine receptor antagonists to inhibit mast cell degranulation suggests that they might be developed as a group of mast cell stabilizers. Recently, a series of experiments with dispersed colon mast cells suggested that there should be at least two pathways in man for mast cells to amplify their own activation-degranulation signals in an autocrine or paracrine manner. In a word, histamine is an important mediator in allergic diseases and IBD, its antagonists may be developed as a group of mast cell stabilizers to treat these diseases.

  9. Modifications of histamine receptor signaling affect bone mechanical properties in rats.

    Science.gov (United States)

    Folwarczna, Joanna; Janas, Aleksandra; Pytlik, Maria; Śliwiński, Leszek; Wiercigroch, Marek; Brzęczek, Anna

    2014-02-01

    Histamine receptors are expressed on bone cells and histamine may be involved in regulation of bone metabolism. The aim of the present study was to investigate the effects of loratadine (an H(1) receptor antagonist), ranitidine (an H(2) receptor antagonist) and betahistine (an H(3) receptor antagonist and H(1) receptor agonist) on bone mechanical properties in rats. Loratadine (5 mg/kg/day, po), ranitidine (50 mg/kg/day, po), or betahistine dihydrochloride (5 mg/kg/day, po), were administered for 4 weeks to non-ovariectomized and bilaterally ovariectomized (estrogen-deficient) 3-month-old rats, and their effects were compared with appropriate controls. Serum levels of bone turnover markers, bone mineralization and mechanical properties of the proximal tibial metaphysis, femoral diaphysis and femoral neck were studied. In rats with normal estrogen level, administration of loratadine slightly favorably affected mechanical properties of compact bone, significantly increasing the strength of the femoral neck (p < 0.05), and tending to increase the strength of the femoral diaphysis. Ranitidine did not significantly affect the investigated parameters, and betahistine decreased the strength of the tibial metaphysis (cancellous bone, p < 0.01). There were no significant effects of the drugs on serum bone turnover markers. In estrogen-deficient rats, the drugs did not significantly affect the investigated skeletal parameters. In conclusion, the effects of histamine H(1), H(2) and H(3) receptor antagonists on the skeletal system in rats were differential and dependent on estrogen status. PMID:24905313

  10. Expression cloning of a cDNA encoding the bovine histamine H1 receptor.

    OpenAIRE

    Yamashita, M; Fukui, H; Sugama, K; Horio, Y; Ito, S.; Mizuguchi, H.; Wada, H

    1991-01-01

    A functional cDNA clone for the histamine H1 receptor was isolated from a cDNA library of bovine adrenal medulla by a combination of molecular cloning in an expression vector and electrophysiological assay in Xenopus oocytes. The H1 receptor cDNA encodes a protein of 491 amino acids (Mr 55,954) with seven putative transmembrane domains, illustrating the similarity to other receptors that couple with guanine nucleotide-binding regulatory proteins (G protein-coupled receptors). The sequence hom...

  11. Proinflammatory role of the histamine H4 receptor in dextrane sodium sulfate-induced acute colitis.

    Science.gov (United States)

    Schirmer, Bastian; Rezniczek, Thomas; Seifert, Roland; Neumann, Detlef

    2015-11-01

    Millions of people worldwide are suffering from inflammatory bowel disease (IBD), which severely affects patients' life qualities and even life expectancies. The cause of the ailment is unknown and a profound understanding of the underlying pathogenetic mechanisms is still lacking. The biogenic amine histamine is one of several inflammatory mediators, to which a pathogenetic role in IBD has been attributed. Out of the four known histamine receptors, the histamine H4 receptor (H4R) has been demonstrated to act proinflammatory in experimental models of several inflammatory diseases. In order to evaluate a potential involvement of H4R in IBD we investigated the effect of genetic or pharmacological blockade of H4R-signaling in the model of dextran sodium sulfate (DSS)-induced colitis in mice. We analysed severity and progression of clinical signs of colitis, as well as histopathologic alterations in the colons and systemic or local cytokine concentrations. Both genetic deficiency and pharmacological blockade of H4R with the selective antagonist JNJ7777120 improved clinical and histological signs of colitis and dampened the inflammatory cytokine response. Our results indicate a proinflammatory role of histamine via H4R in IBD, thus extending the current pathophysiological understanding of IBD and demonstrating the therapeutic potential of selective H4R-antagonists for patients suffering from IBD. PMID:26365468

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

    Science.gov (United States)

    Fabbri, Roberta; Furini, Cristiane Regina Guerino; Passani, Maria Beatrice; Provensi, Gustavo; Baldi, Elisabetta; Bucherelli, Corrado; Izquierdo, Ivan; de Carvalho Myskiw, Jociane; Blandina, Patrizio

    2016-05-10

    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. PMID:27118833

  13. Localization of histamine (H1, H2, H3 and H4) receptors in mouse inner ear.

    Science.gov (United States)

    Takumida, Masaya; Takumida, Hiroshi; Anniko, Matti

    2016-06-01

    Conclusion The present findings show that all four types of histamine receptors (H1R, H2R, H3R, and H4R) are present in the inner ear, thus supporting the hypothesis that histamine plays a physiological role in the inner ear. Objective To analyse the presence of histamine receptors in the normal mouse inner ear. Methods CBA/J mice were used in this study. The localization of H1R, H2R, H3R, and H4R in the inner ear, i.e. cochlea, vestibular end organs, vestibular ganglion, and endolymphatic sac, was studied by real-time PCR and immunohistochemistry. Results The mRNA for each receptor sub-type was detected in the inner ear. In the immunohistochemical study, the organ of Corti, spiral ganglion, vestibular ganglion, vestibular sensory epithelium, and endolymphatic sac cells showed an immunofluorescent reaction to all histamine receptors. PMID:26854127

  14. Identification of histaminic (H1-type receptors in small intestine of broilers by application of histamine and some of its agonists and antagonists

    Directory of Open Access Journals (Sweden)

    Mujezinović Indira

    2010-01-01

    Full Text Available Histamine is a biologically active amine (biogenic amine that has a broad spectra of physiologic and pathologic reactions in the organism. Its effects are shown through 4 types of specific receptors (H1, H2, H3 and H4. Histamine is one of the main causes of intestine disorders and the occurrence of diarrhea, both of which are very common in broilers. Whilst there is no information in scientific literature about the presence of histaminic receptors in smooth muscles of the small intestine wall of broilers (duodenum, jejunum and ileum, we tried to determine their presence, distribution and type in this kind of muscles. Investigations were carried out on isolated smooth muscles of the circular and longitudinal layer of the broiler small intestine (strip dimension 3-4 mm x 2 cm. The muscle strip was then placed in an isolated organ bath and the contractions obtained were registered with isometric transducers on a two-channel printer. This was done following the addition of histamine, betahistine (H1 agonist, and mepiramine (H1 antagonist. Muscle vitality was checked by adding acethylcholine chloride. Using the obtained results, it can be concluded that H1 types of histaminergic receptors are present in smooth muscles of the small intestine of broilers. .

  15. Association of genetic variants of the histamine H1 and muscarinic M3 receptors with BMI and HbA1c values in patients on antipsychotic medication

    NARCIS (Netherlands)

    Vehof, Jelle; Risselada, Arne J.; Al Hadithy, Asmar F. Y.; Burger, Huibert; Snieder, Harold; Wilffert, Bob; Arends, Johan; Wunderink, Lex; Knegtering, Henrikus; Wiersma, Durk; Cohen, Dan; Mulder, Hans; Bruggeman, Richard

    2011-01-01

    Antipsychotic affinity for the histamine H1 receptor and the muscarinic M3 receptor have been associated with the side effects weight gain, and development of diabetes, respectively. We investigated polymorphisms of the histamine H1 (HRH1) and muscarinic acetylcholine receptor M3 (CHRM3) receptor ge

  16. Cellular analysis of the histamine H4 receptor in human myeloid cells.

    Science.gov (United States)

    Capelo, Ricardo; Lehmann, Christoph; Ahmad, Khalil; Snodgrass, Ryan; Diehl, Olaf; Ringleb, Julia; Flamand, Nicolas; Weigert, Andreas; Stark, Holger; Steinhilber, Dieter; Kahnt, Astrid S

    2016-03-01

    The human histamine H4 receptor (H4R) is a Gαi/o-coupled receptor which is mainly expressed on hematopoietic cells. Accordingly, the receptor is implicated in the pathology of various diseases such as autoimmune disorders, bronchial asthma and pruritus. Due to complicated receptor pharmacology, the lack of a reliable antibody and limited availability of primary cells expressing the receptor the physiology of this receptor is still poorly understood. Therefore, we aimed to assess absolute receptor mRNA expression and functionality (intracellular Ca(2+) release) in various human myeloid cell types such as granulocytes, monocytes, macrophages and dendritic cells (DCs). This was put into context with the expression of the H1R and H2R. In addition, the influence of various inflammatory stimuli on H4R expression was investigated in macrophages and monocyte-derived DCs. We found that classically activated macrophages treated with pro-inflammatory stimuli down-regulated histamine receptor mRNA expression as did LPS and zymosan A matured monocyte-derived DCs. In contrast, alternatively activated macrophages (IL-4 or IL-13) upregulated H2R and H4R expression compared to controls. Consistent with existing literature, we found eosinophils to be the major source of the H4R. Since availability of primary eosinophils is limited, we developed a cell model based on the differentiated eosinophilic cell line EOL-1, in which H4R pharmacology and physiology may be studied. PMID:26774453

  17. Involvement of H1 and H2 receptors and soluble guanylate cyclase in histamine-induced relaxation of rat mesenteric collecting lymphatics

    Science.gov (United States)

    Kurtz, Kristine H.; Moor, Andrea N.; Souza-Smith, Flavia M.; Breslin, Jerome W.

    2014-01-01

    Objective This study investigated the roles of the H1 and H2 histamine receptors, nitric oxide (NO) synthase, and soluble guanylate (sGC) cyclase in histamine-induced modulation of rat mesenteric collecting lymphatic pumping. Methods Isolated rat mesenteric collecting lymphatics were treated with 1–100 μM histamine. Histamine receptors were blocked with either the H1 antagonist mepyramine or the H2 antagonist cimetidine. The role of NO/sGC signaling was tested using the arginine analog L-NAME, the sGC inhibitor ODQ, and sodium nitroprusside (SNP) as a positive control. Results Histamine applied at 100 μM decreased tone and contraction frequency (CF) of isolated rat mesenteric collecting lymphatics. Pharmacologic blockade of either H1 or H2 histamine receptors significantly inhibited the response to histamine. Pretreatment with ODQ, but not L-NAME, completely inhibited the histamine-induced decrease in tone. ODQ pretreatment also significantly inhibited SNP-induced lymphatic relaxation. Conclusions H1 and H2 histamine receptors are both involved in histamine-induced relaxation of rat mesenteric collecting lymphatics. NO synthesis does not appear to contribute to the histamine-induced response. However, sGC is critical for the histamine-induced decrease in tone and contributes to the drop in CF. PMID:24702851

  18. Rigidified 2-aminopyrimidines as histamine H4 receptor antagonists: effects of substitution about the rigidifying ring.

    Science.gov (United States)

    Koenig, John R; Liu, Huaqing; Drizin, Irene; Witte, David G; Carr, Tracy L; Manelli, Arlene M; Milicic, Ivan; Strakhova, Marina I; Miller, Thomas R; Esbenshade, Timothy A; Brioni, Jorge D; Cowart, Marlon

    2010-03-15

    Three novel series of histamine H(4) receptor (H(4)R) antagonists containing the 2-aminopyrimidine motif are reported. The best of these compounds display good in vitro potency in both functional and binding assays. In addition, representative compounds are able to completely block itch responses when dosed ip in a mouse model of H(4)-agonist induced scratching, thus demonstrating their activities as H(4)R antagonists. PMID:20171098

  19. Modulation of tissue inflammatory response by histamine receptors in scorpion envenomation pathogenesis: involvement of H4 receptor.

    Science.gov (United States)

    Lamraoui, Amal; Adi-Bessalem, Sonia; Laraba-Djebari, Fatima

    2014-10-01

    The inflammatory response caused by scorpion venoms is a key event in the pathogenesis of scorpion envenomation. This response was assessed in the cardiac, pulmonary, and gastric tissues of envenomed mice. The results reveal an increase of permeability in cardiac, pulmonary, and gastric vessels accompanied by an edema-forming, inflammatory cell infiltration, and imbalanced redox status. These effects are correlated with severe tissue alterations and concomitant increase of metabolic enzymes in sera. Pretreatment of mice with antagonists of H1, H2, or H4 receptors markedly alleviated these alterations in the heart and lungs. Nevertheless, the blockade of the H3 receptor slightly reduced these disorders. Histamine H2 and H4 receptors were the most pharmacological targets involved in the gastric oxidative inflammation. These findings could help to better understand the role of histamine in scorpion venom-induced inflammatory response and propose new therapy using as targets the H4 receptor in addition to histamine H1 and H2 receptors to attenuate the induced inflammatory disorders encountered in scorpion envenoming. PMID:24858599

  20. Quantitative Single-Cell Analysis of Signaling Pathways Activated Immediately Downstream of Histamine Receptor Subtypes.

    Science.gov (United States)

    van Unen, Jakobus; Rashidfarrokhi, Ali; Hoogendoorn, Eelco; Postma, Marten; Gadella, Theodorus W J; Goedhart, Joachim

    2016-09-01

    Genetically encoded biosensors based on Förster resonance energy transfer (FRET) can visualize responses of individual cells in real time. Here, we evaluated whether FRET-based biosensors provide sufficient contrast and specificity to measure activity of G-protein-coupled receptors. The four histamine receptor subtypes (H1R, H2R, H3R, and H4R) respond to the ligand histamine by activating three canonical heterotrimeric G-protein-mediated signaling pathways with a reported high degree of specificity. Using FRET-based biosensors, we demonstrate that H1R activates Gαq. We also observed that H1R activates Gαi, albeit at a 10-fold lower potency. In addition to increasing cAMP levels, most likely via Gαs, we found that the H2R induces Gαq-mediated calcium release. The H3R and H4R activated Gαi with high specificity and a high potency. We demonstrate that a number of FRET sensors provide sufficient contrast to: 1) analyze the specificity of the histamine receptor subtypes for different heterotrimeric G-protein families with single-cell resolution, 2) probe for antagonist specificity, and 3) allow the measurement of single-cell concentration-response curves. PMID:27358232

  1. Histamine H2 receptor blockade augments blood pressure responses to acute submaximal exercise in males.

    Science.gov (United States)

    Doh, Hyung-Woo; Stebbins, Charles L; Choi, Hyun-Min; Park, Joonsung; Nho, Hosung; Kim, Jong-Kyung

    2016-06-01

    Histamine is a potent vasodilator that has been found to increase during exercise. We tested the hypothesis that histamine would attenuate blood pressure (BP), cardiac output (CO), and vascular resistance responses to short-term, submaximal dynamic exercise during H2 receptor blockade. Fourteen healthy men (20-29 years of age) were studied. Systolic (SBP), diastolic (DBP), and mean arterial (MAP) BP and heart rate (HR) were assessed at rest and during the last minute of 10 min of submaximal cycling exercise (60% of peak oxygen consumption) in the absence and presence of histamine H2 receptor blockade (ranitidine, 300 mg). Stroke volume (SV) (impedance cardiography) and plasma norepinephrine (NE) were measured, and CO, rate × pressure product (RPP), and total peripheral resistance (TPR) were calculated. Plasma levels of histamine were also measured. H2 blockade had no effects on any variables at rest. During exercise, SBP (184 ± 3 mm Hg vs. 166 ± 2 mm Hg), MAP (121 ± 2 mm Hg vs. 112 ± 5 mm Hg), and RPP (25.9 ± 0.8 × 10(3) mm Hg·beats/min vs. 23.5 ± 0.8 × 10(3) mm Hg/beats·min) were greater during blocked conditions (P < 0.05), and an interaction was observed for TPR. SV, DBP, HR, and NE levels were unaffected by blockade. Plasma histamine increased from 1.83 ± 0.14 ng/mL at rest to 2.33 ± 0.23 ng/mL during exercise (P < 0.05) and was not affected by H2 blockade (1.56 ± 0.23 ng/mL vs. 1.70 ± 0.24 ng/mL). These findings suggest that, during submaximal exercise, histamine attenuates BP, vascular resistance, and the work of the heart via activation of H2 receptors and that these effects occurred primarily in the vasculature and not in the myocardium. PMID:27191340

  2. Synthesis and functional characterization of imbutamine analogs as histamine H3 and H4 receptor ligands.

    Science.gov (United States)

    Geyer, Roland; Kaske, Melanie; Baumeister, Paul; Buschauer, Armin

    2014-02-01

    Imbutamine (4-(1H-imidazol-4-yl)butanamine) is a potent histamine H3 (H3R) and H4 receptor (H4R) agonist (EC50 values: 3 and 66 nM, respectively). Aiming at improved selectivity for the H4R, the imidazole ring in imbutamine was methyl-substituted or replaced by various differently substituted heterocycles (1,2,3-triazoles, 1,2,4-triazoles, pyridines, pyrimidines) as potential bioisosteres. Investigations in [(35)S]GTPγS binding assays using membranes of Sf9 insect cells expressing the respective human histamine receptor subtype revealed only very weak activity of most of the synthesized hetarylalkylamines at both receptors. By contrast, the introduction of substituents at the 4-imidazolyl ring was most effective regarding H4R selectivity. This holds for methyl substitution in position 2 and, especially, in position 5. 5-Methylimbutamine (H4R: EC50  = 59 nM, α = 0.8) was equipotent with imbutamine at the hH4R, but revealed about 16-fold selectivity for the hH4R compared to the hH3R (EC50 980 nM, α = 0.36), whereas imbutamine preferred the hH3R. The functional activities were in agreement with radioligand binding data. The results support the hypothesis that, by analogy with histamine, methyl substitution in histamine homologs offers a way to shift the selectivity in favor of the H4R. PMID:24493592

  3. The histamine H₄ receptor antagonist, JNJ 39758979, is effective in reducing histamine-induced pruritus in a randomized clinical study in healthy subjects.

    Science.gov (United States)

    Kollmeier, Alexa; Francke, Klaus; Chen, Bin; Dunford, Paul J; Greenspan, Andrew J; Xia, Yichuan; Xu, Xie L; Zhou, Bei; Thurmond, Robin L

    2014-07-01

    The histamine H4 receptor (H4R) is a promising target for the treatment of pruritus. A clinical study was conducted to evaluate the safety and efficacy of the H4R antagonist, JNJ 39758979 [(R)-4-(3-amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine], on histamine-induced pruritus in healthy subjects. A single oral dose of 600 mg JNJ 39758979, 10 mg cetirizine, or placebo was administered in a randomized, three-period, double-blind, crossover study. Treatment periods were separated by 22-day washout periods. A histamine challenge was administered on day -1 and at 2 and 6 hours postdose on day 1 of each treatment period. The primary efficacy endpoint was the area under the curve (AUC) of pruritus score 0-10 minutes after the histamine challenge. Secondary efficacy endpoints included wheal and flare areas assessed 10 minutes after the histamine challenge. Safety was assessed for all subjects. Of the 24 enrolled subjects, 23 individuals completed the study. One subject withdrew after completing two treatment periods. Due to a carryover effect of JNJ 39758979, only treatment period 1 was used for pruritus-related evaluations. Compared with placebo, the reduction of the AUC of pruritus score was significant for JNJ 39758979 at 2 hours (P = 0.0248) and 6 hours (P = 0.0060), and for cetirizine at 6 hours (P = 0.0417). In all treatment periods, JNJ 39758979 did not demonstrate a significant decrease in wheal or flare at either time point, although a significant reduction was achieved with cetirizine at 2 and 6 hours (P 1 patient with JNJ 39758979 were headache (9%) and nausea (13%). In conclusion, JNJ 39758979 was effective in inhibiting histamine-induced pruritus in healthy subjects. PMID:24817035

  4. A search for presynaptic inhibitory histamine receptors in guinea-pig tissues: Further H3 receptors but no evidence for H4 receptors.

    Science.gov (United States)

    Petri, Doris; Schlicker, Eberhard

    2016-07-01

    The histamine H4 receptor is coupled to Gi/o proteins and expressed on inflammatory cells and lymphoid tissues; it was suggested that this receptor also occurs in the brain or on peripheral neurones. Since many Gi/o protein-coupled receptors, including the H3 receptor, serve as presynaptic inhibitory receptors, we studied whether the sympathetic neurones supplying four peripheral tissues and the cholinergic neurones in the hippocampus from the guinea-pig are equipped with release-modulating H4 and H3 receptors. For this purpose, we preincubated tissue pieces from the aorta, atrium, renal cortex and vas deferens with (3)H-noradrenaline and hippocampal slices with (3)H-choline and determined the electrically evoked tritium overflow. The stimulation-evoked overflow in the five superfused tissues was inhibited by the muscarinic receptor agonist oxotremorine, which served as a positive control, but not affected by the H4 receptor agonist 4-methylhistamine. The H3 receptor agonist R-α-methylhistamine inhibited noradrenaline release in the peripheral tissues without affecting acetylcholine release in the hippocampal slices. Thioperamide shifted the concentration-response curve of histamine in the aorta and the renal cortex to the right, yielding apparent pA2 values of 8.0 and 8.1, respectively, which are close to its affinity at other H3 receptors but higher by one log unit than its pKi at the H4 receptor of the guinea-pig. In conclusion, histamine H4 receptors could not be identified in five experimental models of the guinea-pig that are suited for the detection of presynaptic inhibitory receptors whereas H3 receptors could be shown in the peripheral tissues but not in the hippocampus. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID:26211976

  5. Histamine is required for H3 receptor-mediated alcohol reward inhibition, but not for alcohol consumption or stimulation

    Science.gov (United States)

    Vanhanen, J; Nuutinen, S; Lintunen, M; Mäki, T; Rämö, J; Karlstedt, K; Panula, P

    2013-01-01

    Background and Purpose Conflicting data have been published on whether histamine is inhibitory to the rewarding effects of abused drugs. The purpose of this study was to clarify the role of neuronal histamine and, in particular, H3 receptors in alcohol dependence-related behaviours, which represent the addictive effects of alcohol. Experimental Approach Alcohol-induced conditioned place preference (alcohol-CPP) was used to measure alcohol reward. Alcohol-induced locomotor stimulation, alcohol consumption and kinetics were also assessed. mRNA levels were quantified using radioactive in situ hybridization. Key Results Low doses of H3 receptor antagonists, JNJ-10181457 and JNJ-39220675, inhibited alcohol reward in wild-type (WT) mice. However, these H3 receptor antagonists did not inhibit alcohol reward in histidine decarboxylase knock-out (HDC KO) mice and a lack of histamine did not alter alcohol consumption. Thus H3 receptor antagonists inhibited alcohol reward in a histamine-dependent manner. Furthermore, WT and HDC KO mice were similarly stimulated by alcohol. The expression levels of dopamine D1 and D2 receptors, STEP61 and DARPP-32 mRNA in striatal subregions were unaltered in HDC KO mice. No differences were seen in alcohol kinetics in HDC KO compared to WT control animals. In addition, JNJ-39220675 had no effect on alcohol kinetics in WT mice. Conclusions and Implications These data suggest that histamine is required for the H3 receptor-mediated inhibition of alcohol-CPP and support the hypothesis that the brain histaminergic system has an inhibitory role in alcohol reward. Increasing neuronal histamine release via H3 receptor blockade could therefore be a novel way of treating alcohol dependence. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 PMID:23489295

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

    Science.gov (United States)

    Corrêa, Michelle Fidelis; dos Santos Fernandes, João Paulo

    2015-04-01

    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. PMID:25228262

  7. Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases.

    Science.gov (United States)

    Sadek, Bassem; Saad, Ali; Sadeq, Adel; Jalal, Fakhreya; Stark, Holger

    2016-10-01

    The potential contributions of the brain histaminergic system in neurodegenerative diseases, and the possiblity of histamine-targeting treatments is attracting considerable interests. The histamine H3 receptor (H3R) is expressed mainly in the central nervous system, and is, consequently, an attractive pharmacological target. Although recently described clinical trials have been disappointing in attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCH), numerous H3R antagonists, including pitolisant, demonstrate potential in the treatment of narcolepsy, excessive daytime sleepiness associated with cognitive impairment, epilepsy, and Alzheimer's disease (AD). This review focuses on the recent preclinical as well as clinical results that support the relevance of H3R antagonists for the treatment of cognitive symptoms in neuropsychiatric diseases, namely AD, epilepsy and SCH. The review summarizes the role of histaminergic neurotransmission with focus on these brain disorders, as well as the effects of numerous H3R antagonists on animal models and humans. PMID:27363923

  8. Identification and characterization of ZEL-H16 as a novel agonist of the histamine H3 receptor.

    Directory of Open Access Journals (Sweden)

    Ying Shi

    Full Text Available The histamine H3 receptor (H3R has been recognized as a promising target for the treatment of various central and peripheral nervous system diseases. In this study, a non-imidazole compound, ZEL-H16, was identified as a novel histamine H3 receptor agonist. ZEL-H16 was found to bind to human H3R with a Ki value of approximately 2.07 nM and 4.36 nM to rat H3R. Further characterization indicated that ZEL-H16 behaved as a partial agonist on the inhibition of forskolin-stimulated cAMP accumulation (the efficacy was 60% of that of histamine and activation of ERK1/2 signaling (the efficacy was 50% of that of histamine at H3 receptors, but acted as a full agonist just like histamin in the guinea-pig ileum contraction assay. These effects were blocked by pertussis toxin and H3 receptor specific antagonist thioperamide. ZEL-H16 showed no agonist or antagonist activities at the cloned human histamine H1, H2, and H4 receptors and other biogenic amine GPCRs in the CRE-driven reporter assay. Furthermore, our present data demonstrated that treatment of ZEL-H16 resulted in intensive H3 receptor internalization and delayed recycling to the cell surface as compared to that of control with treatment of histamine. Thus, ZEL-H16 is a novel and potent nonimidazole agonist of H3R, which might serve as a pharmacological tool for future investigations or as possible therapeutic agent of H3R.

  9. Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors.

    Science.gov (United States)

    Carlin, Jesse Lea; Tosh, Dilip K; Xiao, Cuiying; Piñol, Ramón A; Chen, Zhoumou; Salvemini, Daniela; Gavrilova, Oksana; Jacobson, Kenneth A; Reitman, Marc L

    2016-02-01

    Adenosine can induce hypothermia, as previously demonstrated for adenosine A1 receptor (A1AR) agonists. Here we use the potent, specific A3AR agonists MRS5698, MRS5841, and MRS5980 to show that adenosine also induces hypothermia via the A3AR. The hypothermic effect of A3AR agonists is independent of A1AR activation, as the effect was fully intact in mice lacking A1AR but abolished in mice lacking A3AR. A3AR agonist-induced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A3AR hypothermia is mediated, at least in part, via mast cells. Central agonist dosing had no clear hypothermic effect, whereas peripheral dosing of a non-brain-penetrant agonist caused hypothermia, suggesting that peripheral A3AR-expressing cells drive the hypothermia. Mast cells release histamine, and blocking central histamine H1 (but not H2 or H4) receptors prevented the hypothermia. The hypothermia was preceded by hypometabolism and mice with hypothermia preferred a cooler environmental temperature, demonstrating that the hypothermic state is a coordinated physiologic response with a reduced body temperature set point. Importantly, hypothermia is not required for the analgesic effects of A3AR agonists, which occur with lower agonist doses. These results support a mechanistic model for hypothermia in which A3AR agonists act on peripheral mast cells, causing histamine release, which stimulates central histamine H1 receptors to induce hypothermia. This mechanism suggests that A3AR agonists will probably not be useful for clinical induction of hypothermia. PMID:26606937

  10. Selective enhancement of histamine H1-receptor responses in guinea-pig ileal smooth muscle by 1,4-dithiothreitol.

    OpenAIRE

    Donaldson, J; Hill, S. J.

    1986-01-01

    1,4-Dithiothreitol (DTT; 1 mM, 30 min preincubation) produced a small, non-specific potentiation of spasmogenic activity in longitudinal muscle strips of guinea-pig small intestine. A direct comparison of contractile responses elicited by histamine and a range of H1- and non-H1-receptor agonists indicated that DTT produced a significantly greater potentiation of H1-receptor responses. This apparently selective increase in tissue sensitivity to histamine H1-receptor agonists did not appear to ...

  11. Inverse regulation of interleukin-6 (IL-6) and IL-6 receptor in histamine deficient histidine decarboxylase-knock-out mice

    NARCIS (Netherlands)

    Horváth, B V; Falus, A; Tóth, S; Szalai, Cs; Lázár-Molnár, E; Holub, M Cs; Buzás, E; Nagy, A; Fulop, A K

    2002-01-01

    Interleukin-6, a multifunctional cytokine upon binding to its receptor on hepatocytes regulates production of acute phase proteins involved in local and systemic inflammation. Gene expression and biosynthesis of IL-6 and its receptor (IL-6 R/gp130) is under complex regulation. Histamine, in addition

  12. Association of bovine Toll-like receptor 4 with tick infestation rates and blood histamine concentration.

    Science.gov (United States)

    Zhao, G; Yu, M; Cui, Q-W; Zhou, X; Zhang, J-C; Li, H-X; Qu, K-X; Wang, G-L; Huang, B-Z

    2013-01-01

    We investigated a possible association between bovine Toll-like receptor 4 (TLR4) and resistance to tick infestation in 103 cattle, including BMY cattle (1/2 Brahman, 1/4 Murray Grey, and 1/4 Yunnan Yellow cattle), Brahman, and Red Angus grazing on improved pasture. The tick infestation weight and number of Rhipicephalus microplus and the blood histamine concentration were measured and compared with those of 32 Chinese Holsteins and 30 Simmentals. A 228-bp fragment was amplified and sequenced to analyze the polymorphisms of the TLR4 gene. After SSCP and sequencing analysis, 4 SNPs, i.e., 535(A>C), 546(T>C), 605(T>A), and 618(G>C), were identified, corresponding to GenBank accession Nos. AY297041 and NW_003104150; the latter two SNPs caused Leu→Gln and Gln→His substitutions, respectively. Genotype AA was completely predominant in the Chinese Holstein and Simmental; genotypes AA and AB were detected in Red Angus, while genotypes AA, AB, BB, and BC were detected in Brahman and in BMY cattle. A negative correlation was identified between blood histamine concentration and number of tick infestation; in BMY cattle this negative association was significant. The tick infestation in cattle with genotype BB was significantly lower than in those with genotype AA. Blood histamine concentration in cattle with genotype BB was significantly higher than in those with genotype AA. The TLR4 gene mutation could affect the blood histamine level and activate the immune reaction after tick infestation. Allele B has potential as a molecular marker for tick-resistance originated from Zebu cattle for use in cattle breeding programs. PMID:23479166

  13. Clinical and preclinical characterization of the histamine H(4) receptor antagonist JNJ-39758979.

    Science.gov (United States)

    Thurmond, Robin L; Chen, Bin; Dunford, Paul J; Greenspan, Andrew J; Karlsson, Lars; La, David; Ward, Peter; Xu, Xie L

    2014-05-01

    The histamine H4 receptor (H(4)R) has been shown to have preclinical involvement in both inflammatory and pruritic responses. JNJ-39758979 [(R)-4-(3-amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine] is a potent and selective H(4)R antagonist with a Ki at the human receptor of 12.5 ± 2.6 nM and greater than 80-fold selectivity over other histamine receptors. The compound also exhibited excellent selectivity versus other targets. JNJ-39758979 showed dose-dependent activity in models of asthma and dermatitis consistent with other H(4)R antagonists. Preclinical toxicity studies of up to 6 months in rats and 9 months in monkeys indicated an excellent safety profile, supporting the clinical testing of the compound. An oral formulation of JNJ-39758979 was studied in a phase 1 human volunteer study to assess safety, pharmacokinetics, and pharmacodynamics. The compound was well tolerated, with the exception of dose-dependent nausea, and no safety issues were noted in the phase 1 study. JNJ-39758979 exhibited good pharmacokinetics upon oral dosing with a plasma half-life of 124-157 hours after a single oral dose. In addition, dose-dependent inhibition of histamine-induced eosinophil shape change was detected, suggesting that the H4R was inhibited in vivo. In conclusion, JNJ-39758979 is a potent and selective H(4)R antagonist that exhibited good preclinical and phase 1 safety in healthy volunteers with evidence of a pharmacodynamics effect in humans. PMID:24549371

  14. Histamine-1 receptor blockade does not prevent nitroglycerin induced migraine. Support for the NO-hypothesis of migraine

    DEFF Research Database (Denmark)

    Lassen, L H; Thomsen, L L; Kruuse, C; Iversen, Helle Klingenberg; Olesen, J

    1996-01-01

    evaluate whether GTN causes headache via liberation of histamine, we studied the effect of GTN 0.5 micrograms.kg-1.min-1 for 20 min in seven migraine sufferers, once after pretreatment with the histamine-1 (H1)-receptor blocker mepyramine (0.5 mg.kg-1) and once without pretreatment. This mepyramine dose is......It has previously been shown that in migraine sufferers infusion of glyceryl trinitrate (GTN) and histamine causes an immediate headache during the infusion and a genuine migraine attack one to several hours after the infusion. This identical time profile indicates a common mechanism of action. To...... known to completely abolish histamine-induced headache. After pretreatment with mepyramine five patients experienced migraine, and without pretreatment six patients did so. The median peak headache score was 7 on a 0-10 scale with and without mepyramine pretreatment. The arterial responses, evaluated...

  15. Vascular Effects of Histamine.

    Science.gov (United States)

    Ebeigbe, Anthony B; Talabi, Olufunke O

    2014-01-01

    Four subtypes of receptors (H1, H2, H3 and H4) mediate the actions of histamine. In the vascular wall, the effects of histamine are mediated via H1 and H2 receptors and the actions are modulated by H3 receptor subtype located on presynaptic neurones. Alterations in vascular responses to histamine are associated with experimental as well as a human form of hypertension, suggesting a role for histanine in cardiovascular regulation. PMID:26196559

  16. A search for functional histamine H4 receptors in the human, guinea pig and mouse brain.

    Science.gov (United States)

    Feliszek, Monika; Speckmann, Valerie; Schacht, Daniel; von Lehe, Marec; Stark, Holger; Schlicker, Eberhard

    2015-01-01

    Histamine H4 receptors are expressed in immune cells, but their potential role in the brain is less clear. Although H4 transcripts have been identified in human and rat brain, the presence of H4 receptors on the protein level has so far not been proven since appropriate antibodies fulfilling the strict criteria for G protein-coupled receptors are missing. Here, we searched for functional H4 receptors in human, guinea pig and mouse cortex. We studied whether H4 receptor activation is associated with increased GTPγS binding and reduced noradrenaline release. The latter two effects have been previously shown for H3 receptors, which, like the H4 receptors, are coupled to G i/o protein. G protein activation was studied using (35)S-GTPγS binding in cortical membranes. The electrically induced (3)H-noradrenaline release was determined in superfused cortical slices. The H4 agonist 4-methylhistamine failed to affect (35)S-GTPγS binding and/or noradrenaline release in human, guinea pig and mouse cortex although an H 3 receptor-mediated increase in (35)S-GTPγS binding and inhibition of noradrenaline release occurred in parallel experiments. In conclusion, functional H4 receptors increasing (35)S-GTPγS binding and/or decreasing noradrenaline release are not found in human, guinea pig and mouse cortex. PMID:25300787

  17. Structure-Based Prediction of Subtype Selectivity of Histamine H3 Receptor Selective Antagonists in Clinical Trials

    DEFF Research Database (Denmark)

    Kim, Soo-Kyung; Fristrup, Peter; Abrol, Ravinder; Goddard, William A., III

    2011-01-01

    applications, including treatment of Alzheimer’s disease, attention deficit hyperactivity disorder (ADHD), epilepsy, and obesity.(1) However, many of these drug candidates cause undesired side effects through the cross-reactivity with other histamine receptor subtypes. In order to develop improved selectivity......Histamine receptors (HRs) are excellent drug targets for the treatment of diseases, such as schizophrenia, psychosis, depression, migraine, allergies, asthma, ulcers, and hypertension. Among them, the human H3 histamine receptor (hH3HR) antagonists have been proposed for specific therapeutic...... and activity for such treatments, it would be useful to have the three-dimensional structures for all four HRs. We report here the predicted structures of four HR subtypes (H1, H2, H3, and H4) using the GEnSeMBLE (GPCR ensemble of structures in membrane bilayer environment) Monte Carlo protocol,(2...

  18. Association of genetic variants of the histamine H1 and muscarinic M3 receptors with BMI and HbA1c values in patients on antipsychotic medication

    NARCIS (Netherlands)

    J. Vehof (Jelle); A.J. Risselada (Arne); A.F.Y. Al Hadithy (Asmar); H. Burger (Herman); H. Snieder (Harold); B. Wilffert (Bob); J. Arends (Johan); L. Wunderink (Lex); H. Knegtering (Henrikus); D. Wiersma (Durk); D. Cohen (Daniel); H. Mulder (Hans Sipko); R. Bruggeman (Richard)

    2011-01-01

    textabstractRationale: Antipsychotic affinity for the histamine H1 receptor and the muscarinic M3 receptor have been associated with the side effects weight gain, and development of diabetes, respectively. Objectives: We investigated polymorphisms of the histamine H1 (HRH1) and muscarinic acetylchol

  19. Combinatorial Consensus Scoring for Ligand-Based Virtual Fragment Screening: A Comparative Case Study for Serotonin 5-HT(3)A, Histamine H(1), and Histamine H(4) Receptors.

    Science.gov (United States)

    Schultes, Sabine; Kooistra, Albert J; Vischer, Henry F; Nijmeijer, Saskia; Haaksma, Eric E J; Leurs, Rob; de Esch, Iwan J P; de Graaf, Chris

    2015-05-26

    In the current study we have evaluated the applicability of ligand-based virtual screening (LBVS) methods for the identification of small fragment-like biologically active molecules using different similarity descriptors and different consensus scoring approaches. For this purpose, we have evaluated the performance of 14 chemical similarity descriptors in retrospective virtual screening studies to discriminate fragment-like ligands of three membrane-bound receptors from fragments that are experimentally determined to have no affinity for these proteins (true inactives). We used a complete fragment affinity data set of experimentally determined ligands and inactives for two G protein-coupled receptors (GPCRs), the histamine H1 receptor (H1R) and the histamine H4 receptor (H4R), and one ligand-gated ion channel (LGIC), the serotonin receptor (5-HT3AR), to validate our retrospective virtual screening studies. We have exhaustively tested consensus scoring strategies that combine the results of multiple actives (group fusion) or combine different similarity descriptors (similarity fusion), and for the first time systematically evaluated different combinations of group fusion and similarity fusion approaches. Our studies show that for these three case study protein targets both consensus scoring approaches can increase virtual screening enrichments compared to single chemical similarity search methods. Our cheminformatics analyses recommend to use a combination of both group fusion and similarity fusion for prospective ligand-based virtual fragment screening. PMID:25815783

  20. Cetirizine a histamine H1 receptor antagonist improves viral myocarditis

    Directory of Open Access Journals (Sweden)

    Yamamoto Kanjo

    2010-08-01

    Full Text Available Abstract Background We showed that mast cells played a critical role in the progression of heart failure induced by pressure overload and viral myocarditis in mice. In this study, we investigated the effect of cetirizine, a selective H1 receptor antagonist, on experimental viral myocarditis induced by encephalomyocarditis (EMC virus. Methods Four-week-old inbred male DBA/2 mice were inoculated intraperitoneally with 10 plaque-forming units (pfu of the EMC virus. Cetirizine was administered orally at a dose of 1 or 10 mg/kg per day for the survival study, and 1 mg/kg for the histologic and gene expression studies, beginning on the day of viral inoculation. Results Cetirizine improved survival dose dependently. Heart weight to body weight ratio was significantly decreased in mice treated with cetirizine. The area of myocardial necrosis was significantly smaller in the hearts of mice treated with cetirizine compared with controls. Gene expressions of tumor necrosis factor, interleukin 6, and metalloproteinase 2 were significantly suppressed in the hearts of mice treated with cetirizine. Conclusion These results suggest that cetirizine exerts its beneficial effects on viral myocarditis by suppressing expression of pro-inflammatory cytokines, genes related to cardiac remodeling in the hearts of mice.

  1. Effect of tracer metabolism on PET measurement of [11C]pyrilamine binding to histamine H1 receptors

    International Nuclear Information System (INIS)

    The present study was carried out to investigate the time course of [11C]pyrilamine metabolism and the degree of entry of metabolites into the brain. PET studies were performed in seven healthy volunteers and arterial plasma concentrations of [11C]pyrilamine and its labeled metabolites were determined. After intravenous injection, [11C]pyrilamine metabolized gradually in the human body, with less than 10% of plasma activity being original radioligand at 60 min. Tracer metabolism markedly affected the input function and the calculated impulse response function of the brain. Rat experiments demonstrated that although metabolites of [11C]pyrilamine might enter the brain, they were not retained for prolonged periods of time. At 30-90 min after injection of [11C]pyrilamine, less than 1% of the radioactivity in the brain was originating from metabolites of [11C]pyrilamine. Based on the rat data, the contribution of 11C-labeled metabolites to total [11C]pyrilamine radioactivity in the human brain was estimated and found to be negligible. These results suggest that the metabolites of [11C]pyrilamine do not accumulate within the cerebral extravascular space and that there is minimal metabolism of [11C]pyrilamine by brain tissue itself. Therefore, [11C]pyrilamine metabolites can be neglected in kinetic analysis, using either a compartmental or a noncompartmental model, of the [11C]pyrilamine binding to histamine H1 receptors. (author)

  2. Temporal responses of cutaneous blood flow and plasma catecholamine concentrations to histamine H1- or H2-receptor stimulation in man

    DEFF Research Database (Denmark)

    Knigge, U; Alsbjørn, B; Thuesen, B;

    1988-01-01

    continuously with a laser Doppler flowmeter, and noradrenaline and adrenaline concentrations were determined in blood samples drawn every 15 min. The infusion of histamine caused an immediate and sustained vasodilatation. The Concomitant infusion of mepyramine prevented the immediate vasodilatation, but had no...... noradrenaline, while the increase during concomitant H1-receptor blockade was delayed but achieved the level observed during the histamine infusion. The response to histamine during H2-receptor blockade was small and transient. The rise in plasma adrenaline was not significant. These findings suggest that...... histamine infusion, while the plasma noradrenaline concentration was still elevated....

  3. In vitro histamine H2-antagonist activity of the novel compound HUK 978

    International Nuclear Information System (INIS)

    Histamine stimulated adenylate cyclase from guinea-pig fundic mucosa and 3H-tiotidine binding in guinea-pig cerebral cortex were used to assess the in-vitro histamine H2-activity of the novel H2-antagonist HUK 978. The results showed that HUK 978 was a more potent H2-antagonist than either cimetidine or ranitidine. HUK 978 was also shown to be devoid of activity at the histamine H-1-receptor, the muscarinic receptor and the α and β-adrenergic receptors

  4. Involvement of histamine 1 receptor in seizure susceptibility and neuroprotection in immature mice.

    Science.gov (United States)

    Kukko-Lukjanov, Tiina-Kaisa; Lintunen, Minnamaija; Jalava, Niina; Laurén, Hanna B; Lopez-Picon, Francisco R; Michelsen, Kimmo A; Panula, Pertti; Holopainen, Irma E

    2010-06-01

    The central histaminergic neuronal system is a powerful modulator of brain activity, and its functional disturbance is related to e.g. epilepsy. We have recently shown in the slice culture system that histaminergic neurons attenuate kainic acid (KA)-induced epileptiform activity and neuronal damage in the hippocampus through histamine 1 (H1) receptors. We now further examined the role of H1 receptors in the regulation of KA-induced seizures and neuronal damage in immature 9-day-old H1 receptor knock out (KO) mice. In the H1 receptor KO mice, behavioral seizures were significantly more severe and duration of seizures was significantly longer when compared to the wild type (WT) mice at the KA dose of 2mg/kg. Moreover, neuronal damage correlated with seizure severity, and it was significantly increased in the thalamus and retrosplenial granular cortex (RGC) of the KO mice. The H1 receptor antagonist triprolidine treatment supported these findings by showing significantly increased seizures severity and neuronal damage in the septum, thalamus, CA3 region of the hippocampus, and RGC in the KA-treated WT mice. Our present novel findings suggest that H1 receptors play a pivotal role in the regulation of seizure intensity and duration as well as seizure-induced neuronal damage in the immature P9 mice. PMID:20359868

  5. Identification of histaminergic neurons through histamine 3 receptor-mediated autoinhibition.

    Science.gov (United States)

    De Luca, Roberto; Suvorava, Tatsiana; Yang, Danqing; Baumgärtel, Wilhelm; Kojda, Georg; Haas, Helmut L; Sergeeva, Olga A

    2016-07-01

    Using a reporter mouse model with expression of the tomato fluorescent protein under the dopamine transporter promoter (Tmt-DAT) we discovered a new group of neurons in the histaminergic tuberomamillary nucleus (TMN), which, in contrast to tuberoinfundibular dopaminergic neurons of the dorsomedial arcuate nucleus, do not express tyrosine hydroxylase but can synthesize and store dopamine. Tmt-DAT neurons located within TMN share electrophysiological properties with histaminergic neurons: spontaneous firing at a membrane potential around -50 mV and presence of hyperpolarization-activated cyclic nucleotide-gated ion channels. Histamine (30 μM) depolarizes and excites Tmt-DAT neurons through H1R activation but inhibits histaminergic neurons through H3R activation thus allowing a pharmacological identification of the different neurons. Single-cell RT-PCR revealed that all histaminergic neurons expressing histidine decarboxylase (HDC) also express H3R. This includes neurons retrogradely traced from the striatum whose inhibition by a selective H3R agonist was indistinguishable from the whole population. Prolonged depolarization reduces the autoinhibition. The potency of histamine at H3R depends on membrane potential and on extracellular and intracellular calcium. Autoinhibition can be impaired by preincubation with capsaicin, a ligand of the calcium-permeable TRPV1 channel or by blockade of Ca(2+)-ATPase with thapsigargin. The pharmacology of autoinhibition is revisited and physiological conditions for its functionality are determined. Usage of reporter mouse models for the safe identification of aminergic neurons under pathophysiological conditions is recommended. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID:26297536

  6. Functional characterization of histamine H4 receptor on human mast cells.

    Science.gov (United States)

    Jemima, E Angel; Prema, A; Thangam, E Berla

    2014-11-01

    Among the four different types of histamine receptors (H1-H4), H4R is predominantly expressed in immune cells and involved in immunomodulatory response. Here, in this study we determined the expression of H4R in human mast cells (HMC-1, LAD-2 and primary cord blood derived CD34+ human mast cells) and characterized its functional properties. Interestingly, we found that human mast cells responded to both histamine (natural ligand) and 4-methylhistamine (selective H4R agonist) for sustained intracellular calcium mobilization, degranulation and cytokine production. However, only histamine induced the release of cAMP, but 4-methylhistamine down regulates cAMP indicating that H4R mediates its effect through Gαi/o protein and H1R via Gαq protein. Furthermore, both histamine and 4-methylhistamine induced the production of cysteinyl leukotrienes and LTB4. Using human inflammation antibody array membrane, we found that H4R induced the expression of various inflammatory proteins, involving pro-inflammatory cytokines and chemokines and these are TGF-β1, TNF-α, TNF-β, PDGF-BB, TIMP-2, M-CSF, IP-10, IL-16, IL-6, IL-3, IL-10, MIP-1α, IL-1α, ICAM-1, Eotaxin-2, RANTES, IL-8, MCP-1, and IL-6sR. We also quantified the level of various inflammatory cytokines produced by human mast cells through H4R. It was observed that, the production level of Th2 cytokines IL-4(401.34 pg/ml), IL-5 (64.21 pg/ml) and IL-13 (1044 pg/ml) and classical proinflammatory cytokines IL-6 (221.27 pg/ml) and IL-1β (34.24 pg/ml) and chemokines MCP-1(106 pg/ml) and IL-8 (818.32 pg/ml). Furthermore, activation of H4R caused the phosphorylation of ERK and PI3K in a time dependent manner. Taken together these data demonstrate that, the activation of H4R in human mast cells produced not only inflammatory mediators that are associated with allergic reactions but also other inflammatory conditions. PMID:24934979

  7. Phorbol ester-mediated desensitization of histamine Hl receptors on a cultured smooth muscle cell line

    International Nuclear Information System (INIS)

    The present study was undertaken in order to examine the effect of protein kinase C (PKC) on histamine Hl receptors, (HlR) present on the smooth muscle cell line, DDT1MF-2. [3H]-pyrilamine binding revealed that specific [3H]-pyrilamine binding sites were reduced be pretreatment with 12-O-tetra-decanoylphorbol-13-acetate (TPA), an activator of PKC, but not the Kd. The TPA analogue, 4α phorbol 12,13-didecanoate, which does not activate PKC, failed to induce down-regulation of HlR. TPA-induced down regulation of HlR was inhibited by pretreatment with 1-(5-Isoquinilinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), a PKC inhibitor, in a dose dependent manner. The H-7 analogue, H-8, which is a less potent inhibitor of PKC, but a potent inhibitor of cyclic nucleotide dependent protein kinase, had no effect on HlR. Moreover, treatment with TPA inhibited histamine-induced increases in [Ca2+]/sub i/ in cells loaded with the fluorescent indicator, indo-1. These data suggest that HlR in DDT1MF-2 cells were functionally regulated by PKC

  8. Histamine induces postprandian tachycardia through a direct effect on cardiac H2-receptors in pythons

    DEFF Research Database (Denmark)

    Jensen, Nini Skovgaard; Møller, Kate; Gesser, Hans; Wang, Tobias

    2009-01-01

    snakes histamine caused a systemic vasodilatation and a marked increase in heart rate and cardiac output mediated through a direct effect on H2-receptors. Our study strongly indicates that histamine regulates heart rate during the initial phase of digestion in pythons. This study describes a novel...... doubling of intrinsic heart rate. The H2-antagonist did not affect heart rate of fasting snakes, but decreased heart rate by 15-20 min-1 at 24h into digestion, while it had no effects at 48h. Thus, the histaminergic tone on the heart rose from none to 30% at 24h, but vanished after 48h. In anesthetised...

  9. The modulatory role of spinally located histamine receptors in the regulation of the blood glucose level in d-glucose-fed mice.

    Science.gov (United States)

    Sim, Yun-Beom; Park, Soo-Hyun; Kim, Sung-Su; Kim, Chea-Ha; Kim, Su-Jin; Lim, Su-Min; Jung, Jun-Sub; Ryu, Ohk-Hyun; Choi, Moon-Gi; Suh, Hong-Won

    2014-02-01

    The possible roles of spinal histamine receptors in the regulation of the blood glucose level were studied in ICR mice. Mice were intrathecally (i.t.) treated with histamine 1 (H1) receptor agonist (2-pyridylethylamine) or antagonist (cetirizine), histamine 2 (H2) receptor agonist (dimaprit) or antagonist (ranitidine), histamine 3 (H3) receptor agonist (α-methylhistamine) or antagonist (carcinine) and histamine 4 (H4) receptor agonist (VUF 8430) or antagonist (JNJ 7777120), and the blood glucose level was measured at 30, 60 and 120 min after i.t. administration. The i.t. injection with α-methylhistamine, but not carcinine slightly caused an elevation of the blood glucose level. In addition, histamine H1, H2, and H4 receptor agonists and antagonists did not affect the blood glucose level. In D-glucose-fed model, i.t. pretreatment with cetirizine enhanced the blood glucose level, whereas 2-pyridylethylamine did not affect. The i.t. pretreatment with dimaprit, but not ranitidine, enhanced the blood glucose level in D-glucose-fed model. In addition, α-methylhistamine, but not carcinine, slightly but significantly enhanced the blood glucose level D-glucose-fed model. Finally, i.t. pretreatment with JNJ 7777120, but not VUF 8430, slightly but significantly increased the blood glucose level. Although histamine receptors themselves located at the spinal cord do not exert any effect on the regulation of the blood glucose level, our results suggest that the activation of spinal histamine H2 receptors and the blockade of spinal histamine H1 or H3 receptors may play modulatory roles for up-regulation and down-regulation, respectively, of the blood glucose level in D-glucose fed model. PMID:24634595

  10. Effects of administration of histamine and its H1, H2, and H3 receptor antagonists into the primary somatosensory cortex on inflammatory pain in rats

    Directory of Open Access Journals (Sweden)

    Esmaeal Tamaddonfard

    2014-01-01

    These results indicate that at PSC levels, histamine through post-synaptic H1, H2, and pre-synaptic H3 receptors might be involved in pain modulation. The endogenous opioid system may be involved in histamine- and thioperamide-induced antinociception.

  11. Effect of disodium cromoglycate (DSCG) and antihistamines on postirradiation cerebral blood flow and plasma levels of histamine and neurotensin

    Energy Technology Data Exchange (ETDEWEB)

    Cockerham, L.G.; Pautler, E.L.; Carraway, R.E.; Cochrane, D.E.; Hampton, J.D.

    1988-02-01

    In an attempt to elucidate mechanisms underlying the irradiation-induced decrease in regional cerebral blood flow (rCBF) in primates, hippocampal and visual cortical blood flows of rhesus monkeys were measured by hydrogen clearance, before and after exposure to 100 Gy, whole-body, gamma irradiation. Systemic blood pressures were monitored simultaneously. Systemic arterial plasma histamine and neurotensin levels were determined preirradiation and postirradiation. Compared to control animals, the irradiated monkeys exhibited an abrupt decline in systemic blood pressure to 23% of the preirradiation level within 10 min postirradiation, falling to 12% by 60 min. A decrease in hippocampal blood flow to 32% of the preirradiation level was noted at 10 min postirradiation, followed by a slight recovery to 43% at 30 min and a decline to 23% by 60 min. The cortical blood flow for the same animals showed a steady decrease to 29% of the preirradiation levels by 60 min postirradiation. Animals given the mast cell stabilizer disodium cromoglycate and the antihistamines mepyramine and cimetidine before irradiation did not exhibit an abrupt decline in blood pressure but displayed a gradual decrease to a level 33% below preirradiation levels by 60 min postirradiation. Also, the treated, irradiated monkeys displayed rCBF values that were not significantly different from the nonirradiated controls. The plasma neurotensin levels in the irradiated animals, treated and untreated, indicated a nonsignificant postirradiation increase above control levels. However, the postirradiation plasma histamine levels in both irradiated groups showed an increase of approximately 1600% above the preirradiation levels and the postirradiation control levels.

  12. Effect of disodium cromoglycate (DSCG) and antihistamines on postirradiation cerebral blood flow and plasma levels of histamine and neurotensin

    International Nuclear Information System (INIS)

    In an attempt to elucidate mechanisms underlying the irradiation-induced decrease in regional cerebral blood flow (rCBF) in primates, hippocampal and visual cortical blood flows of rhesus monkeys were measured by hydrogen clearance, before and after exposure to 100 Gy, whole-body, gamma irradiation. Systemic blood pressures were monitored simultaneously. Systemic arterial plasma histamine and neurotensin levels were determined preirradiation and postirradiation. Compared to control animals, the irradiated monkeys exhibited an abrupt decline in systemic blood pressure to 23% of the preirradiation level within 10 min postirradiation, falling to 12% by 60 min. A decrease in hippocampal blood flow to 32% of the preirradiation level was noted at 10 min postirradiation, followed by a slight recovery to 43% at 30 min and a decline to 23% by 60 min. The cortical blood flow for the same animals showed a steady decrease to 29% of the preirradiation levels by 60 min postirradiation. Animals given the mast cell stabilizer disodium cromoglycate and the antihistamines mepyramine and cimetidine before irradiation did not exhibit an abrupt decline in blood pressure but displayed a gradual decrease to a level 33% below preirradiation levels by 60 min postirradiation. Also, the treated, irradiated monkeys displayed rCBF values that were not significantly different from the nonirradiated controls. The plasma neurotensin levels in the irradiated animals, treated and untreated, indicated a nonsignificant postirradiation increase above control levels. However, the postirradiation plasma histamine levels in both irradiated groups showed an increase of approximately 1600% above the preirradiation levels and the postirradiation control levels

  13. Waking action of ursodeoxycholic acid (UDCA involves histamine and GABAA receptor block.

    Directory of Open Access Journals (Sweden)

    Yevgenij Yanovsky

    Full Text Available Since ancient times ursodeoxycholic acid (UDCA, a constituent of bile, is used against gallstone formation and cholestasis. A neuroprotective action of UDCA was demonstrated recently in models of Alzheimer's disease and retinal degeneration. The mechanisms of UDCA action in the nervous system are poorly understood. We show now that UDCA promotes wakefulness during the active period of the day, lacking this activity in histamine-deficient mice. In cultured hypothalamic neurons UDCA did not affect firing rate but synchronized the firing, an effect abolished by the GABA(AR antagonist gabazine. In histaminergic neurons recorded in slices UDCA reduced amplitude and duration of spontaneous and evoked IPSCs. In acutely isolated histaminergic neurons UDCA inhibited GABA-evoked currents and sIPSCs starting at 10 µM (IC(50 = 70 µM and did not affect NMDA- and AMPA-receptor mediated currents at 100 µM. Recombinant GABA(A receptors composed of α1, β1-3 and γ2L subunits expressed in HEK293 cells displayed a sensitivity to UDCA similar to that of native GABA(A receptors. The mutation α1V256S, known to reduce the inhibitory action of pregnenolone sulphate, reduced the potency of UDCA. The mutation α1Q241L, which abolishes GABA(AR potentiation by several neurosteroids, had no effect on GABA(AR inhibition by UDCA. In conclusion, UDCA enhances alertness through disinhibition, at least partially of the histaminergic system via GABA(A receptors.

  14. Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands.

    Science.gov (United States)

    Łażewska, Dorota; Więcek, Małgorzata; Ner, Joanna; Kamińska, Katarzyna; Kottke, Tim; Schwed, J Stephan; Zygmunt, Małgorzata; Karcz, Tadeusz; Olejarz, Agnieszka; Kuder, Kamil; Latacz, Gniewomir; Grosicki, Marek; Sapa, Jacek; Karolak-Wojciechowska, Janina; Stark, Holger; Kieć-Kononowicz, Katarzyna

    2014-08-18

    A series of novel 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazine derivatives with different aryl substituents in the 6-position was designed, synthesized and evaluated for histamine H4 receptor (H4R) affinity in Sf9 cells expressing human H4R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-(p-chlorophenyl) substituent showed the highest affinity with hH4R Ki value of 203 nM and was classified as an antagonist in cAMP accumulation assay. This compound, identified as a new lead structure, demonstrated also anti-inflammatory properties in preliminary studies in mice (carrageenan-induced edema test) and neither possessed significant antiproliferative activity, nor modulated CYP3A4 activity up to concentration of 25 μM. In order to discuss structure-activity relationships molecular modeling and docking studies were undertaken. PMID:24996140

  15. Histamine H3 receptor: A novel therapeutic target in alcohol dependence?

    Directory of Open Access Journals (Sweden)

    Pertti ePanula

    2012-05-01

    Full Text Available The brain histaminergic system is one of the diffuse modulatory neurotransmitter systems which regulate neuronal activity in many brain areas. Studies on both rats and mice indicate that histamine H3 receptor antagonists decrease alcohol drinking in several models, like operant alcohol administration and drinking in the dark paradigm. Alcohol-induced place preference is also affected by these drugs. Moreover, mice lacking H3R do not drink alcohol like their wild type littermates, and they do not show alcohol-induced place preference. Although the mechanisms of these behaviors are still being investigated, we propose that H3R antagonists are promising candidates for use in human alcoholics, as these drugs are already tested for treatment of other disorders like narcolepsy and sleep disorders.

  16. [Isoforms of the human histamine H3 receptor: Generation, expression in the central nervous system and functional implications].

    Science.gov (United States)

    García-Gálvez, Ana Maricela; Arias-Montaño, José Antonio

    2016-01-01

    Histamine plays a significant role as a neuromodulator in the human central nervous system. Histamine-releasing neurons are exclusively located in the tuberomammillary nucleus of the hypothalamus, project to all major areas of the brain, and participate in functions such as the regulation of sleep/wakefulness, locomotor activity, feeding and drinking, analgesia, learning, and memory. The functional effects of histamine are exerted through the activation of four G protein-coupled receptors (H1, H2, H3 and H4), and in the central nervous system the first three receptors are widely expressed. The H3 receptor (H3R) is found exclusively in neuronal cells, where it functions as auto- and hetero-receptor. One remarkable characteristic of the H3R is the existence of isoforms, generated by alternative splicing of the messenger RNA. For the human H3R, 20 isoforms have been reported; although a significant number lack those regions required for agonist binding or receptor signaling, at least five isoforms appear functional upon heterologous expression. In this work we review the evidence for the generation of human H3R isoforms, their expression, and the available information regarding the functionality of such receptors. PMID:26927649

  17. Histamine acting on H1 receptor promotes inhibition of proliferation via PLC, RAC, and JNK-dependent pathways

    International Nuclear Information System (INIS)

    It is well established that histamine modulates cell proliferation through the activation of the histamine H1 receptor (H1R), a G protein-coupled receptor (GPCR) that is known to couple to phospholipase C (PLC) activation via Gq. In the present study, we aimed to determine whether H1R activation modulates Rho GTPases, well-known effectors of Gq/G11-coupled receptors, and whether such modulation influences cell proliferation. Experiments were carried out in CHO cells stably expressing H1R (CHO-H1R). By using pull-down assays, we found that both histamine and a selective H1R agonist activated Rac and RhoA in a time- and dose-dependent manner without significant changes in the activation of Cdc42. Histamine response was abolished by the H1R antagonist mepyramine, RGS2 and the PLC inhibitor U73122, suggesting that Rac and RhoA activation is mediated by H1R via Gq coupling to PLC stimulation. Histamine caused a marked activation of serum response factor activity via the H1R, as determined with a serum-responsive element (SRE) luciferase reporter, and this response was inhibited by RhoA inactivation with C3 toxin. Histamine also caused a significant activation of JNK which was inhibited by expression of the Rac-GAP β2-chimaerin. On the other hand, H1R-induced ERK1/2 activation was inhibited by U73122 but not affected by C3 or β2-chimaerin, suggesting that ERK1/2 activation was dependent on PLC and independent of RhoA or Rac. [3H]-Thymidine incorporation assays showed that both histamine and the H1R agonist inhibited cell proliferation in a dose-dependent manner and that the effect was independent of RhoA but partially dependent on JNK and Rac. Our results reveal that functional coupling of the H1R to Gq-PLC leads to the activation of RhoA and Rac small GTPases and suggest distinct roles for Rho GTPases in the control of cell proliferation by histamine.

  18. Histamine acting on H1 receptor promotes inhibition of proliferation via PLC, RAC, and JNK-dependent pathways

    Energy Technology Data Exchange (ETDEWEB)

    Notcovich, Cintia [Laboratorio de Patologia y Farmacologia Molecular, Instituto de Biologia y Medicina Experimental (Argentina); Laboratorio de Farmacologia de Receptores, Catedra de Quimica Medicinal, Departamento de Farmacologia, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires (Argentina); Diez, Federico [Laboratorio de Farmacologia de Receptores, Catedra de Quimica Medicinal, Departamento de Farmacologia, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires (Argentina); Tubio, Maria Rosario [Laboratorio de Patologia y Farmacologia Molecular, Instituto de Biologia y Medicina Experimental (Argentina); Laboratorio de Farmacologia de Receptores, Catedra de Quimica Medicinal, Departamento de Farmacologia, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires (Argentina); Baldi, Alberto [Laboratorio de Patologia y Farmacologia Molecular, Instituto de Biologia y Medicina Experimental (Argentina); Consejo Nacional de Investigaciones Cientificas y Tecnicas, Buenos Aires (Argentina); Kazanietz, Marcelo G. [Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 (United States); Davio, Carlos [Laboratorio de Farmacologia de Receptores, Catedra de Quimica Medicinal, Departamento de Farmacologia, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires (Argentina); Consejo Nacional de Investigaciones Cientificas y Tecnicas, Buenos Aires (Argentina); Shayo, Carina, E-mail: cshayo@dna.uba.ar [Laboratorio de Patologia y Farmacologia Molecular, Instituto de Biologia y Medicina Experimental (Argentina); Consejo Nacional de Investigaciones Cientificas y Tecnicas, Buenos Aires (Argentina)

    2010-02-01

    It is well established that histamine modulates cell proliferation through the activation of the histamine H1 receptor (H1R), a G protein-coupled receptor (GPCR) that is known to couple to phospholipase C (PLC) activation via Gq. In the present study, we aimed to determine whether H1R activation modulates Rho GTPases, well-known effectors of Gq/G{sub 11}-coupled receptors, and whether such modulation influences cell proliferation. Experiments were carried out in CHO cells stably expressing H1R (CHO-H1R). By using pull-down assays, we found that both histamine and a selective H1R agonist activated Rac and RhoA in a time- and dose-dependent manner without significant changes in the activation of Cdc42. Histamine response was abolished by the H1R antagonist mepyramine, RGS2 and the PLC inhibitor U73122, suggesting that Rac and RhoA activation is mediated by H1R via Gq coupling to PLC stimulation. Histamine caused a marked activation of serum response factor activity via the H1R, as determined with a serum-responsive element (SRE) luciferase reporter, and this response was inhibited by RhoA inactivation with C3 toxin. Histamine also caused a significant activation of JNK which was inhibited by expression of the Rac-GAP {beta}2-chimaerin. On the other hand, H1R-induced ERK1/2 activation was inhibited by U73122 but not affected by C3 or {beta}2-chimaerin, suggesting that ERK1/2 activation was dependent on PLC and independent of RhoA or Rac. [{sup 3}H]-Thymidine incorporation assays showed that both histamine and the H1R agonist inhibited cell proliferation in a dose-dependent manner and that the effect was independent of RhoA but partially dependent on JNK and Rac. Our results reveal that functional coupling of the H1R to Gq-PLC leads to the activation of RhoA and Rac small GTPases and suggest distinct roles for Rho GTPases in the control of cell proliferation by histamine.

  19. Drug-likeness approach of 2-aminopyrimidines as histamine H3 receptor ligands

    Directory of Open Access Journals (Sweden)

    Sadek B

    2014-09-01

    Full Text Available Bassem Sadek,1 Annemarie Schreeb,2 Johannes Stephan Schwed,2,3 Lilia Weizel,2 Holger Stark3 1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 2Biocenter, Institute of Pharmaceutical Chemistry, Johann-Wolfgang Goethe University, Frankfurt, Germany; 3Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Duesseldorf, Germany Abstract: A small series of compounds containing derivatives of 2,4-diamino- and 2,4,6-triaminopyrimidine (compounds 2–7 was synthesized and tested for binding affinity to human histamine H3 receptors (hH3Rs stably expressed in HEK-293 cells and human H4Rs (hH4Rs co-expressed with Gαi2 and Gβ1γ2 subunits in Sf9 cells. Working in part from the lead compound 6-(4-methylpiperazin-1-yl-N4-(3-(piperidin-1-ylpropylpyrimidine-2,4-diamine (compound 1 with unsatisfactory affinity and selectivity to hH3Rs, our structure-activity relationship studies revealed that replacement of 4-methylpiperazino by N-benzylamine and substitution of an amine group at the 2-position of the 2-aminopyrimidine core structure with 3-piperidinopropoxyphenyl moiety as an hH3R pharmacophore resulted in N4-benzyl-N2-(4-(3-(piperidin-1-ylpropoxyphenylpyrimidine-2,4-diamine (compound 5 with high hH3R affinity (ki =4.49±1.25 nM and H3R receptor subtype selectivity of more than 6,500×. Moreover, initial metric analyses were conducted based on their target-oriented drug-likeness for predictively quantifying lipophilicity, ligand efficiency, lipophilicity-dependent ligand efficiency, molecular size-independent efficiency, and topological molecular polar surface. As to the development of potential H3R ligands, results showed that integration of the hH3R pharmacophore in hH4R-affine structural scaffolds resulted in compounds with high hH3R affinity (4.5–650 nM, moderate to low hH4R affinity (4,500–30,000 nM, receptor subtype selectivity

  20. Possible role of histamine in pathogenesis of autoimmune diseases: implications for immunotherapy with histamine-2 receptor antagonists

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Hammer, J H

    1992-01-01

    The immunosuppressive chemical drugs cyclosporine A (CsA) and methotrexate (Mx) have recently been shown to be of benefit in several different diseases of autoimmune origin. Cellular immune responses may play a major role in autoimmunity as autoreactive T lymphocytes appear to recognize...... autoantigens and major histocompatibility complex (MHC) class II restriction molecules presented by non-immune, aberrant cells, subsequently leading to damage on healthy tissues. Psoriasis is suggested to be an autoimmune disease and in severe, uncontrollable psoriasis CsA and Mx are of value in reducing...... possibility, that histamine is one of the molecules involved in pathogenesis of autoimmune diseases. T cell mediated regulation and suppression of autoreactive T cells seem to be ineffective in controlling the enhanced immune reaction in patients where the discrimination between self and non-self is changed...

  1. The role of histamine H1 and H4 receptors in atopic dermatitis: from basic research to clinical study.

    Science.gov (United States)

    Ohsawa, Yusuke; Hirasawa, Noriyasu

    2014-12-01

    Histamine plays important roles in inflammation and nervous irritability in allergic disorders, including atopic dermatitis (AD). It has been shown to regulate the expression of pruritic factors, such as nerve growth factor and semaphorin 3A, in skin keratinocytes via histamine H1 receptor (H1R). Furthermore, H1R antagonist reduced the level of IL-31, a cytokine involving the skin barrier and pruritus, in chronic dermatitis lesions in NC/Nga mice and patients with AD. Histamine plays roles in the induction of allergic inflammation by activating eosinophils, mast cells, basophils, and Th2 cells via histamine H4 receptor (H4R). H4R, in addition to H1R, is expressed on sensory neurons, and a decrease in scratching behaviors was observed in H4R-deficient mice and mice treated with a H4R antagonist. We found that the combined administration of H1R and H4R antagonists inhibited the itch response and chronic allergic inflammation, and had a pharmacological effect similar to that of prednisolone. Although the oral administration of H1R antagonists is widely used to treat AD, it is not very effective. In contrast, JNJ39758979, a novel H4R antagonist, had marked effects against pruritus in Japanese patients with AD in a phase II clinical trial. Next generation antihistaminic agents possessing H1R and H4R antagonistic actions may be a potent therapeutic drug for AD. PMID:25249063

  2. Contractile 5-HT1B receptors in human cerebral arteries

    DEFF Research Database (Denmark)

    Nilsson, T; Longmore, J; Shaw, D;

    1999-01-01

    immunocytochemistry with antibodies selective for human 5-HT1B and human 5-HT1D receptors and also studied the contractile effects of a range of 5-HT receptor agonists and antagonists in HCA. 2 Immunocytochemistry of cerebral arteries showed dense 5-HT1B receptor immunoreactivity (but no 5-HT1D receptor......1 The cerebrovascular receptor(s) that mediates 5-hydroxytryptamine (5-HT)-induced vasoconstriction in human cerebral arteries (HCA)has proven difficult to characterize, yet these are essential in migraine. We have examined 5-HT receptor subtype distribution in cerebral blood vessels by...... immunoreactivity) within the smooth muscle wall of the HCA. The endothelial cell layer was well preserved and weak 5-HT1B receptor immunoreactivity was present. 3 Pharmacological experiments on HCA with intact endothelium showed that 5-carboxamidotryptamine was significantly more potent than alpha-methyl-5-HT, 2...

  3. 组胺H3受体参与低氧调控的研究进展%Role of histamine H3 receptor in regulation of hypoxia

    Institute of Scientific and Technical Information of China (English)

    廉靖靖; 颜玲娣; 周培岚; 苏瑞斌

    2016-01-01

    Hypoxia refers to the reduction in tissue oxygen supply or utilization. It occurs in various pathological symptoms like embolism,anthracemia,and chronic obstructive sleep. At high altitude, lower partial pressure of oxygen compromises the supply of adequate oxygen to the tissues and leads to many clinical syndromes,such as acute mountain sickness,high-altitude cerebral edema,and high-altitude pulmonary edema. Histamine H3 receptor, primarily as a presynaptic receptor, is widely expressed in the central and peripheral systems. Histamine,dopamine,acetylcholine and many other neurotransmitters are regulated by histamine H3 receptor. Studies have shown that histamine H3 receptor is involved in the hypoxic response of the respiratory network. In addition,histamine,espe⁃cially histamine H3 receptor,participates in the regulation of cerebral ischemia in the central nervous system. In this paper,we reviewed the structure and functions of histamine H3 receptor and explained its role in the regulation of hypoxia so as to evaluate the possibility of histamine H3 receptor as a drug target for the therapy of hypoxia-induced injuries.%低氧是指机体供氧不足或用氧障碍,栓死、一氧化碳中毒和阻塞性呼吸睡眠等多种病理过程均与低氧相关。高原地区特有的低氧环境会使人因供氧不足而产生急性高原反应,甚至高原肺水肿和脑水肿。组胺H3受体广泛分布于中枢及外周组织,主要作为突触前膜受体,调控组胺及多巴胺、乙酰胆碱等多种神经递质的释放。低氧条件下组胺H3受体可分别于颈动脉体及呼吸中枢延髓参与呼吸活动的调控。此外,组胺能系统在中枢参与低血低氧性脑损伤调控,其中组胺H3受体发挥了重要作用。本文就组胺H3受体的结构特征、功能及其参与低氧调控的可能机制做一综述,阐述靶向组胺H3受体研发抗低氧药物的可能性。

  4. Histamine modulates contraction and cyclic nucleotides in cultured rat mesangial cells. Differential effects mediated by histamine H1 and H2 receptors.

    OpenAIRE

    Sedor, J R; Abboud, H. E.

    1985-01-01

    Histamine influences the glomerular microcirculation and modulates immune-inflammatory responses. In the rat kidney, histamine is synthesized by glomeruli and stimulates cyclic nucleotide production specifically in glomeruli. We investigated the in vitro effect of histamine on cyclic nucleotide accumulation in rat cultured glomerular mesangial and epithelial cells. Histamine stimulated cyclic AMP (cAMP) accumulation in cultured mesangial cells (64.0 +/- 22.1 to 511.4 +/- 86.6 pmol/mg protein,...

  5. BODIPY(®) FL histamine as a new modality for quantitative detection of histamine receptor upregulation upon IgE sensitization in murine bone marrow-derived mast cells.

    Science.gov (United States)

    Mirzahosseini, Arash; Kovács, Marianna; Kánai, Károly; Csutora, Péter; Dalmadi, Balázs

    2015-01-01

    Flow cytometry is one of the most widely used methods for the qualitative and quantitative analysis of cell surface expressed proteins by making use of fluorescent specific antibodies. Lacking an antibody validated for flow cytometry, an alternative approach for labeling cell surface receptors is the use of fluorescently tagged ligands. In this study, histamine H4 receptor transfected Chinese hamster ovary cells and murine bone marrow-derived mast cells (mBMMCs) were selected for studying the possibility of staining individual histamine receptors using BODIPY(®) FL histamine and selective antagonists. Flow cytometric measurements and supporting calculations showed that BODIPY FL histamine is suitable tool for quantitating cell surface histamine receptors. The binding, and competitive inhibition of this fluorescent ligand were characterized, which were in good agreement with a semi-empirical model constructed from fundamental protein-binding relationships. Using this method it was shown for the first time that even though mature mBMMCs express H2R and H4R to the same extent, immunoglobulin E sensitization results in H4R upregulation only, while the surface expression of H2R remains unchanged. PMID:25212523

  6. Histamine H4 receptor antagonism reduces hapten-induced scratching behaviour but not inflammation.

    Science.gov (United States)

    Rossbach, Kristine; Wendorff, Stephanie; Sander, Kerstin; Stark, Holger; Gutzmer, Ralf; Werfel, Thomas; Kietzmann, Manfred; Bäumer, Wolfgang

    2009-01-01

    Effects of the histamine H(4) receptor antagonist JNJ 7777120 (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine) were tested in two models of allergic contact dermatitis. Dermatitis was induced by 2,4-dinitrochlorobenzene and toluene-2,4-diisocyanate, which differ in their Th1-Th2 profile in that way that 2,4-dinitrochlorobenzene is a classical contact allergen with a pronounced Th1-mediated inflammation, while the respiratory chemical allergen toluene-2,4-diisocyanate induces a Th2-dominated inflammation. JNJ 7777120 (15 mg/kg) administered 2 h and 30 min before and 1 h after challenge did not reduce the hapten-induced ear swelling determined 24 h after challenge. This was confirmed by histological evaluation of the ear skin. A repeated administration of the haptens to the rostral part of the back of sensitized animals resulted in a frequent scratching behaviour. An administration of JNJ 7777120 (15 mg/kg) 30 min before challenge reduced this hapten-induced scratching significantly. The H(1) receptor antagonist cetirizine also reduced the scratching bouts in sensitized mice. A combination of H(1) and H(4) receptor antagonists resulted in the strongest inhibition of scratching behaviour associated with allergic dermatitis. These results indicate that H(4) receptor antagonism fails to reduce the allergic inflammatory response but strongly inhibits allergen-induced itch. Thus, a combination of H(4) and H(1) receptor antagonism might be a new strategy to treat pruritus related to allergic diseases like atopic dermatitis. PMID:18647342

  7. H4 histamine receptors inhibit steroidogenesis and proliferation in Leydig cells.

    Science.gov (United States)

    Abiuso, Adriana María Belén; Berensztein, Esperanza; Pagotto, Romina María; Pereyra, Elba Nora; Medina, Vanina; Martinel Lamas, Diego José; Besio Moreno, Marcos; Pignataro, Omar Pedro; Mondillo, Carolina

    2014-12-01

    The histamine H4 receptor (HRH4), discovered only 13 years ago, is considered a promising drug target for allergy, inflammation, autoimmune disorders and cancer, as reflected by a steadily growing number of scientific publications and patent applications. Although the presence of HRH4 has been evidenced in the testis, its specific localization or its role has not been established. Herein, we sought to identify the possible involvement of HRH4 in the regulation of Leydig cell function. We first evaluated its expression in MA-10 Leydig tumor cells and then assessed the effects of two HRH4 agonists on steroidogenesis and proliferation. We found that HRH4 is functionally expressed in MA-10 cells, and that its activation leads to the inhibition of LH/human chorionic gonadotropin-induced cAMP production and StAR protein expression. Furthermore, we observed decreased cell proliferation after a 24-h HRH4 agonist treatment. We then detected for the sites of HRH4 expression in the normal rat testis, and detected HRH4 immunostaining in the Leydig cells of rats aged 7-240 days, while 21-day-old rats also presented HRH4 expression in male gametes. Finally, we evaluated the effect of HRH4 activation on the proliferation of normal progenitor and immature rat Leydig cell culture, and both proved to be susceptible to the anti-proliferative effect of HRH4 agonists. Given the importance of histamine (2-(1H-imidazol-4-yl)ethanamine) in human (patho)physiology, continued efforts are directed at elucidating the emerging properties of HRH4 and its ligands. This study reveals new sites of HRH4 expression, and should be considered in the design of selective HRH4 agonists for therapeutic purposes. PMID:25253872

  8. QSAR study on the histamine (H3 receptor antagonists using the genetic algorithm: Multi parameter linear regression

    Directory of Open Access Journals (Sweden)

    Adimi Maryam

    2012-01-01

    Full Text Available A quantitative structure activity relationship (QSAR model has been produced for predicting antagonist potency of biphenyl derivatives as human histamine (H3 receptors. The molecular structures of the compounds are numerically represented by various kinds of molecular descriptors. The whole data set was divided into training and test sets. Genetic algorithm based multiple linear regression is used to select most statistically effective descriptors. The final QSAR model (N =24, R2=0.916, F = 51.771, Q2 LOO = 0.872, Q2 LGO = 0.847, Q2 BOOT = 0.857 was fully validated employing leaveone- out (LOO cross-validation approach, Fischer statistics (F, Yrandomisation test, and predictions based on the test data set. The test set presented an external prediction power of R2 test=0.855. In conclusion, the QSAR model generated can be used as a valuable tool for designing similar groups of new antagonists of histamine (H3 receptors.

  9. (2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands.

    Science.gov (United States)

    Kamińska, Katarzyna; Ziemba, Julia; Ner, Joanna; Schwed, Johannes Stephan; Łażewska, Dorota; Więcek, Małgorzata; Karcz, Tadeusz; Olejarz, Agnieszka; Latacz, Gniewomir; Kuder, Kamil; Kottke, Tim; Zygmunt, Małgorzata; Sapa, Jacek; Karolak-Wojciechowska, Janina; Stark, Holger; Kieć-Kononowicz, Katarzyna

    2015-10-20

    Within the constantly growing number of histamine H4 (H4R) receptor ligands there is a large group of azine derivatives. A series of novel compounds in the group of 4-methylpiperazine-1,3,5-triazine-2-amines were designed and obtained. Considered structures were modified at the triazine 6-position by introduction of variously substituted arylethenyl moieties. Their affinities to histamine H4 receptors were evaluated in radioligand binding assays with use of Sf9 cells, transiently expressing human H4R. Pharmacological studies results allowed to identify 4-[(E)-2-(3-chlorophenyl)ethenyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (Ki = 253 nM) as the most potent compound in the present series. PMID:26360048

  10. Receptor-independent, vacuolar ATPase-mediated cellular uptake of histamine receptor-1 ligands: Possible origin of pharmacological distortions and side effects

    International Nuclear Information System (INIS)

    The aims of this study were to investigate whether several histamine receptor agonists and antagonists are subjected to receptor-independent ion trapping into acidic organelles, and whether this sequestration influences their pharmacological or toxicological properties. Vacuolar (V)-ATPase-dependent intracellular sequestration of agonists was recognized as morphological alterations (large fluid-filled vacuoles for betahistine and 1-methylhistamine, granular uptake for fluorescent BODIPY FL histamine) prevented by the specific V-ATPase inhibitor bafilomycin A1 in rabbit vascular smooth muscle cells. Lipophilicity was the major determinant of these cellular effects (order of potency: BODIPY FL histamine > betahistine > 1-methylhistamine > histamine) that occurred at high concentrations. This ranking was dissociable from the potency order for H1 receptor-mediated contraction of the rabbit aorta, a response uninfluenced by bafilomycin. Antihistamines are inherently more lipophilic and caused vacuolization of a proportion of cells at 5-500 μM. Agonist or antagonist-induced vacuoles were of macroautophagic nature (labeled with GFP-conjugated LC3, Rab7 and CD63; detection of LC3 II). Further, the 2 most lipophilic antihistamines tested, astemizole and terfenadine, were potentiated by V-ATPase blockade in the aortic contractility assay (13- and 3.6-fold more potent, respectively, pA2 scale), suggesting that V-ATPase-mediated cation trapping sequesters these antagonists from the vicinity of H1 receptors in the therapeutic concentration range. This potentiation did not apply to less lipophilic antagonists (pyrilamine, diphenhydramine). While some agonists and all tested antagonists of the histamine H1 receptors induce the V-ATPase-dependent vacuolar and autophagic cytopathology, sequestration affects the pharmacology of only the most lipophilic antagonists, the ones prone to off-target arrhythmogenic side effects

  11. Plasticity of histamine H3 receptor expression and binding in the vestibular nuclei after labyrinthectomy in rat

    Directory of Open Access Journals (Sweden)

    Karlstedt Kaj

    2004-09-01

    Full Text Available Abstract Background In rat, deafferentation of one labyrinth (unilateral labyrinthectomy results in a characteristic syndrome of ocular and motor postural disorders (e.g., barrel rotation, circling behavior, and spontaneous nystagmus. Behavioral recovery (e.g., diminished symptoms, encompassing 1 week after unilateral labyrinthectomy, has been termed vestibular compensation. Evidence suggesting that the histamine H3 receptor plays a key role in vestibular compensation comes from studies indicating that betahistine, a histamine-like drug that acts as both a partial histamine H1 receptor agonist and an H3 receptor antagonist, can accelerate the process of vestibular compensation. Results Expression levels for histamine H3 receptor (total as well as three isoforms which display variable lengths of the third intracellular loop of the receptor were analyzed using in situ hybridization on brain sections containing the rat medial vestibular nucleus after unilateral labyrinthectomy. We compared these expression levels to H3 receptor binding densities. Total H3 receptor mRNA levels (detected by oligo probe H3X as well as mRNA levels of the three receptor isoforms studied (detected by oligo probes H3A, H3B, and H3C showed a pattern of increase, which was bilaterally significant at 24 h post-lesion for both H3X and H3C, followed by significant bilateral decreases in medial vestibular nuclei occurring 48 h (H3X and H3B and 1 week post-lesion (H3A, H3B, and H3C. Expression levels of H3B was an exception to the forementioned pattern with significant decreases already detected at 24 h post-lesion. Coinciding with the decreasing trends in H3 receptor mRNA levels was an observed increase in H3 receptor binding densities occurring in the ipsilateral medial vestibular nuclei 48 h post-lesion. Conclusion Progressive recovery of the resting discharge of the deafferentated medial vestibular nuclei neurons results in functional restoration of the static postural and

  12. TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch

    OpenAIRE

    Wilson, Sarah R.; Kristin A Gerhold; Bifolck-Fisher, Amber; Liu, Qin; Patel, Kush N.; Dong, Xinzhong; Bautista, Diana M.

    2011-01-01

    SUMMARY Itch, the unpleasant sensation that evokes a desire to scratch, accompanies numerous skin and nervous system disorders. In many cases, pathological itch is insensitive to antihistamine treatment. Recent studies have identified members of the Mas-related GPCR (Mrgpr) family that are activated by mast cell mediators and promote histamine-independent itch. MrgprA3 and MrgprC11 act as receptors for the pruritogens chloroquine and BAM8–22, respectively. However, the signaling pathways and ...

  13. VIP/PACAP receptors in cerebral arteries of rat

    DEFF Research Database (Denmark)

    Erdling, André; Sheykhzade, Majid; Maddahi, Aida;

    2013-01-01

    BACKGROUND: Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP)-containing nerves surround cerebral blood vessels. The peptides have potent vasodilator properties via smooth muscle cell receptors and activation of adenylate cyclase. The purpose of this......-465 inhibited the VIP induced relaxation. Western blot showed the presence of the receptor proteins in cerebral vasculature and immunohistochemistry showed that all three receptors are present and located in the cytoplasm of smooth muscle cells. CONCLUSION: In both systems, the two blockers antagonized the...... relaxant VIP effect; the potency order of agonists and the immunohistochemistry suggest the presence of the dilatory VPAC(1) and VPAC(2) receptors on the smooth muscle cells....

  14. Histamine H(1) and H(3) receptors in the rat thalamus and their modulation after systemic kainic acid administration.

    Science.gov (United States)

    Jin, Congyu; Lintunen, Minnamaija; Panula, Pertti

    2005-07-01

    In rat thalamus, histamine H(1) receptor and isoforms of H(3) receptor were expressed predominantly in the midline and intralaminar areas. Correspondingly, higher H(1) and H(3) receptor binding was also detected in these areas. All isoforms of H(3) receptor were expressed in several thalamic nuclei, but there were minor differences between their expression patterns. H(1) mRNA expression was high in the ventral thalamus, but the H(1) binding level was low in these areas. Since increased brain histamine appears to have an antiepileptic effect through the H(1) receptor activity, kainic acid (KA)-induced status epilepticus in rat was used to study modulation of H(1) and H(3) receptors in the thalamus following seizures. After systemic KA administration, transient decreases in mRNA expression of H(1) receptor and H(3) receptor isoforms with full-length third intracellular loops were seen in the midline areas and the H(1) receptor mRNA expression also decreased in the ventral thalamus. After 1 week, a robust increase in mRNA expression of H(3) receptor isoforms with a full-length third intracellular loop was found in the ventral posterior, posterior, and geniculate nuclei. The changes indicate a modulatory role of H(3) receptor in the sensory and motor relays, and might be involved in possible neuroprotective and compensatory mechanisms after KA administration. However, short-term increases in the H(3) receptor binding appeared earlier (72 h) than the increases of H(3) mRNA expression (1-4 w). The elevations in H(3) binding were evident in the intralaminar area, laterodorsal, lateral posterior, posterior and geniculate nuclei, and were likely to be related to the cortical and subcortical inputs to thalamus. PMID:15899242

  15. Histamine and the striatum.

    Science.gov (United States)

    Bolam, J Paul; Ellender, Tommas J

    2016-07-01

    The neuromodulator histamine is released throughout the brain during periods of wakefulness. Combined with an abundant expression of histamine receptors, this suggests potential widespread histaminergic control of neural circuit activity. However, the effect of histamine on many of these circuits is unknown. In this review we will discuss recent evidence for histaminergic modulation of the basal ganglia circuitry, and specifically its main input nucleus; the striatum. Furthermore, we will discuss recent findings of histaminergic dysfunction in several basal ganglia disorders, including in Parkinson's disease and most prominently, in Tourette's syndrome, which has led to a resurgence of interest in this neuromodulator. Combined, these recent observations not only suggest a central role for histamine in modulating basal ganglia activity and behaviour, but also as a possible target in treating basal ganglia disorders. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID:26275849

  16. Histamine induces the production of matrix metalloproteinase-9 in human astrocytic cultures via H1-receptor subtype.

    Science.gov (United States)

    Patel, Aarti; Vasanthan, Vishnu; Fu, Wen; Fahlman, Richard P; MacTavish, David; Jhamandas, Jack H

    2016-05-01

    Accumulation of β-amyloid (Aβ) protein within the brain is a neuropathological hallmark of Alzheimer's disease (AD). One strategy to facilitate Aβ clearance from the brain is to promote Aβ catabolism. Matrix metalloproteinase-9 (MMP-9), a member of the family of Zn(+2)-containing endoproteases, known to be expressed and secreted by astrocytes, is capable of degrading Aβ. Histamine, a major aminergic brain neurotransmitter, stimulates the production of MMP-9 in keratinocytes through the histamine H1 receptor (H1R). In the present study, we show that histamine evokes a concentration- and calcium-dependent release of MMP-9 from human astrocytic U373 cells and primary cultures of human and rat astrocytes through the H1R subtype. Activation of H1R on astrocytes elevated intracellular levels of Ca(2+) that was accompanied by time-dependent increases in MAP kinase p44/p42 and PKC. In-cell western blots revealed dose-dependent increases in both enzymes, confirming involvement of these signal transduction pathways. We next investigated the extent of recombinant human MMP-9 (rhMMP-9) proteolytic activity on soluble oligomeric Aβ (soAβ). Mass spectrometry demonstrated time-dependent cleavage of soAβ (20 μM), but not another amyloidogenic protein amylin, upon incubation with rhMMP-9 (100 nM) at 1, 4 and 17 h. Furthermore, Western blots showed a shift in soAβ equilibrium toward lower order, less toxic monomeric species. In conclusion, both MAPK p44/p42 and PKC pathways appear to be involved in histamine-upregulated MMP-9 release via H1Rs in astrocytes. Furthermore, MMP-9 appears to cleave soAβ into less toxic monomeric species. Given the key role of histamine in MMP-9 release, this neurotransmitter may serve as a potential therapeutic target for AD. PMID:25682263

  17. The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation.

    Science.gov (United States)

    Cowden, Jeffery M; Zhang, Mai; Dunford, Paul J; Thurmond, Robin L

    2010-04-01

    The role of histamine H(4) receptor (H(4)R) was investigated in a T-helper type 2 (Th2)-cell-mediated mouse skin inflammation model that mimics several of the features of atopic dermatitis. Treatment with two specific H(4)R antagonists before challenge with FITC led to a significant reduction in ear edema, inflammation, mast cell, and eosinophil infiltration. This was accompanied by a reduction in the levels of several cytokines and chemokines in the ear tissue. Upon ex vivo antigen stimulation of lymph nodes, H(4)R antagonism reduced lymphocyte proliferation and IL-4, IL-5, and IL-17 levels. One explanation for this finding is that lymph nodes from animals dosed with the H(4)R antagonist, JNJ 7777120, contained a lower number of FITC-positive dendritic cells. The effect of H(4)R antagonism on dendritic cell migration in vivo may be an indirect result of the reduction in tissue cytokines and chemokines or a direct effect on chemotaxis. In addition to anti-inflammatory effects, JNJ 7777120 also significantly inhibited the pruritus shown in the model. Therefore, the dual effects of H(4)R antagonists on pruritus and Th2-cell-mediated inflammation point to their therapeutic potential for the treatment of Th2-mediated skin disorders, including atopic dermatitis. PMID:19907432

  18. Discovery and SAR of 6-alkyl-2,4-diaminopyrimidines as histamine H₄ receptor antagonists.

    Science.gov (United States)

    Savall, Brad M; Chavez, Frank; Tays, Kevin; Dunford, Paul J; Cowden, Jeffery M; Hack, Michael D; Wolin, Ronald L; Thurmond, Robin L; Edwards, James P

    2014-03-27

    This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects. PMID:24495018

  19. Expression of histamine receptors in the human endolymphatic sac: the molecular rationale for betahistine use in Menieres disease.

    Science.gov (United States)

    Møller, M Nue; Kirkeby, S; Vikeså, J; Nielsen, F Cilius; Caye-Thomasen, P

    2016-07-01

    The human endolymphatic sac (ES) is situated in a duplicature of the dura in the posterior cranial fossa and constitutes a part of the inner ear. The sac possesses immunological capacities and is responsible for a major part of the trans-epithelial ion transport occurring within the inner ear, via molecular mechanisms similar to that of the kidney collecting duct epithelia. Dysfunction of the trans-epithelial ion transport has been hypothesized as the reason for the endolymphatic hydrops occurring in Menieres diseases. Thus, candidate drug selection for medical treatment of Menieres disease has been based on a potential capability of improving trans-epithelial ion transport. However, recent human studies seems to rule out diuretic therapy and The Committee for Medicinal Products for Human Use redrew the recommendation for trimetazidine (Vastarel) treatment in the management of Meniere disease in 2012. This leaves betahistine (Betaserc) as the only drug for potential prevention of the incapacitating attacks of dizziness, tinnitus and hearing loss. However, the histamine receptors targeted by betahistine have never been demonstrated in the human ES. Accordingly, this study aims to investigate the expression of histamine receptors of the human ES epithelium and sub-epithelial stroma. Following sampling of human endolymphatic sac tissue during translabyrinthine surgery, the expression of histamine receptor genes was determined by cDNA microarray analysis. Results were subsequently verified by immuno-histochemistry. The combined results of microarrays and immuno-histochemistry showed expression of the histamine receptor HRH1 in the epithelial lining of the ES, whereas HRH3 was expressed exclusively in the sub-epithelial capillary network. Receptors HRH2 and -4 were not expressed. The present data provide the first direct evidence of a molecular rationale for betahistine treatment in Menieres disease. A potential betahistine effect in Menieres disease may primarily be

  20. Histamine 1 receptor knock out mice show age-dependent susceptibility to status epilepticus and consequent neuronal damage.

    Science.gov (United States)

    Kukko-Lukjanov, Tiina-Kaisa; Grönman, Maria; Lintunen, Minnamaija; Laurén, Hanna B; Michelsen, Kimmo A; Panula, Pertti; Holopainen, Irma E

    2012-06-01

    The central histaminergic neuron system is an important regulator of activity stages such as arousal and sleep. In several epilepsy models, histamine has been shown to modulate epileptic activity and histamine 1 (H1) receptors seem to play a key role in this process. However, little is known about the H1 receptor-mediated seizure regulation during the early postnatal development, and therefore we examined differences in severity of kainic acid (KA)-induced status epilepticus (SE) and consequent neuronal damage in H1 receptor knock out (KO) and wild type (WT) mice at postnatal days 14, 21, and 60 (P14, P21, and P60). Our results show that in P14 H1 receptor KO mice, SE severity and neuronal damage were comparable to those of WT mice, whereas P21 KO mice had significantly decreased survival, more severe seizures, and enhanced neuronal damage in various brain regions, which were observed only in males. In P60 mice, SE severity did not differ between the genotypes, but in KO group, neuronal damage was significantly increased. Our results suggest that H1 receptors could contribute to regulation of seizures and neuronal damage age-dependently thus making the histaminergic system as a challenging target for novel drug design in epilepsy. PMID:22348791

  1. Histamine receptors coupled to [3H]cAMP accumulation in brain: pharmacological characterization in a vesicular preparation of guinea pig cortex

    International Nuclear Information System (INIS)

    The histamine-stimulated accumulation of [3H]cAMP (formed by prelabeling with [3H]adenine) was characterized pharmacologically in a vesicular preparation of guinea pig cortex. The H2 antagonist cimetidine maximally blocked 80% of the response, whereas only 45% of the response could be inhibited by H1 antagonists. A combination of H1 and H2 antagonists completely abolished the response. These and other findings show that both H1 and H2 receptors mediate the response, but 25% of the response may require simultaneous activation of both receptors. A role for adenosine as a mediator of the histamine response was investigated. Adenosine deaminase (EC 3.5.4.4., 2.5 units/ml) decreased basal [3H]cAMP levels, abolished the cimetidine-resistant component of the histamine response, and reduced maximal H1 antagonism of the histamine response to 30%. Treatment with a combination of adenosine deaminase and the calcium chelator EGTA (2 mM) appeared to eliminate the H1 component completely. Under these latter conditions only H2 receptors appeared to mediate the histamine response. Thus, both H1 and H2 receptors stimulate [3H]cAMP accumulation in the vesicular preparation, but the H1 response seems to require either concomitant adenosine or H2 receptor stimulation and may be calcium dependent. These findings differ from those found in broken cell membrane preparations, where only H2 receptors appear to be coupled to adenylate cyclase activation

  2. H1-histamine receptors may mediate the contractile response of guinea-pig ileum to 'histamine-free' splenic extracts.

    OpenAIRE

    Ainz, L. F.; Casis, E.; de Gandarias, J. M.; Gil-Rodrigo, C. E.; Goiriena de Gandarias, J. J.

    1983-01-01

    A water-soluble splenic factor, which produces a contractile response of the guinea-pig ileum, that is resistant to cholinoceptor and adrenoceptor antagonists is described. The ileal contractions elicited by the splenic extract showed some significant differences from those elicited by 5-hydroxytryptamine. The responses to splenic extract were not affected by the D-tryptamine-receptor antagonist, methysergide. The effect of the splenic extract on the guinea-pig ileum was similar to that of hi...

  3. Cerebrovascular angiotensin AT1 receptor regulation in cerebral ischemia

    DEFF Research Database (Denmark)

    Edvinsson, Lars

    2008-01-01

    The mechanism behind the positive response to the inhibition of the angiotensin II receptor AT(1) in conjunction with stroke is elusive. Here we demonstrate that cerebrovascular AT(1) receptors show increased expression (upregulation) after cerebral ischemia via enhanced translation. This enhanced...

  4. Drug-likeness approach of 2-aminopyrimidines as histamine H3 receptor ligands.

    Science.gov (United States)

    Sadek, Bassem; Schreeb, Annemarie; Schwed, Johannes Stephan; Weizel, Lilia; Stark, Holger

    2014-01-01

    A small series of compounds containing derivatives of 2,4-diamino- and 2,4,6-triaminopyrimidine (compounds 2-7) was synthesized and tested for binding affinity to human histamine H3 receptors (hH3Rs) stably expressed in HEK-293 cells and human H4Rs (hH4Rs) co-expressed with Gαi2 and Gβ1γ2 subunits in Sf9 cells. Working in part from the lead compound 6-(4-methylpiperazin-1-yl)-N (4)-(3-(piperidin-1-yl)propyl)pyrimidine-2,4-diamine (compound 1) with unsatisfactory affinity and selectivity to hH3Rs, our structure-activity relationship studies revealed that replacement of 4-methylpiperazino by N-benzylamine and substitution of an amine group at the 2-position of the 2-aminopyrimidine core structure with 3-piperidinopropoxyphenyl moiety as an hH3R pharmacophore resulted in N (4)-benzyl-N (2)-(4-(3-(piperidin-1-yl)propoxy)phenyl)pyrimidine-2,4-diamine (compound 5) with high hH3R affinity (k(i) =4.49 ± 1.25 nM) and H3R receptor subtype selectivity of more than 6,500×. Moreover, initial metric analyses were conducted based on their target-oriented drug-likeness for predictively quantifying lipophilicity, ligand efficiency, lipophilicity-dependent ligand efficiency, molecular size-independent efficiency, and topological molecular polar surface. As to the development of potential H3R ligands, results showed that integration of the hH3R pharmacophore in hH4R-affine structural scaffolds resulted in compounds with high hH3R affinity (4.5-650 nM), moderate to low hH4R affinity (4,500-30,000 nM), receptor subtype selectivity (ratio hH4R/hH3R; 8-6,500), and promising calculated drug-likeness properties. PMID:25278747

  5. In situ detection of H1-receptor mRNA and absence of apoptosis in the transient histamine system of the embryonic rat brain.

    Science.gov (United States)

    Kinnunen, A; Lintunen, M; Karlstedt, K; Fukui, H; Panula, P

    1998-04-27

    In the developing brain, histamine is one of the first neurotransmitters to appear. The concentration of histamine in the prenatal brain is fivefold that of adult levels. During the prenatal development a large transiently histamine-immunoreactive cell population distinct from the adult histaminergic system can be found within a subpopulation of the developing serotonergic raphe nuclei neurons. Also histamine-immunoreactive nerve fibers are widely distributed already during the prenatal development extending to the diencephalon, the thalamus, the cortex, and the spinal cord. Large numbers of histamine-containing mast cells also migrate into the brain during the late prenatal life. The wide distribution and high prenatal concentrations imply important functions for the histaminergic system during intrauterine development. However, little is known about the actual functions of histamine during development, and which of the histamine receptors are present in the prenatal rat brain is currently unknown. In the present study, we used in situ hybridization to study the distribution of H1-receptor (H1R) mRNA in the embryonic rat brain and spinal cord. H1R mRNA could be detected in rat brain and in spinal cord on embryonic day (E) 14, and the expression pattern seemed to partially localize in areas containing histamine-immunoreactive nerve fibers through E14-E20. H1R mRNA was also detected by reverse transcriptase polymerase chain reaction from embryonic brain samples and by Northern hybridization. The possible involvement of apoptosis in the disappearance of the developing transiently histaminergic system was studied by using apoptosis detection based on the terminal dUTP nick end labeling (TUNEL) technique and with c-Fos immunostaining. Although histamine immunoreactivity disappears dramatically from the developing raphe nuclei after E18, only occasional apoptotic nuclei could be seen in the histamine-immunoreactive cell bodies. The presence of H1R mRNA during the

  6. Regulatory mechanism of endothelin receptor B in the cerebral arteries after focal cerebral ischemia

    DEFF Research Database (Denmark)

    Grell, Anne-Sofie; Thigarajah, Rushani; Edvinsson, Lars;

    2014-01-01

    BACKGROUND AND PURPOSE: Increased expression of endothelin receptor type B (ETBR), a vasoactive receptor, has recently been implied in the reduced cerebral blood flow and exacerbated neuronal damage after ischemia-reperfusion (I/R). The study explores the regulatory mechanisms of ETBR to identify...... drug targets to restore normal cerebral artery contractile function as part of successful neuroprotective therapy. METHODS: We have employed in vitro methods on human and rat cerebral arteries to study the regulatory mechanisms and the efficacy of target selective inhibitor, Mithramycin A (MitA), to...... arteries. RESULTS: Increased expression of specificity protein (Sp1) was observed in human and rat cerebral arteries after organ culture, strongly correlating with the ETBR upregulation. Similar observations were made in MCAO rats. Treatment with MitA, a Sp1 specific inhibitor, significantly downregulated...

  7. Effect of histamine and histamine antagonists on portal blood pressure in patients with hepatosplenic schistosomiasis.

    OpenAIRE

    el-Gendi, M A; Nassar, S H

    1980-01-01

    1 Histamine injection via the cannulated portal vein significantly raised the portal pressure in normal volunteers. This elevation was reversed by an H1-receptor blocker but not an H2-receptor blocker. When an H1-receptor blocker was injected first followed by histamine, no significant change in portal pressure was obtained. On the other hand, an H2-receptor blocker failed to antagonize the effect of histamine. 2 Histamine injection induced a non-significant increase in the portal pressure in...

  8. Pre-synaptic histamine H₃ receptors modulate glutamatergic transmission in rat globus pallidus.

    Science.gov (United States)

    Osorio-Espinoza, A; Alatorre, A; Ramos-Jiménez, J; Garduño-Torres, B; García-Ramírez, M; Querejeta, E; Arias-Montaño, J-A

    2011-03-10

    The globus pallidus, a neuronal nucleus involved in the control of motor behavior, expresses high levels of histamine H(3) receptors (H(3)Rs) most likely located on the synaptic afferents to the nucleus. In this work we studied the effect of the activation of rat pallidal H(3)Rs on depolarization-evoked neurotransmitter release from slices, neuronal firing rate in vivo and turning behavior. Perfusion of globus pallidus slices with the selective H(3)R agonist immepip had no effect on the release of [(3)H]-GABA ([(3)H]-γ-aminobutyric acid) or [(3)H]-dopamine evoked by depolarization with high (20 mM) K(+), but significantly reduced [(3)H]-d-aspartate release (-44.8 ± 2.6% and -63.7 ± 6.2% at 30 and 100 nM, respectively). The effect of 30 nM immepip was blocked by 10 μM of the selective H(3)R antagonist A-331440 (4'-[3-[(3(R)-dimethylamino-1-pyrrolidinyl]propoxy]-[1,1-biphenyl]-4'-carbonitrile). Intra-pallidal injection of immepip (0.1 μl, 100 μM) decreased spontaneous neuronal firing rate in anaesthetized rats (peak inhibition 68.8±10.3%), and this effect was reversed in a partial and transitory manner by A-331440 (0.1 μl, 1 mM). In free-moving rats the infusion of immepip (0.5 μl; 10, 50 and 100 μM) into the globus pallidus induced dose-related ipsilateral turning following systemic apomorphine (0.5 mg/kg, s.c.). Turning behavior induced by immepip (0.5 μl, 50 μM) and apomorphine was partially prevented by the local injection of A-331440 (0.5 μl, 1 mM) and was not additive to the turning evoked by the intra-pallidal injection of antagonists at ionotropic glutamate receptors (0.5 μl, 1 mM each of AP-5, dl-2-amino-5-phosphonovaleric acid, and CNQX, 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione). These results indicate that pre-synaptic H(3)Rs modulate glutamatergic transmission in rat globus pallidus and thus participate in the control of movement by basal ganglia. PMID:21195747

  9. Are basophil histamine release and high affinity IgE receptor expression involved in asymptomatic skin sensitization?

    DEFF Research Database (Denmark)

    Jensen, Bettina Margrethe; Assing, K; Jensen, Lone Hummelshøj; Glue, C; Skov, P S; Poulsen, L K

    2006-01-01

    . However, a relationship between the AS status and FcepsilonRI has not been investigated. We aimed to characterize basophils from AS by looking at histamine release (HR) (sensitivity and reactivity) and the FcepsilonRI molecule, and compare it with nonatopic (NA) or allergic (A) persons.......Immunoglobulin (Ig)E-sensitized persons with positive skin prick test, but no allergy symptoms, are classified as being asymptomatic skin sensitized (AS). The allergic type 1 disease is dependant on IgE binding to the high affinity IgE-receptor (FcepsilonRI) expressed on basophils and mast cells...

  10. Virtual fragment screening on GPCRs: a case study on dopamine D3 and histamine H4 receptors.

    Science.gov (United States)

    Vass, Márton; Schmidt, Éva; Horti, Ferenc; Keserű, György M

    2014-04-22

    Prospective structure based virtual fragment screening methodologies on two GPCR targets namely the dopamine D3 and the histamine H4 receptors with a library of 12,905 fragments were evaluated. Fragments were docked to the X-ray structure and the homology model of the D3 and H4 receptors, respectively. Representative receptor conformations for ensemble docking were obtained from molecular dynamics trajectories. In vitro confirmed hit rates ranged from 16% to 32%. Hits had high ligand efficiency (LE) values in the range of 0.31-0.74 and also acceptable lipophilic efficiency. The X-ray structure, the homology model and structural ensembles were all found suitable for docking based virtual screening of fragments against these GPCRs. However, there was little overlap among different hit sets and methodologies were thus complementary to each other. PMID:24607587

  11. Involvement of histamine H1 and H2 receptors in hypothermia induced by ionizing radiation in guinea pigs

    International Nuclear Information System (INIS)

    Radiation-induced hypothermia was examined in guinea pigs. Exposure to the head alone or whole-body irradiation induced hypothermia, whereas exposure of the body alone produced a small insignificant response. Systemic injection of disodium cromoglycate (a mast cell stabilizer) and cimetidine (H2-receptor antagonist) had no effect on radiation-induced hypothermia, whereas systemic and central administration of mepyramine (H1-receptor antagonist) or central administration of disodium cromoglycate or cimetidine attenuated it, indicating the involvement of central histamine through both H1 and H2 receptors in this response. Serotonin is not involved, since the serotonin antagonist methysergide had no effect on radiation-induced hypothermia. These results indicate that central histaminergic systems may be involved in radiation-induced hypothermia. 34 references, 5 figures, 2 tables

  12. Histamine H4 receptor activation alleviates neuropathic pain through differential regulation of ERK, JNK, and P38 MAPK phosphorylation.

    Science.gov (United States)

    Sanna, Maria D; Stark, Holger; Lucarini, Laura; Ghelardini, Carla; Masini, Emanuela; Galeotti, Nicoletta

    2015-12-01

    Histamine plays a complex role in pain modulation with opposite roles in nociception for histamine receptor subtypes 1, 2, and 3. The histamine H4 receptor (H4R) is expressed primarily on cells involved in inflammation and immune responses with a proinflammatory activity, but little is known about the role in nociception of neuronal H4R. To investigate the effects of neuronal H4R in pain transmission, the effects produced by the H4R agonist ST-1006 were detected in the spared nerve injury model of neuropathic pain. ST-1006 counteracted mechanical allodynia in neuropathic mice, an effect prevented by the H4R antagonist JNJ 10191584. In spared nerve injury mice, an early over-phosphorylation of ERK1 and ERK2 was observed in the dorsal root ganglia (DRG), spinal cord, and sciatic nerve. A progressive and long-lasting activation of JNK1 was observed in the sciatic nerve and, to a lesser extent, in the spinal cord and DRG. An increased p-P38 content was detected in the spinal cord and DRG, with no modification in the sciatic nerve. Administration of ST-1006 prevented phosphorylation of all 3 MAPK within DRG, and phosphorylation of ERK1, ERK2, and pJNK1 in the sciatic nerve. In the spinal cord, the H4R agonist prevented selectively the pERK2 increase with no effect on pJNK1 and p-P38 levels. Double immunofluorescence experiments showed a neuronal localization and site of action for H4R. These findings suggest a prevalent modulation of ERK activity after H4R stimulation and indicate the DRG as prominent site of action for H4R-mediated antineuropathic activity. Targeting neuronal H4R with selective agonists could have therapeutic potential for neuropathic pain treatment. PMID:26270581

  13. Cerebrovascular endothelin receptor upregulation in cerebral ischemia

    DEFF Research Database (Denmark)

    Edvinsson, Lars

    2009-01-01

    Stroke is a serious neurological disease and the third leading cause of death in the western world. In roughly 15 % of the cases, the cause is due to an intracranial haemorrhage, and the remaining 85 % represent ischemic strokes. Ischemic stroke is caused by the occlusion of a cerebral artery eit...

  14. Cerebrovascular endothelin receptor upregulation in cerebral ischemia

    DEFF Research Database (Denmark)

    Edvinsson, Lars

    2009-01-01

    Stroke is a serious neurological disease and the third leading cause of death in the western world. In roughly 15 % of the cases, the cause is due to an intracranial haemorrhage, and the remaining 85 % represent ischemic strokes. Ischemic stroke is caused by the occlusion of a cerebral artery...

  15. Adrenergic receptor subtypes in the cerebral circulation of newborn piglets

    International Nuclear Information System (INIS)

    The purpose of this study was to identify the α-adrenergic receptor subtype mediating cerebral vasoconstriction during sympathetic nerve stimulation in the newborn piglet. The effect of α1- and α2-antagonists prazosin and yohimbine on the cerebrovascular response to unilateral electrical stimulation (15 Hz, 15 V) of the superior cervical sympathetic trunk was studied in 25 newborn piglets. Regional cerebral blood flow was measured with tracer microspheres. Sympathetic stimulation decreased blood flow to the ipsilateral cerebrum hippocampus, choroid plexus, and masseter muscle. α1-Adrenergic receptor blockade with prazosin inhibited the sympathetic vasoconstriction in the cerebrum, hippocampus, and masseter muscle and abolished it in the choroid plexus. α/sub s/-Adrenergic receptor blockade with yohimbine had no effect. Following the higher dose of yohimbine, however, blood flow to all brain regions was increased by approximately two-fold, possibly due to enhanced cerebral metabolism. These data demonstrate that vascular α1-adrenergic receptors mediate vasoconstriction to neuroadrenergic stimulation in cerebral resistance vessels in the newborn piglet

  16. Morphological and lectin histochemical characteristics of spleen under the experimental application of H1-histamine receptor blockers

    Directory of Open Access Journals (Sweden)

    Dudok O.V.

    2016-03-01

    Full Text Available Background. It is well known that histamine modulate immunocompetent cells cooperation, since plenty of them expose H- and H2- receptors for this biogenic amine. However, the influence of synthetic blockers of these receptors on the structure and function of the spleen – the immune system organ – remains obscure. Objective. To investigate the influence of widely used H1-receptor blocker Loratadine on the microstructure and lectin histochemistry characteristics of a rat spleen. Methods. Daily intragastric insertion of Loratadine at a dose of 0.15 mg/kg was maintained for 30 days. Thereafter (on days 10th, 30th of experiment and on days 10th, 20th and 30th after its completion tissue samples of spleen were excised and subjected to general morphology and lectin histochemistry investigation. Results. On the early stages of Loratadine administration it was detected the increased white pulp content. Further changes included the appearance of germinative centers in lymphoid follicles with simultaneous compactization of periarterial zones. Lectin histochemistry revealed the accumulation of dendritic cells, which were selectively labeled by PNA and GNA, while WGA demonstrated its suitability for differential staining of white and red pulp in the rat spleen. Conclusion. Prolonged Loratadine administration induce antigenic stimulation of the spleen. Lectins PNA and GNA can be recommended for selective labeling of activated dendritic cells, WGA – for differential staining of white and red pulp of the rat spleen. Citation: Dudok OV, Yashchenko AM, Lutsyk OD. [Morphological and lectin histochemical characteristics of spleen under the experimental application of H1-histamine receptor blockers]. Morphologia. 2016;10(1:32-7. Ukrainian.

  17. Distinct signalling pathways of murine histamine H1- and H4-receptors expressed at comparable levels in HEK293 cells.

    Directory of Open Access Journals (Sweden)

    Silke Beermann

    Full Text Available Histamine (HA is recognized by its target cells via four G-protein-coupled receptors, referred to as histamine H1-receptor (H1R, H2R, H3R, and H4R. Both H1R and H4R exert pro-inflammatory functions. However, their signal transduction pathways have never been analyzed in a directly comparable manner side by side. Moreover, the analysis of pharmacological properties of the murine orthologs, representing the main targets of pre-clinical research, is very important. Therefore, we engineered recombinant HEK293 cells expressing either mouse (mH1R or mH4R at similar levels and analyzed HA-induced signalling in these cells. HA induced intracellular calcium mobilization via both mH1R and mH4R, with the mH1R being much more effective. Whereas cAMP accumulation was potentiated via the mH1R, it was reduced via the mH4R. The regulation of both second messengers via the H4R, but not the H1R, was sensitive to pertussis toxin (PTX. The mitogen-activated protein kinases (MAPKs ERK 1/2 were massively activated downstream of both receptors and demonstrated a functional involvement in HA-induced EGR-1 gene expression. The p38 MAPK was moderately activated via both receptors as well, but was functionally involved in HA-induced EGR-1 gene expression only in H4R-expressing cells. Surprisingly, in this system p38 MAPK activity reduced the HA-induced gene expression. In summary, using this system which allows a direct comparison of mH1R- and mH4R-induced signalling, qualitative and quantitative differences on the levels of second messenger generation and also in terms of p38 MAPK function became evident.

  18. Comparison of Different 2D and 3D-QSAR Methods on Activity Prediction of Histamine H3 Receptor Antagonists.

    Science.gov (United States)

    Dastmalchi, Siavoush; Hamzeh-Mivehroud, Maryam; Asadpour-Zeynali, Karim

    2012-01-01

    Histamine H3 receptor subtype has been the target of several recent drug development programs. Quantitative structure-activity relationship (QSAR) methods are used to predict the pharmaceutically relevant properties of drug candidates whenever it is applicable. The aim of this study was to compare the predictive powers of three different QSAR techniques, namely, multiple linear regression (MLR), artificial neural network (ANN), and HASL as a 3D QSAR method, in predicting the receptor binding affinities of arylbenzofuran histamine H3 receptor antagonists. Genetic algorithm coupled partial least square as well as stepwise multiple regression methods were used to select a number of calculated molecular descriptors to be used in MLR and ANN-based QSAR studies. Using the leave-group-out cross-validation technique, the performances of the MLR and ANN methods were evaluated. The calculated values for the mean absolute percentage error (MAPE), ranging from 2.9 to 3.6, and standard deviation of error of prediction (SDEP), ranging from 0.31 to 0.36, for both MLR and ANN methods were statistically comparable, indicating that both methods perform equally well in predicting the binding affinities of the studied compounds toward the H3 receptors. On the other hand, the results from 3D-QSAR studies using HASL method were not as good as those obtained by 2D methods. It can be concluded that simple traditional approaches such as MLR method can be as reliable as those of more advanced and sophisticated methods like ANN and 3D-QSAR analyses. PMID:25317190

  19. Effects of H1-receptor antagonists on 14C-aminopyrine accumulated in histamine-stimulated rabbit gastric glands

    International Nuclear Information System (INIS)

    After stimulation of gastric acid production there is a considerable delay before the acid starts to appear in the gastric lumen. The present study was carried out on isolated gastric glands to test the hypothesis that there may be a mechanisms in the parietal cell that contributes to this delay by preventing emptying of the secretory canaliculi. Glands were incubated with 14C-aminopyrine and stimulated with histamine. After accumulation of 14C-aminopyrine, various concentration of H1-receptor antagonists were added. Clemastine, promethazine, and hydroxyzine effectively and cetirizine and tripelennamine less effectively decreased the accumulated 14C-aminopyrine content in a dose-dependent manner without significantly reducing the oxygen consumption. The H1-receptor antagonists influenced the 14C-aminopyrine content in another manner than H2-receptor antagonists. No effects were obtained by atropine or lidocaine, indicating that the elimination of 14C-amionopyrine is not an inticholinergic effect or due to membrane effects as exerted by local anesthetics. Stimulation of glands by further addition of histamine did not significantly stimulate the uptake of 14C-aminopyrine in the glands, whereas stimulation with db-cAMP produced an increase that was most pronounced when low concentrations of hydroxyzine had been used. It is suggested that H1-receptor antagonists do not inhibit stimulation of acid production in the secretory canaliculi. They may, however, interfere with a mechanism preventing acid from leaving the parietal cell. Such a mechanism may contribute to the delay in appearance of acid in the gastric lumen after stimulation of gastric acid production. 37 refs., 7 figs

  20. Histamine H4 Receptor mediates interleukin-8 and TNF-α release in human mast cells via multiple signaling pathways.

    Science.gov (United States)

    Chen, X-F; Zhang, Z; Dou, X; Li, J-J; Zhang, W; Yu, Y-Y; Yu, B; Yu, B

    2016-01-01

    Histamine, mainly produced by mast cells, is an important inflammatory mediator in immune response. Recently Histamine H4 Receptor (H4R) was also identified in mast cells, from which pro-inflammatory cytokines and chemokines are released. However, the mechanism of how H4R mediates these cytokines and chemokines release in mast cells was still unclear. To further explore the role of H4R in the immune inflammatory response in mast cells, we tested the release of inflammatory cytokine tumor necrosis factor-α (TNF-α), chemokine interleukin-8 (IL-8) and the relevant signaling pathways activated by H4R on LAD2 cells (a human mast cell line). We found that the release of IL-8 and TNF-α were blocked by inhibitors of PI3K, ERK and Ca2+-Calcineurin-NFAT signaling pathways, while the release of these cytokines and chemokines were enhanced by the inhibitor of P38 signaling pathway. However, inhibitors of the JNK and NF-κB signaling pathways had little effect on the expression of the pro-inflammatory mediators. Moreover, activation of the H4R could induce phosphorylation of ERK, p38 and AKT in mast cells. In conclusion, we found that H4R mediates the release of inflammatory cytokine TNF-α and chemokine IL-8 in human mast cells via PI3K, Ca2+-Calcineurin-NFAT and MAPKs signaling pathways. PMID:26828993

  1. The histamine H4 -receptor (H4 R) regulates eosinophilic inflammation in ovalbumin-induced experimental allergic asthma in mice.

    Science.gov (United States)

    Hartwig, Christina; Munder, Antje; Glage, Silke; Wedekind, Dirk; Schenk, Heiko; Seifert, Roland; Neumann, Detlef

    2015-04-01

    Via the histamine H4 -receptor (H4 R), histamine promotes the pathogenesis of experimental allergic asthma in mice. Application of H4 R antagonists during sensitization as well as during provocation reduces the severity of the disease. However, the specific cell types functionally expressing H4 R in experimental allergic asthma have not been well characterized in vivo. In this study, we identified the cell type(s) responsible for H4 R activity in experimental asthma and related physiological mechanisms. Using H4 R-deficient mice, we studied the role of H4 R in the sensitization and effector phase. DCs lacking H4 R expression during the in vitro sensitization reaction resulted in effector T cells unable to induce an entire eosinophilic inflammation in the lung upon adoptive transfer in vivo. Recipient mice lacking H4 R expression, which were adoptively transferred with H4 R(+/+) T cells polarized in the presence of H4 R(+/+) DCs, showed reduced signs of inflammation and ameliorated lung function. Here, we provide in vivo evidence that in experimental asthma in mice the H4 R specifically regulates activation of DCs during sensitization, while in the effector phase the H4 R is active in cells involved in the activation of eosinophils, and possibly other cells. A putative therapy targeting the H4 R may be an option for asthma patients developing IL-5-dependent eosinophilia. PMID:25501767

  2. Delineating the role of histamine-1- and -4-receptors in a mouse model of Th2-dependent antigen-specific skin inflammation.

    Directory of Open Access Journals (Sweden)

    Subhashree Mahapatra

    Full Text Available BACKGROUND: Histamine drives pruritus in allergic skin diseases which clinically constitutes a most disruptive symptom. Skin pathology in allergic skin diseases is crucially influenced by different T-helper subsets. However, the contribution of different histamine-receptors to T-helper cell dependent skin pathology has not been definitively answered. Models which can specifically address the functional role of T-helper subsets and the mediators involved are therefore valuable to gain further insights into molecular pathways which contribute to allergic skin disease. They might also be helpful to probe amendable therapeutic interventions such as histamine-receptor antagonism. OBJECTIVE: Establishing an adoptive transfer model for antigen-specific Th cells, we aimed to delineate the role of histamine H1- and H4-receptors in Th2-dependent skin inflammation. METHODS: In-vitro differentiated and OVA primed Th2 cells were adoptively transferred into congenic recipient mice. In vivo treatment with specific histamine H1- and H4-receptor antagonists was performed to analyze the contribution of these histamine-receptors to Th2-dependent skin pathology in our model. Analysis four days after epicutaneous challenge comprised skin histology, flow cytometric detection of transferred T-helper cells and analysis of antigen-cytokine profiles in skin-draining lymph nodes. RESULTS: Use of specific H1- and H4-receptor antagonists revealed a crucial role for H1- and H4-receptors for Th2 migration and cytokine secretion in a Th2-driven model of skin inflammation. While H1- and H4-receptor antagonists both reduced Th2 recruitment to the site of challenge, local cytokine responses in skin-draining lymph nodes were only reduced by the combined application of H1- and H4-receptor antagonists and mast cell counts remained altogether unchanged by either H1R-, H4R- or combined antagonism. CONCLUSION: Our model demonstrates a role for H1- and H4-receptors in Th2 cell

  3. Role of serotonin 5-HT2C and histamine H1 receptors in antipsychotic-induced diabetes: A pharmacoepidemiological-pharmacodynamic study in VigiBase.

    Science.gov (United States)

    Montastruc, François; Palmaro, Aurore; Bagheri, Haleh; Schmitt, Laurent; Montastruc, Jean-Louis; Lapeyre-Mestre, Maryse

    2015-10-01

    Pharmacodynamic mechanisms of diabetes induced by antipsychotic drugs remain unclear, while numerous receptors have been suspected to be involved in the genesis of this Adverse Drug Reaction (ADR). We investigated potential relationships between antipsychotics׳ receptor occupancy (serotonin 5-HT1A, 5-HT2A, 5-HT2C, histamine H1, muscarinic M3, adrenergic α1, α2 or dopaminergic D2 D3 occupancies) and reports of diabetes using VigiBase(®), the World Health Organization (WHO) global Individual Case Safety Report (ICSR) database. All ADR reports from 15 first and second generation antipsychotic drugs recorded in VigiBase(®) were extracted. Logistic regression models, completed by disproportionality analysis, were used to determine the associations between antipsychotics׳ receptor occupancy and ICSRs of diabetes on VigiBase(®). During the study period, 94,460 ICSRs involved at least one of the 15 antipsychotics of interest. Diabetes was reported in 1799 (1.9%) patients. Clozapine was the most frequently suspected drug (n=953; 53.0%). A significant and positive association was found between histamine H1, muscarinic M3 and serotonin 5-HT2C, 5-HT2A receptor occupancies and reports of diabetes. A multivariable stepwise regression model showed that only serotonin 5-HT2c (AOR=2.13, CI 95% 1.72-2.64) and histamine H1 (AOR=1.91, CI 95% 1.38-2.64) predicted the risk for diabetes mellitus (p<0.001). Using an original pharmacoepidemiology-pharmacodynamic (PE-PD) approach, our study supports that antipsychotic drugs blocking simultaneously histamine H1 and serotonin 5-HT2C receptors are more frequently associated with diabetes reports in VigiBase(®) than other antipsychotics. These findings should encourage investigation of histamine H1 and serotonin 5-HT2C properties for predicting the risk of glycemic effects in candidate antipsychotics. PMID:26256010

  4. Implication of prostaglandins and histamine H1 and H2 receptors in radiation-induced temperature responses of rats

    International Nuclear Information System (INIS)

    Exposure of rats to 1-15 Gy gamma radiation (60Co) induced hyperthermia, whereas 20-200 Gy induced hypothermia. Exposure either to the head or to the whole body to 10 Gy induced hyperthermia, while body-only exposure produced hypothermia. This observation indicates that radiation-induced fever is a result of a direct effect on the brain. The hyperthermia due to 10 Gy was significantly attenuated by the pre- or post-treatment with a cyclooxygenase inhibitor, indomethacin. Hyperthermia was also altered by the central administration of a mu-receptor antagonist naloxone but only at low doses of radiation. These findings suggest that radiation-induced hyperthermia may be mediated through the synthesis and release of prostaglandins in the brain and to a lesser extent to the release of endogenous opioid peptides. The release of histamine acting on H1 and H2 receptors may be involved in radiation-induced hypothermia, since both the H1 receptor antagonist, mepyramine, and H2 receptor antagonist, cimetidine, antagonized the hypothermia. The results of these studies suggest that the release of neurohumoral substances induced by exposure to ionizing radiation is dose dependent and has different consequences on physiological processes such as the regulation of body temperature. Furthermore, the antagonism of radiation-induced hyperthermia by indomethacin may have potential therapeutic implications in the treatment of fever resulting from accidental irradiations

  5. Implication of prostaglandins and histamine H1 and H2 receptors in radiation-induced temperature responses of rats

    Energy Technology Data Exchange (ETDEWEB)

    Kandasamy, S.B.; Hunt, W.A.; Mickley, G.A.

    1988-04-01

    Exposure of rats to 1-15 Gy gamma radiation (/sup 60/Co) induced hyperthermia, whereas 20-200 Gy induced hypothermia. Exposure either to the head or to the whole body to 10 Gy induced hyperthermia, while body-only exposure produced hypothermia. This observation indicates that radiation-induced fever is a result of a direct effect on the brain. The hyperthermia due to 10 Gy was significantly attenuated by the pre- or post-treatment with a cyclooxygenase inhibitor, indomethacin. Hyperthermia was also altered by the central administration of a mu-receptor antagonist naloxone but only at low doses of radiation. These findings suggest that radiation-induced hyperthermia may be mediated through the synthesis and release of prostaglandins in the brain and to a lesser extent to the release of endogenous opioid peptides. The release of histamine acting on H1 and H2 receptors may be involved in radiation-induced hypothermia, since both the H1 receptor antagonist, mepyramine, and H2 receptor antagonist, cimetidine, antagonized the hypothermia. The results of these studies suggest that the release of neurohumoral substances induced by exposure to ionizing radiation is dose dependent and has different consequences on physiological processes such as the regulation of body temperature. Furthermore, the antagonism of radiation-induced hyperthermia by indomethacin may have potential therapeutic implications in the treatment of fever resulting from accidental irradiations.

  6. Implication of prostaglandins and histamine h1 and h2 receptors in radiation-induced temperature responses of rats

    Energy Technology Data Exchange (ETDEWEB)

    Kandasamy, S.B.; Hunt, W.A.; Mickley, G.A .

    1988-01-01

    Exposure of rats to 1-15 Gy cobalt 60 gamma radiation induced hyperthermia, whereas 20-200 Gy induced hypothermia. Exposure either to the head or to the whole body to 10 Gy induced hyperthermia, while body-only exposure produced hypothermia. This observation indicates that radiation-induced fever is a result of a direct effect on the brain. The hyperthermia due to 10 Gy was significantly attenuated by the pre- or post-treatment with a cyclooxgenase inhibitor, indomethacin. Hyperthermia was also altered by the central administration of a mu receptor antagonist naloxone but only at low doses of radiation. These findings suggest that radiation-induced hyperthermia may be mediated through the synthesis and release of prostaglandins in the brain and to a lesser extent to the release of endogenous opioid peptides. The release of histamine acting on H(1) and H(2) receptors may be involved in radiation-induced hypothermia since both the H(1) receptor antagonist, mepyramine, and H(2) receptor antagonist, cimetidine, antagonized the hypothermia. The results of these studies suggested that the release of neurohumoral substances induced by exposure to ionizing radiation is dose dependent and has different consequences on physiological processes such as the regulation of body temperature. Furthermore, the antagonism of radiation-induced hyperthermia by indomethacin may have potential therapeutic implications in the treatment of fever resulting from accidental irradiations.

  7. Agonist-induced desensitization of histamine H1 receptor-mediated inositol phospholipid hydrolysis in human umbilical vein endothelial cells.

    OpenAIRE

    McCreath, G; Hall, I P; Hill, S. J.

    1994-01-01

    1. The regulation of histamine-induced [3H]-inositol phosphate formation was studied in human cultured umbilical vein endothelial cells (HUVEC). 2. Histamine (EC50 4.8 microM) produced a 12.7 fold increase in [3H]-inositol phosphate formation over basal levels. Prior exposure to 0.1 mM histamine (2 h) produced a 78% reduction in the response to subsequent histamine (0.1 mM) challenge. The IC50 for this histamine-induced desensitization was 0.9 microM. 3. The inositol phosphate response to his...

  8. Acute exposure to high-peak-power pulsed microwaves affecting the histamine H3 receptor expression in rat hippocampus

    International Nuclear Information System (INIS)

    In the Morris Water test, high-peak-power pulsed microwave (MW)-exposed rats displayed some learning and memory behavior dysfunctions, and their escape time and swimming distance to the submerged platform were longer than those of the sham-exposed rats. to understand the molecular mechanism involved, the reverse transcription-polymerase chain reation (RT-PCR) and the Western-blotting technique were used for investigating the mRNA and protein expression patterns of the histamine H3 receptor (H3R) in rat hippocampus. High-peak-power pulsed microwave-exposure did not remarkably lead to the change in expression of H3R mRNA in rat hippocampi; however, it promoted the up-regulatory expression of the H3R protein, which was possibly triggered through the mitogen-activated protein kinase (MAPK) pathways. Therefore, further investigation of the molecular mechanism of the MW effects on the learning and memory behaviors is required. (authors)

  9. Anticonvulsant and procognitive properties of the non-imidazole histamine H3 receptor antagonist DL77 in male adult rats.

    Science.gov (United States)

    Sadek, Bassem; Saad, Ali; Subramanian, Dhanasekaran; Shafiullah, Mohamed; Łażewska, Dorota; Kieć-Kononowiczc, Katarzyna

    2016-07-01

    It has become clear that histamine H3 receptors (H3Rs) are implicated in modulating epilepsy and memory in laboratory animals. The new non-imidazole H3R antagonist DL77 has excellent selectivity profile and shows high in-vivo potency as well as in-vitro antagonist affinity with ED50 values of 2.1 ± 0.2 mg/kg and 8.4 ± 1.3 [nM], respectively. In the present study, the anticonvulsant effects of DL77 on maximal electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced seizure models were investigated. Moreover, the procognitive properties of DL77 were tested on acquisition, consolidation and retrieval processes in a one-trial inhibitory avoidance task in male Wistar rats. The results indicate that DL77 (5, 10, and 15 mg/kg, i.p.) significantly and dose-dependently reduced MES-induced seizure duration, whereas no protection was observed in PTZ- or STR-induced seizures. Importantly, the protective action observed for DL77 in MES-induced seizure was comparable to that of the reference antiepileptic drug (AED) phenytoin (PHT), and was also reversed when rats were pretreated with the CNS penetrant pyrilamine (PYR) (10 mg/kg, i.p.), or with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10 mg/kg, i.p.). Furthermore, the procognitive studies indicate that acute pre-training systemic administration of DL77 (2.5 mg/kg, i.p.) facilitated acquisition, whereas pre-testing acute administration of DL77 (5 and 10 mg/kg, i.p.) improved retrieval. Interestingly, the procognitive effect of DL77 on retrieval was completely abrogated when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL) but not the centrally acting H1R antagonist PYR, indicating that histaminergic pathways through activation of H2Rs appear to be participating in neuronal circuits involved in retrieval processes. Taken together, our results show that DL77 demonstrates anticonvulsant properties in the MES-induced seizure model and improves cognitive

  10. Radioprotective effects of histamine H2 receptor antagonists famotidine and ranitidine on gamma ray induced chromosome damage

    International Nuclear Information System (INIS)

    Histamine H2 receptor antagonist such as Cimetidine, Famotidine and Ranitidine are used in the clinical treatment of peptic ulcer. In vitro metaphase analysis and micronucleus assay were used to test the effects of famotidine and ranitidine on Cobalt 60 γ-ray induced clastogenic effects. Heparinised whole blood was obtained from healthy non-smoker volunteers. Blood samples were irradiated at a dose of 3Gy and incubated at 37 deg C for 1h. Lymphocyte cultures were initiated for metaphase chromosomes and cytochalasin B blocked micronucleus analysis. Aqueous solution of Famotidine (150 g/ml) and Ranitidine (500 g/ml) was added to the whole blood cultures at 0h and 24h. Cultures were harvested and processed at 48h and 72h for chromosome aberrations and micronucleus analysis respectively. Cultures treated with Famotidine at 0h and 24h after 3Gy γ-ray irradiation induce 60.90% and 56.52% inhibition in dicentrics, 48.70% and 43.61% inhibition in total aberrations. Ranitidine at 0h and 24h after 3Gy γ-ray irradiation induce 52.17% and 43.47% inhibition in dicentrics, 33.60% and 46.15% inhibition in total aberrations, when compared with 3Gy γ-ray irradiation alone. 43-54% inhibition in Binucleated cells with micronuclei and 47.72% inhibition in micronuclei at 0h treatment respectively. In conclusion radioprotective effects of Histamine H2 receptor antagonists famotidine and ranitidine on γ-ray induced chromosome damage is observed and the drugs effectively reduced the frequency of radiation induced chromosome aberrations and micronucleus. Famotidine was found to be more effective. The mechanism in which these drugs reduce clastogenic effect of γ-radiation is not fully understood. It might be due to their antioxidant and free radical-scavenging properties. (author)

  11. Effect of tracer metabolism on PET measurement of [[sup 11]C]pyrilamine binding to histamine H[sub 1] receptors

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sang Eun (Sungkyunkwan Univ., Seoul (Korea, Republic of). School of Medicine); Szabo, Z.; Seki, Chie; Ravert, H.T.; Scheffel, U.; Dannals, R.F.; Wagner, H.N. Jr.

    1999-04-01

    The present study was carried out to investigate the time course of [[sup 11]C]pyrilamine metabolism and the degree of entry of metabolites into the brain. PET studies were performed in seven healthy volunteers and arterial plasma concentrations of [[sup 11]C]pyrilamine and its labeled metabolites were determined. After intravenous injection, [[sup 11]C]pyrilamine metabolized gradually in the human body, with less than 10% of plasma activity being original radioligand at 60 min. Tracer metabolism markedly affected the input function and the calculated impulse response function of the brain. Rat experiments demonstrated that although metabolites of [[sup 11]C]pyrilamine might enter the brain, they were not retained for prolonged periods of time. At 30-90 min after injection of [[sup 11]C]pyrilamine, less than 1% of the radioactivity in the brain was originating from metabolites of [[sup 11]C]pyrilamine. Based on the rat data, the contribution of [sup 11]C-labeled metabolites to total [[sup 11]C]pyrilamine radioactivity in the human brain was estimated and found to be negligible. These results suggest that the metabolites of [[sup 11]C]pyrilamine do not accumulate within the cerebral extravascular space and that there is minimal metabolism of [[sup 11]C]pyrilamine by brain tissue itself. Therefore, [[sup 11]C]pyrilamine metabolites can be neglected in kinetic analysis, using either a compartmental or a noncompartmental model, of the [[sup 11]C]pyrilamine binding to histamine H[sub 1] receptors. (author)

  12. Effect of tracer metabolism on PET measurement of [{sup 11}C]pyrilamine binding to histamine H{sub 1} receptors

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sang Eun [Sungkyunkwan Univ., Seoul (Korea, Republic of). School of Medicine; Szabo, Z.; Seki, Chie; Ravert, H.T.; Scheffel, U.; Dannals, R.F.; Wagner, H.N. Jr.

    1999-04-01

    The present study was carried out to investigate the time course of [{sup 11}C]pyrilamine metabolism and the degree of entry of metabolites into the brain. PET studies were performed in seven healthy volunteers and arterial plasma concentrations of [{sup 11}C]pyrilamine and its labeled metabolites were determined. After intravenous injection, [{sup 11}C]pyrilamine metabolized gradually in the human body, with less than 10% of plasma activity being original radioligand at 60 min. Tracer metabolism markedly affected the input function and the calculated impulse response function of the brain. Rat experiments demonstrated that although metabolites of [{sup 11}C]pyrilamine might enter the brain, they were not retained for prolonged periods of time. At 30-90 min after injection of [{sup 11}C]pyrilamine, less than 1% of the radioactivity in the brain was originating from metabolites of [{sup 11}C]pyrilamine. Based on the rat data, the contribution of {sup 11}C-labeled metabolites to total [{sup 11}C]pyrilamine radioactivity in the human brain was estimated and found to be negligible. These results suggest that the metabolites of [{sup 11}C]pyrilamine do not accumulate within the cerebral extravascular space and that there is minimal metabolism of [{sup 11}C]pyrilamine by brain tissue itself. Therefore, [{sup 11}C]pyrilamine metabolites can be neglected in kinetic analysis, using either a compartmental or a noncompartmental model, of the [{sup 11}C]pyrilamine binding to histamine H{sub 1} receptors. (author)

  13. The histamine H4-receptor and the central and peripheral nervous system: A critical analysis of the literature.

    Science.gov (United States)

    Schneider, Erich H; Seifert, Roland

    2016-07-01

    Expression and function of histamine H4R in central and peripheral nervous system have been a matter of controversy for more than a decade. The scientific discussion is often limited to a few publications postulating the presence of functional H4R on neurons of the central and peripheral nervous system, but the even larger number of reports showing negative data is often neglected. In this article, we critically review the existing literature on H4R in central and peripheral nervous system and discuss the weak points often overlooked by the community. We identified as most important problems (i) insufficient validation or quality of antibodies, (ii) missing knockout controls, (iii) uncritical interpretation of RT-PCR results instead of qPCR experiments, (iv) insufficient controls to confirm specificity of pharmacological tools, (v) uncritical reliance on results produced by a single method and (vi) uncritical reliance on results not reproduced by independent research groups. Additionally, there may be a publication as well as a citation bias favoring the awareness of positive results, but neglecting negative data. We conclude that H4R expression on neurons of the brain is not convincingly supported by the current literature, at least as long as the positive data are not reproduced by independent research groups. Expression and function of H4R on peripheral neurons or non-neuronal cells of the nervous system, specifically on microglia is an interesting alternative hypothesis that, however, requires further verification. This article is part of a Special Issue entitled 'Histamine Receptors'. PMID:25986697

  14. Paradoxical stimulatory effects of the "standard" histamine H4-receptor antagonist JNJ7777120: the H4 receptor joins the club of 7 transmembrane domain receptors exhibiting functional selectivity.

    Science.gov (United States)

    Seifert, Roland; Schneider, Erich H; Dove, Stefan; Brunskole, Irena; Neumann, Detlef; Strasser, Andrea; Buschauer, Armin

    2011-04-01

    The histamine H(4) receptor (H(4)R) is expressed in several cell types of the immune system and is assumed to play an important pro-inflammatory role in various diseases, including bronchial asthma, atopic dermatitis, and pruritus. Accordingly, H(4)R antagonists have been suggested to provide valuable drugs for the treatment of these diseases. Over the past decade, the indole derivative 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ7777120) has become the "standard" H(4)R antagonist and has been extensively used to assess the pathophysiological role of the H(4)R. However, the situation has now become more complicated by recent data (p. 749 and Naunyn Schmiedebergs Arch Pharmacol doi: 10.1007/s00210-011-0612-3) showing that JNJ7777120 can also activate β-arrestin in a supposedly G(i)-protein-independent (pertussis toxin-insensitive) manner and that at certain H(4)R species orthologs, JNJ7777120 exhibits partial agonist efficacy with respect to G(i)-protein activation (steady-state high-affinity GTPase activity). These novel findings can be explained within the concept of functional selectivity or biased signaling, assuming unique ligand-specific receptor conformations with distinct signal transduction capabilities. Thus, great caution must be exerted when interpreting in vivo effects of JNJ7777120 as H(4)R antagonism. We discuss future directions to get out of the current dilemma in which there is no "standard" H(4)R antagonist available to the scientific community. PMID:21266488

  15. Histamine H3 receptor activation inhibits dopamine synthesis but not release or uptake in rat nucleus accumbens.

    Science.gov (United States)

    Aquino-Miranda, Guillermo; Escamilla-Sánchez, Juan; González-Pantoja, Raúl; Bueno-Nava, Antonio; Arias-Montaño, José-Antonio

    2016-07-01

    We studied the effect of activating histamine H3 receptors (H3Rs) on rat nucleus accumbens (rNAcc) dopaminergic transmission by analyzing [(3)H]-dopamine uptake by synaptosomes, and dopamine synthesis and depolarization-evoked [(3)H]-dopamine release in slices. The uptake of [(3)H]-dopamine by rNAcc synaptosomes was not affected by the H3R agonist RAMH (10(-10)-10(-6) M). In rNAcc slices perfusion with RAMH (1 μM) had no significant effect on [(3)H]-dopamine release evoked by depolarization with 30 mM K(+) (91.4 ± 4.5% of controls). The blockade of dopamine D2 autoreceptors with sulpiride (1 μM) enhanced K(+)-evoked [(3)H]-dopamine release (168.8 ± 15.5% of controls), but under this condition RAMH (1 μM) also failed to affect [(3)H]-dopamine release. Dopamine synthesis was evaluated in rNAcc slices incubated with the l-dihydroxyphenylalanine (DOPA) decarboxylase inhibitor NSD-1015 (1 mM). Forskolin-induced DOPA accumulation (220.1 ± 10.4% of controls) was significantly reduced by RAMH (41.1 ± 6.5% and 43.5 ± 9.1% inhibition at 100 nM and 1 μM, respectively), and this effect was prevented by the H3R antagonist ciproxifan (10 μM). DOPA accumulation induced by preventing cAMP degradation with IBMX (iso-butyl-methylxantine, 1 mM) or by activating receptors for the vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) with PACAP-27 (1 μM) was reduced (IBMX) or prevented (PACAP-27) by RAMH (100 nM). In contrast, DOPA accumulation induced by 8-Bromo-cAMP (1 mM) was not affected by RAMH (100 nM). These results indicate that in rNAcc H3Rs do not modulate dopamine uptake or release, but regulate dopamine synthesis by inhibiting cAMP formation and thus PKA activation. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID:26169221

  16. 2,4-Diaminopyrimidines as dual ligands at the histamine H1 and H4 receptor-H1/H4-receptor selectivity.

    Science.gov (United States)

    Hammer, Sebastian G; Gobleder, Susanne; Naporra, Franziska; Wittmann, Hans-Joachim; Elz, Sigurd; Heinrich, Markus R; Strasser, Andrea

    2016-01-15

    Distinct diaminopyrimidines, for example, 4-(4-methylpiperazin-1-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine are histamine H4 receptor (H4R) antagonists and show high affinity to the H4R, but only a moderate affinity to the histamine H1 receptor (H1R). Within previous studies it was shown that an aromatic side chain with a distinct distance to the basic amine and aromatic core is necessary for affinity to the human H1R (hH1R). Thus, a rigid aminopyrimidine with a tricyclic core was used as a lead structure. There, (1) the flexible aromatic side chain was introduced, (2) the substitution pattern of the pyrimidine core was exchanged and (3) rigidity was decreased by opening the tricyclic core. Within the present study, two compounds with similar affinity in the one digit μM range to the human H1R and H4R were identified. While the affinity at the hH1R increased about 4- to 8-fold compared to the parent diaminopyrimidine, the affinity to the hH4R decreased about 5- to 8-fold. In addition to the parent diaminopyrimidine, two selected compounds were docked into the H1R and H4R and molecular dynamic studies were performed to predict the binding mode and explain the experimental results on a molecular level. The two new compounds may be good lead structures for the development of dual H1/H4 receptor ligands with affinities in the same range. PMID:26718844

  17. H4 histamine receptors mediate cell cycle arrest in growth factor-induced murine and human hematopoietic progenitor cells.

    Directory of Open Access Journals (Sweden)

    Anne-France Petit-Bertron

    Full Text Available The most recently characterized H4 histamine receptor (H4R is expressed preferentially in the bone marrow, raising the question of its role during hematopoiesis. Here we show that both murine and human progenitor cell populations express this receptor subtype on transcriptional and protein levels and respond to its agonists by reduced growth factor-induced cell cycle progression that leads to decreased myeloid, erythroid and lymphoid colony formation. H4R activation prevents the induction of cell cycle genes through a cAMP/PKA-dependent pathway that is not associated with apoptosis. It is mediated specifically through H4R signaling since gene silencing or treatment with selective antagonists restores normal cell cycle progression. The arrest of growth factor-induced G1/S transition protects murine and human progenitor cells from the toxicity of the cell cycle-dependent anticancer drug Ara-C in vitro and reduces aplasia in a murine model of chemotherapy. This first evidence for functional H4R expression in hematopoietic progenitors opens new therapeutic perspectives for alleviating hematotoxic side effects of antineoplastic drugs.

  18. Evidence for the role of histamine H3 receptor in alcohol consumption and alcohol reward in mice.

    Science.gov (United States)

    Nuutinen, Saara; Lintunen, Minnamaija; Vanhanen, Jenni; Ojala, Tiia; Rozov, Stanislav; Panula, Pertti

    2011-09-01

    Recent research suggests that histamine H3 receptor (H3R) antagonism may diminish motivational aspects of alcohol dependence. We studied the role of H3Rs in alcohol-related behaviors using H3R knockout (KO) mice and ligands. H3R KO mice consumed less alcohol than wild-type (WT) mice in a two-bottle free-choice test and in a 'drinking in the dark' model. H3R antagonist ciproxifan suppressed and H3R agonist immepip increased alcohol drinking in C57BL/6J mice. Impairment in reward mechanisms in H3R KO mice was confirmed by the lack of alcohol-evoked conditioned place preference. Plasma alcohol concentrations of H3R KO and WT mice were similar. There were no marked differences in brain biogenic amine levels in H3R KO mice compared with the control animals after alcohol drinking. In conclusion, the findings of this study provide evidence for the role of H3R receptor in alcohol-related behaviors, especially in alcohol drinking and alcohol reward. Thus, targeting H3Rs with a specific antagonist might be a potential means to treat alcoholism in the future. PMID:21654737

  19. In vitro radioprotective effects of histamine H2 receptor antagonists against gamma-rays induced chromosomal aberrations in human lymphocytes

    International Nuclear Information System (INIS)

    Background: Radioprotective capability of histamine H2 receptor antagonists have been shown in several in vivo studies mainly using animal models. However, to verify the effectiveness of these agents in clinical applications, studies should be performed on human lymphocytes using metaphase analysis. Materials and Methods: In vitro metaphase analysis technique was used to test the effects of cimetidine, ranitidine and famotidine on radiation induced clastogenic effects. Lymphocytes in whole peripheral blood were exposed to 3 Gy gamma-rays at a dose rate of 73.7 c Gy/min in the presence or absence of various doses of the drugs used in this study. The frequency of chromosomal aberrations were determined after standard metaphase preparations and staining slides in 5% Giemsa. Results: Results show that radiation produced a high number of chromosomal aberrations in lymphocytes compared to controls (p2-receptor antagonists used in this study effectively reduced the clastogenic effects of radiation with a dose reduction factor of 1.5-2 in human lymphocytes in vitro. The way in which these drugs reduce the clastogenic effects of radiation might be via radical scavenging mechanism

  20. Histamine in brain development and tumors.

    Science.gov (United States)

    Panula, P; Lintunen, M; Karlstedt, K

    2000-02-01

    Histamine is found in developing mammalian brain in both neurons and mast cells. Under normal conditions, histamine H1 and H2 receptors are found in neural, glial and endothelial cells, and H3 receptors at least on neurons. Experimental brain tumors display both H1 and H2 receptors, and histamine increases permeability in the tumors and in the neighboring areas. Many studies have addressed histaminergic signalling mechanisms in cell lines originating from brain tumors. However, the role of histamine in normal development of brain structures, proliferation and differentiation of neurons and glial cells, and growth of malignant tumors in situ is still poorly understood. PMID:10888266

  1. Arpromidine-related acylguanidines: synthesis and structure-activity relationships of a new class of guanidine-type histamine H2 receptor agonists with reduced basicity

    OpenAIRE

    Ghorai, Prasanta

    2006-01-01

    There has been increasing evidence that histamine receptor stimulation might be an interesting aspect for the development of future drugs as well. Arpromidine and related imidazolylpropylguanidines are the most potent H2R agonists on the isolated guinea pig right atrium. The strongly basic guanidino group is essential for the agonistic activity but it is also responsible for very low oral bioavailability, non-H2R-mediated effects and lack of penetration across the blood-brain barrier. Therefo...

  2. Effects of proton pump inhibitors and histamine-2 receptor antagonists on response to fidaxomicin or vancomycin in patients with Clostridium difficile-associated diarrhoea

    OpenAIRE

    WEISS, Karl; Louie, Thomas; Miller, Mark A; Mullane, Kathleen; Crook, Derrick W.; Gorbach, Sherwood L.

    2015-01-01

    Objective It has been established that use of proton pump inhibitors (PPIs) is associated with an increased risk of acquiring Clostridium difficile-associated diarrhoea (CDAD). However, it is not known whether the use of PPIs or histamine-2 receptor antagonists (H2RAs) concurrently with CDAD-targeted antibiotic treatment affects clinical response or recurrence rates. Design In two phase 3 trials, patients with toxin-positive CDAD were randomised to receive fidaxomicin 200 mg twice daily or va...

  3. Effect of histamine and histamine analogues on human isolated myometrial strips.

    OpenAIRE

    Martínez-Mir, M. I.; Estañ, L.; Morales-Olivas, F. J.; Rubio, E.

    1992-01-01

    1. The effect of histamine and histamine H1- and H2-receptor agonists on isolated myometrium strips of premenopausal women has been examined. The effect of acetylcholine was also determined. 2. Histamine, 2-pyridylethylamine, 4-methylhistamine and acetylcholine, but not dimaprit, produced a concentration-related contractile response in human isolated myometrial strips. Histamine also produced a further contraction in human isolated myometrial strips precontracted with KCl (55 mM). 3. The cont...

  4. Increased expression of the histamine H4 receptor following differentiation and mediation of the H4 receptor on interleukin-8 mRNA expression in HaCaT keratinocytes.

    Science.gov (United States)

    Suwa, Eriko; Yamaura, Katsunori; Sato, Shiori; Ueno, Koichi

    2014-02-01

    Recent in vivo studies have demonstrated involvement of the histamine H4 receptor in pruritus and skin inflammation. We previously reported that an H4 receptor antagonist attenuated scratching behaviour and improved skin lesions in an experimental model of atopic dermatitis. We also reported the expression of the H4 receptor in human epidermal tissues. In this study, we investigated the expression of H4 receptor mRNA and the function of the receptor in a culture system that mimics in vivo inflammation on the HaCaT human keratinocyte cell line. Increased expression of the H4 receptor was observed in HaCaT cells following differentiation. Treatment of HaCaT cells with histamine and TNFα enhanced the mRNA expression of interleukin (IL)-8. These increases in expression were significantly inhibited by the H4 receptor antagonist JNJ7777120. Our results indicate that IL-8 mRNA expression might be enhanced by histamine and TNFα via H4 receptor stimulation in keratinocytes. PMID:24372819

  5. Effect of disodium cromoglycate (DSCG) and antihistamines on post-irradiation cerebral blood flow and plasma levels of histamine and neurotensin

    Energy Technology Data Exchange (ETDEWEB)

    Cockerham, L.G.; Pautler, E.L.; Carraway, R.E.; Cochrane, D.E.; Hampton, J.D.

    1988-01-01

    In an attempt to elucidate mechanisms underlying the irradiation-induced decrease in regional cerebral blood flow (rCBF) in primates, hippocampal and visual cortical blood flows of rhesus monkeys were measured by hydrogen clearance, before and after exposure to 100-Gy, whole-body, gamma irradiation. Systemic blood pressures were monitored simultaneously. Systemic arterial plasma histamine and neurotensin levels were determined preirradiation and postirradiation. Compared to control animals, the irradiated monkeys exhibited an abrupt decline in systemic blood pressure to 23% of the preirradiation level within 10-min postirradiation, falling to 12% by 60 min. A decrease in hippocampal blood flow to 32% of the preirradiation level was noted at 10-min postirradiation, followed by a slight recovery to 43% at 30 min and a decline to 23% by 60 min. The cortical blood flow for the same animals showed a steady decrease to 29% of the preirradiation levels by 60-min postirradiation. Animals given the mast-cell stabilizer disodium cromoglycate and the antihistamines mepyramine and cimetidine before irradiation did not exhibit an abrupt decline in blood pressure but displayed a gradual decrease to a level 33% below preirradiation levels by 60 min postirradiation. Also, the treated, irradiated monkeys displayed rCBF values that were not significantly different from the nonirradiated controls. The plasma neurotensin levels in the irradiated animals, treated and untreated, indicated a nonsignificant postirradiation increase above control levels.

  6. No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation

    DEFF Research Database (Denmark)

    Estrup, T M; Paulson, O B; Strandgaard, S

    2001-01-01

    Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral cir...

  7. Histamine H4 receptor antagonism diminishes existing airway inflammation and dysfunction via modulation of Th2 cytokines

    Directory of Open Access Journals (Sweden)

    Thurmond Robin L

    2010-06-01

    Full Text Available Abstract Background Airway remodeling and dysfunction are characteristic features of asthma thought to be caused by aberrant production of Th2 cytokines. Histamine H4 receptor (H4R perturbation has previously been shown to modify acute inflammation and Th2 cytokine production in a murine model of asthma. We examined the ability of H4R antagonists to therapeutically modify the effects of Th2 cytokine production such as goblet cell hyperplasia (GCH, and collagen deposition in a sub-chronic model of asthma. In addition, effects on Th2 mediated lung dysfunction were also determined. Methods Mice were sensitized to ovalbumin (OVA followed by repeated airway challenge with OVA. After inflammation was established mice were dosed with the H4R antagonist, JNJ 7777120, or anti-IL-13 antibody for comparison. Airway hyperreactivity (AHR was measured, lungs lavaged and tissues collected for analysis. Results Therapeutic H4R antagonism inhibited T cell infiltration in to the lung and decreased Th2 cytokines IL-13 and IL-5. IL-13 dependent remodeling parameters such as GCH and lung collagen were reduced. Intervention with H4R antagonist also improved measures of central and peripheral airway dysfunction. Conclusions These data demonstrate that therapeutic H4R antagonism can significantly ameliorate allergen induced, Th2 cytokine driven pathologies such as lung remodeling and airway dysfunction. The ability of H4R antagonists to affect these key manifestations of asthma suggests their potential as novel human therapeutics.

  8. Conformational Restriction and Enantioseparation Increase Potency and Selectivity of Cyanoguanidine-Type Histamine H4 Receptor Agonists.

    Science.gov (United States)

    Geyer, Roland; Nordemann, Uwe; Strasser, Andrea; Wittmann, Hans-Joachim; Buschauer, Armin

    2016-04-14

    2-Cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[2-(phenylsulfanyl)ethyl]guanidine (UR-PI376, 1) is a potent and selective agonist of the human histamine H4 receptor (hH4R). To gain information on the active conformation, we synthesized analogues of 1 with a cyclopentane-1,3-diyl linker. Affinities and functional activities were determined at recombinant hHxR (x: 1-4) subtypes on Sf9 cell membranes (radioligand binding, [(35)S]GTPγS, or GTPase assays) and in part in luciferase assays on human or mouse H4R (HEK-293 cells). The most potent H4R agonists among 14 racemates were separated by chiral HPLC, yielding eight enantiomerically pure compounds. Configurations were assigned based on X-ray structures of intermediates and a stereocontrolled synthetic pathway. (+)-2-Cyano-1-{[trans-(1S,3S)-3-(1H-imidazol-4-yl)cyclopentyl]methyl}-3-[2-(phenylsulfanyl)ethyl]guanidine ((1S,3S)-UR-RG98, 39a) was the most potent H4R agonist in this series (EC50 11 nM; H4R vs H3R, >100-fold selectivity; H1R, H2R, negligible activities), whereas the optical antipode proved to be an H4R antagonist ([(35)S]GTPγS assay). MD simulations confirmed differential stabilization of the active and inactive H4R state by the enantiomers. PMID:27007611

  9. Acute exposure to high-peak-power pulsed microwaves affecting the histamine H3 receptor expression in rat hippocampus

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    In the Morris Water Maze test, high-peak-power pulsed microwave (MW)-exposed rats displayed some learning and memory behavior dysfunctions, and their escape time and swimming distance to the submerged platform were longer than those of the sham-exposed rats. To understand the molecular mechanism involved, the reverse transcription-polymerase chain reaction (RT-PCR) and the Western-blotting technique were used for investigating the mRNA and protein expression patterns of the histamine H3 receptor (H3R) in rat hippocampus. High-peak-power pulsed microwave-exposure did not remarkably lead to the change in expression of H3R mRNA in rat hippocampi;however, it promoted the up-regulatory expression of the H3R protein, which was possibly triggered through the mitogen-activated protein kinase (MAPK) pathways. Therefore, further investigation of the molecular mechanism of the MW effects on the learning and memory behaviors is required.

  10. Structure-activity studies on a series of a 2-aminopyrimidine-containing histamine H4 receptor ligands.

    Science.gov (United States)

    Altenbach, Robert J; Adair, Ronald M; Bettencourt, Brian M; Black, Lawrence A; Fix-Stenzel, Shannon R; Gopalakrishnan, Sujatha M; Hsieh, Gin C; Liu, Huaqing; Marsh, Kennan C; McPherson, Michael J; Milicic, Ivan; Miller, Thomas R; Vortherms, Timothy A; Warrior, Usha; Wetter, Jill M; Wishart, Neil; Witte, David G; Honore, Prisca; Esbenshade, Timothy A; Hancock, Arthur A; Brioni, Jorge D; Cowart, Marlon D

    2008-10-23

    A series of 2-aminopyrimidines was synthesized as ligands of the histamine H4 receptor (H4R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried out to optimize the potency, which led to compound 3, 4- tert-butyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-ylamine. We further studied this compound by systematically modifying the core pyrimidine moiety, the methylpiperazine at position 4, the NH2 at position 2, and positions 5 and 6 of the pyrimidine ring. The pyrimidine 6 position benefited the most from this optimization, especially in analogs in which the 6- tert-butyl was replaced with aromatic and secondary amine moieties. The highlight of the optimization campaign was compound 4, 4-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzonitrile, which was potent in vitro and was active as an anti-inflammatory agent in an animal model and had antinociceptive activity in a pain model, which supports the potential of H 4R antagonists in pain. PMID:18811133

  11. Effect of carnosine on the immunosuppressive effect of histamine

    International Nuclear Information System (INIS)

    This paper studies the ability of carnosine (beta-imidazole-lactate) to affect histamine-induced immunosuppression of proliferative activity of various lymphocyte subpopulations and the realization of this effect through surface histamine receptors of the cells. The experiments were carried out on mice; lymphocytes were incubated with tritium-labeled thymidine for 4 h, after which their radioactivity was determined on a scintillation counter. The results show that histamine has an inhibitory action on antigen-induced proliferation of T suppressor lymphocytes through H-2 histamine receptors, for this effect was considerably inhibited by the H-2 histamine blockers metiamide, but not by the H-1 histamine blocker mepyramine

  12. Effect of carnosine on the immunosuppressive effect of histamine

    Energy Technology Data Exchange (ETDEWEB)

    Sharpan, Yu. V.

    1985-04-01

    This paper studies the ability of carnosine (beta-imidazole-lactate) to affect histamine-induced immunosuppression of proliferative activity of various lymphocyte subpopulations and the realization of this effect through surface histamine receptors of the cells. The experiments were carried out on mice; lymphocytes were incubated with tritium-labeled thymidine for 4 h, after which their radioactivity was determined on a scintillation counter. The results show that histamine has an inhibitory action on antigen-induced proliferation of T suppressor lymphocytes through H-2 histamine receptors, for this effect was considerably inhibited by the H-2 histamine blockers metiamide, but not by the H-1 histamine blocker mepyramine.

  13. The Synthesis of 1,3,5-triazine Derivatives and JNJ7777120 Analogues with Histamine H4 Receptor Affinity and Their Interaction with PTEN Promoter.

    Science.gov (United States)

    Latacz, Gniewomir; Kechagioglou, Petros; Papi, Rigini; Łażewska, Dorota; Więcek, Małgorzata; Kamińska, Katarzyna; Wencel, Przemysław; Karcz, Tadeusz; Schwed, Johannes S; Stark, Holger; Kyriakidis, Dimitrios A; Kieć-Kononowicz, Katarzyna

    2016-08-01

    The involvement of histamine and H4 receptor (H4 R) in cancer has been investigated recently using the H4 R agonists and antagonists. The scope of the research project was synthesis and exploration of the consequences of a group of compounds with histamine H4 receptor (H4 R) affinity on the promoter of PTEN gene encoding the antitumor PTEN protein. The series of novel compounds based either on H4 R antagonists JNJ7777120 structure or 1,3,5-triazine scaffold were synthesized, evaluated for histamine H4 R affinity and used in this study. Compounds 5 and 7 belonging to the group of JNJ7777120 analogues showed the highest interaction with the promoter of PTEN gene and weak affinity against H4 R with Ki value >100 μm. These compounds showed no significant effect on neuroblastoma IMR-32 cells viability indicating no correlation between PTEN gene promoter affinity and antitumor activity. Compound 6, another JNJ7777120 analogue, showed the highest effect on IMR-32 viability with calculated IC50 = 23.27 μm. The 1,3,5-triazine derivatives exhibited generally low or medium interaction with PTEN gene promoter. However, the 1,3,5-triazine derivative 11 with the para-bromo substituent showed the highest affinity against H4 R with Ki value of 520 nm and may be considered as a new lead structure. PMID:26931395

  14. Histamine in regulation of bone remodeling processes

    Directory of Open Access Journals (Sweden)

    Marek Wiercigroch

    2013-08-01

    Full Text Available Bone remodeling is under autocrine, paracrine, endocrine and central nervous system control. One of the potential endogenous factors affecting bone remodeling is histamine, an endogenous amine which acts as a mediator of allergic reactions and neuromediator, and induces production of gastric acid. Histamine H1 receptor antagonists are widely used in the treatment of allergic conditions, H2 receptor antagonists in peptic ulcer disease, and betahistine (an H3 receptor antagonist and H1 receptor agonist is used in the treatment of Ménière’s disease.Excess histamine release in mastocytosis and allergic diseases may lead to development of osteoporosis. Clinical and population-based studies on the effects of histamine receptor antagonists on the skeletal system have not delivered unequivocal results.Expression of mRNA of histamine receptors has been discovered in bone cells (osteoblasts and osteoclasts. Histamine synthesis has been demonstrated in osteoclast precursors. Histamine increases bone resorption both by direct effects on osteoclast precursors and osteoclasts, and indirectly, by increasing the expression of RANKL in osteoblasts. In in vivo studies, H1 and H2 receptor antagonists exerted protective effects on the bone tissue, although not in all experimental models. In the present article, in vitro and in vivo studies conducted so far, concerning the effects of histamine and drugs modifying its activity on the skeletal system, have been reviewed.

  15. [Histamine in regulation of bone remodeling processes].

    Science.gov (United States)

    Wiercigroch, Marek; Folwarczna, Joanna

    2013-01-01

    Bone remodeling is under autocrine, paracrine, endocrine and central nervous system control. One of the potential endogenous factors affecting bone remodeling is histamine, an endogenous amine which acts as a mediator of allergic reactions and neuromediator, and induces production of gastric acid. Histamine H₁ receptor antagonists are widely used in the treatment of allergic conditions, H₂ receptor antagonists in peptic ulcer disease, and betahistine (an H₃ receptor antagonist and H₁ receptor agonist) is used in the treatment of Ménière's disease. Excess histamine release in mastocytosis and allergic diseases may lead to development of osteoporosis. Clinical and population-based studies on the effects of histamine receptor antagonists on the skeletal system have not delivered unequivocal results. Expression of mRNA of histamine receptors has been discovered in bone cells (osteoblasts and osteoclasts). Histamine synthesis has been demonstrated in osteoclast precursors. Histamine increases bone resorption both by direct effects on osteoclast precursors and osteoclasts, and indirectly, by increasing the expression of RANKL in osteoblasts. In in vivo studies, H₁ and H₂ receptor antagonists exerted protective effects on the bone tissue, although not in all experimental models. In the present article, in vitro and in vivo studies conducted so far, concerning the effects of histamine and drugs modifying its activity on the skeletal system, have been reviewed. PMID:24018454

  16. Histamine enhances interleukin (IL)-1-induced IL-1 gene expression and protein synthesis via H2 receptors in peripheral blood mononuclear cells. Comparison with IL-1 receptor antagonist.

    OpenAIRE

    Vannier, E; Dinarello, C A

    1993-01-01

    Histamine and IL-1 have been implicated in the pathogenesis of chronic inflammatory diseases, such as pulmonary allergic reactions and rheumatoid arthritis. We therefore investigated whether histamine modulated the synthesis of IL-1 beta. Human PBMC were stimulated with IL-1 alpha (10 ng/ml) in the absence or presence of histamine (10(-9)-10(-4) M). Histamine alone did not induce protein synthesis or mRNA accumulation for IL-1 beta. IL-1 alpha-induced IL-1 beta synthesis was enhanced two to t...

  17. Discovery of naturally occurring splice variants of the rat histamine H3 receptor that act as dominant-negative isoforms.

    Science.gov (United States)

    Bakker, Remko A; Lozada, Adrian Flores; van Marle, André; Shenton, Fiona C; Drutel, Guillaume; Karlstedt, Kaj; Hoffmann, Marcel; Lintunen, Minnamaija; Yamamoto, Yumiko; van Rijn, Richard M; Chazot, Paul L; Panula, Pertti; Leurs, Rob

    2006-04-01

    We described previously the cDNA cloning of three functional rat histamine H3 receptor (rH3R) isoforms as well as the differential brain expression patterns of their corresponding mRNAs and signaling properties of the resulting rH3A, rH3B, and rH3C receptor isoforms (Mol Pharmacol 59:1-8). In the current report, we describe the cDNA cloning, mRNA localization in the rat central nervous system, and pharmacological characterization of three additional rH3R splice variants (rH3D, rH3E, and rH3F) that differ from the previously published isoforms in that they result from an additional alternative-splicing event. These new H3R isoforms lack the seventh transmembrane (TM) helix and contain an alternative, putatively extracellular, C terminus (6TM-rH3 isoforms). After heterologous expression in COS-7 cells, radioligand binding or functional responses upon the application of various H3R ligands could not be detected for the 6TM-rH3 isoforms. In contrast to the rH3A receptor (rH3AR), detection of the rH3D isoform using hemagglutinin antibodies revealed that the rH3D isoform remains mainly intracellular. The expression of the rH3D-F splice variants, however, modulates the cell surface expression-levels and subsequent functional responses of the 7TM H3R isoforms. Coexpression of the rH3AR and the rH3D isoforms resulted in the intracellular retention of the rH3AR and reduced rH3AR functionality. Finally, we show that in rat brain, the H3R mRNA expression levels are modulated upon treatment with the convulsant pentylenetetrazole, suggesting that the rH3R isoforms described herein thus represent a novel physiological mechanism for controlling the activity of the histaminergic system. PMID:16415177

  18. Effect of chronic (-)-nicotine treatment on rat cerebral benzodiazepine receptors

    International Nuclear Information System (INIS)

    The purpose of this study was to clarify the effect of (-)-nicotine on cerebral benzodiazepine receptors (BzR) with radiotracer methods. The effect of (-)-nicotine on BzR was examined in in vitro studies using chronic (-)-nicotine-treated rats using 3H-diazepam. The in vitro radioreceptor assay showed a 14% increase in the maximum number of binding sites of BzR in chronic (-)-nicotine-treated rats in comparison with the control rats. Moreover, a convenient in vivo uptake index of 125I-iomazenil was calculated and a higher uptake of the radioactivity was observed in the chronic (-)-nicotine-treated group than in the control group. Although further studies of the mechanism of (-)-nicotine on such BzR changes are required, an increase in the amount of BzR in the cerebral cortex was found in rats that underwent chronic (-)-nicotine treatment, and this result contributed to the understanding of the effects of (-)-nicotine and smoking on neural functions

  19. Spatiotemporal expression of Nogo-66 receptor after focal cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Yue Cao; Ya-xian Dong; Jie Xu; Guo-liang Chu; Zhi-hua Yang; Yan-ming Liu

    2016-01-01

    NgR, the receptor for the neurite outgrowth inhibitor Nogo-66, plays a critical role in the plasticity and regeneration of the nervous system after injury such as ischemic stroke. In the present study, we used immunohistochemistry to investigate the regional expression of NgR in rat brain following middle cerebral artery occlusion (MCAO). NgR protein expression was not observed in the center of the lesion, but was elevated in the marginal zone compared with control and sham-operated rats. The cerebral cortex and hippocampus (CA1, CA2, and CA3) showed the greatest expression of NgR. Furthermore, NgR expression was higher in the ipsilesional hemisphere than on the control side in the same coronal section. Although time-dependent changes in NgR expression across brain regions had their own characteristics, the overall trend complied with the following rules: NgR expression changes with time showed two peaks and one trough; the ifrst peak in expression appeared between 1 and 3 days after MCAO; expression declined at 5 days; and the second peak occurred at 28 days.

  20. Role of histamine H1-receptor on behavioral states and wake maintenance during deficiency of a brain activating system: A study using a knockout mouse model.

    Science.gov (United States)

    Parmentier, Régis; Zhao, Yan; Perier, Magali; Akaoka, Hideo; Lintunen, Minnamaija; Hou, Yiping; Panula, Pertti; Watanabe, Takeshi; Franco, Patricia; Lin, Jian-Sheng

    2016-07-01

    Using knockout (KO) mice lacking the histamine (HA)-synthesizing enzyme (histidine decarboxylase, HDC), we have previously shown the importance of histaminergic neurons in maintaining wakefulness (W) under behavioral challenges. Since the central actions of HA are mediated by several receptor subtypes, it remains to be determined which one(s) could be responsible for such a role. We have therefore compared the cortical-EEG, sleep and W under baseline conditions or behavioral/pharmacological stimuli in littermate wild-type (WT) and H1-receptor KO (H1-/-) mice. We found that H1-/- mice shared several characteristics with HDC KO mice, i.e. 1) a decrease in W after lights-off despite its normal baseline daily amount; 2) a decreased EEG slow wave sleep (SWS)/W power ratio; 3) inability to maintain W in response to behavioral challenges demonstrated by a decreased sleep latency when facing various stimuli. These effects were mediated by central H1-receptors. Indeed, in WT mice, injection of triprolidine, a brain-penetrating H1-receptor antagonist increased SWS, whereas ciproxifan (H3-receptor antagonist/inverse agonist) elicited W; all these injections had no effect in H1-/- mice. Finally, H1-/- mice showed markedly greater changes in EEG power (notably in the 0.8-5 Hz band) and sleep-wake cycle than in WT mice after application of a cholinergic antagonist or an indirect agonist, i.e., scopolamine or physostigmine. Hence, the role of HA in wake-promotion is largely ensured by H1-receptors. An upregulated cholinergic system may account for a quasi-normal daily amount of W in HDC or H1-receptor KO mice and likely constitutes a major compensatory mechanism when the brain is facing deficiency of an activating system. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID:26723880

  1. Effect of histamine H1 and H2 receptor antagonists, microinjected into cerebellar vermis, on emotional memory consolidation in mice

    International Nuclear Information System (INIS)

    This study investigated the effects of histamine H1 or H2 receptor antagonists on emotional memory consolidation in mice submitted to the elevated plus maze (EPM). The cerebellar vermis of male mice (Swiss albino) was implanted using a cannula guide. Three days after recovery, behavioral tests were performed in the EPM on 2 consecutive days (T1 and T2). Immediately after exposure to the EPM (T1), animals received a microinjection of saline (SAL) or the H1 antagonist chlorpheniramine (CPA; 0.016, 0.052, or 0.16 nmol/0.1 µL) in Experiment 1, and SAL or the H2 antagonist ranitidine (RA; 0.57, 2.85, or 5.7 nmol/0.1 µL) in Experiment 2. Twenty-four hours later, mice were reexposed to the EPM (T2) under the same experimental conditions but they did not receive any injection. Data were analyzed using one-way ANOVA and the Duncan test. In Experiment 1, mice microinjected with SAL and with CPA entered the open arms less often (%OAE) and spent less time in the open arms (%OAT) in T2, and there was no difference among groups. The results of Experiment 2 demonstrated that the values of %OAE and %OAT in T2 were lower compared to T1 for the groups that were microinjected with SAL and 2.85 nmol/0.1 µL RA. However, when animals were microinjected with 5.7 nmol/0.1 µL RA, they did not show a reduction in %OAE and %OAT. These results demonstrate that CPA did not affect behavior at the doses used in this study, while 5.7 nmol/0.1 µL RA induced impairment of memory consolidation in the EPM

  2. Effect of histamine H1 and H2 receptor antagonists, microinjected into cerebellar vermis, on emotional memory consolidation in mice

    Energy Technology Data Exchange (ETDEWEB)

    Gianlorenço, A.C.L.; Serafim, K.R. [Laboratório de Neurociências, Departamento de Fisioterapia, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, São Carlos, SP, Brasil, Laboratório de Neurociências, Departamento de Fisioterapia, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, São Carlos, SP (Brazil); Canto-de-Souza, A. [Laboratório de Psicologia da Aprendizagem, Departamento de Psicologia, Centro de Educação e Ciências Humanas, Universidade Federal de São Carlos, São Carlos, SP, Brasil, Laboratório de Psicologia da Aprendizagem, Departamento de Psicologia, Centro de Educação e Ciências Humanas, Universidade Federal de São Carlos, São Carlos, SP (Brazil); Programa de Pós-Graduação em Ciências Fisiológicas, Universidade Federal de São Carlos, São Carlos, SP, Brasil, Programa de Pós-Graduação em Ciências Fisiológicas, Universidade Federal de São Carlos, São Carlos, SP (Brazil); Instituto de Neurociências e Comportamento, Universidade de São Paulo, Ribeirão Preto, SP, Brasil, Instituto de Neurociências e Comportamento, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Mattioli, R. [Laboratório de Neurociências, Departamento de Fisioterapia, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, São Carlos, SP, Brasil, Laboratório de Neurociências, Departamento de Fisioterapia, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos, São Carlos, SP (Brazil)

    2014-02-17

    This study investigated the effects of histamine H1 or H2 receptor antagonists on emotional memory consolidation in mice submitted to the elevated plus maze (EPM). The cerebellar vermis of male mice (Swiss albino) was implanted using a cannula guide. Three days after recovery, behavioral tests were performed in the EPM on 2 consecutive days (T1 and T2). Immediately after exposure to the EPM (T1), animals received a microinjection of saline (SAL) or the H1 antagonist chlorpheniramine (CPA; 0.016, 0.052, or 0.16 nmol/0.1 µL) in Experiment 1, and SAL or the H2 antagonist ranitidine (RA; 0.57, 2.85, or 5.7 nmol/0.1 µL) in Experiment 2. Twenty-four hours later, mice were reexposed to the EPM (T2) under the same experimental conditions but they did not receive any injection. Data were analyzed using one-way ANOVA and the Duncan test. In Experiment 1, mice microinjected with SAL and with CPA entered the open arms less often (%OAE) and spent less time in the open arms (%OAT) in T2, and there was no difference among groups. The results of Experiment 2 demonstrated that the values of %OAE and %OAT in T2 were lower compared to T1 for the groups that were microinjected with SAL and 2.85 nmol/0.1 µL RA. However, when animals were microinjected with 5.7 nmol/0.1 µL RA, they did not show a reduction in %OAE and %OAT. These results demonstrate that CPA did not affect behavior at the doses used in this study, while 5.7 nmol/0.1 µL RA induced impairment of memory consolidation in the EPM.

  3. Effect of histamine H1 and H2 receptor antagonists, microinjected into cerebellar vermis, on emotional memory consolidation in mice

    Directory of Open Access Journals (Sweden)

    A.C.L. Gianlorenco

    2014-02-01

    Full Text Available This study investigated the effects of histamine H1 or H2 receptor antagonists on emotional memory consolidation in mice submitted to the elevated plus maze (EPM. The cerebellar vermis of male mice (Swiss albino was implanted using a cannula guide. Three days after recovery, behavioral tests were performed in the EPM on 2 consecutive days (T1 and T2. Immediately after exposure to the EPM (T1, animals received a microinjection of saline (SAL or the H1 antagonist chlorpheniramine (CPA; 0.016, 0.052, or 0.16 nmol/0.1 µL in Experiment 1, and SAL or the H2 antagonist ranitidine (RA; 0.57, 2.85, or 5.7 nmol/0.1 µL in Experiment 2. Twenty-four hours later, mice were reexposed to the EPM (T2 under the same experimental conditions but they did not receive any injection. Data were analyzed using one-way ANOVA and the Duncan test. In Experiment 1, mice microinjected with SAL and with CPA entered the open arms less often (%OAE and spent less time in the open arms (%OAT in T2, and there was no difference among groups. The results of Experiment 2 demonstrated that the values of %OAE and %OAT in T2 were lower compared to T1 for the groups that were microinjected with SAL and 2.85 nmol/0.1 µL RA. However, when animals were microinjected with 5.7 nmol/0.1 µL RA, they did not show a reduction in %OAE and %OAT. These results demonstrate that CPA did not affect behavior at the doses used in this study, while 5.7 nmol/0.1 µL RA induced impairment of memory consolidation in the EPM.

  4. Activation of histamine H4 receptor inhibits TNFα/IMD-0354-induced apoptosis in human salivary NS-SV-AC cells.

    Science.gov (United States)

    Stegajev, Vasili; Kouri, Vesa-Petteri; Salem, Abdelhakim; Rozov, Stanislav; Stark, Holger; Nordström, Dan C E; Konttinen, Yrjö T

    2014-12-01

    Apoptosis is involved in the pathogenesis of Sjögren's syndrome (SS), an autoimmune disease affecting exocrine glands. Our recent studies revealed diminished histamine H4 receptor (H₄R) expression and impaired histamine transport in the salivary gland epithelial cells in SS. The aim was now to test if nanomolar histamine and high-affinity H₄R signaling affect apoptosis of human salivary gland epithelial cell. Simian virus 40-immortalized acinar NS-SV-AC cells were cultured in serum-free keratinocyte medium ± histamine H₄R agonist HST-10. Expression and internalization of H₄R were studied by immunofluorescence staining ± clathrin inhibitor methyl-β-cyclodextrin (MβCD). Apoptosis induced using tumor necrosis factor-α with nuclear factor-κB inhibitor IMD-0354 was studied using phase contrast microscopy, Western blot, flow cytometry and polymerase chain reaction (qRT-PCR). HST-10-stimulated H₄R internalization was inhibited by MβCD. Western blotting revealed diminished phosphorylated c-Jun N-terminal kinase JNK, but unchanged levels of phosphorylated extracellular signal regulated kinase pERK1/2 in H₄R-stimulated samples compared to controls. qRT-PCR showed up-regulated expression of anti-apoptotic B cell lymphoma-extra large/Bcl-xL mRNAs and proteins, whereas pro-apoptotic Bcl-2-associated X protein/BAX remained unchanged in H4R-stimulated samples. H₄R stimulation diminished cleavage of PARP and flow cytometry showed significant dose-dependent inhibitory effect of H₄R stimulation on apoptosis. As far as we know this is the first study showing inhibitory effect of H₄R activation on apoptosis of human salivary gland cells. Diminished H₄R-mediated activation may contribute to loss of immune tolerance in autoimmune diseases and in SS in particular. PMID:25239604

  5. In vivo localization and quantification of cerebral dopamine receptors

    International Nuclear Information System (INIS)

    This thesis is based on a number of studies directed upon the development of methods for in vivo determination of Dopamine (DA) receptors with positron-emitting compounds. A synthesis has been developed for the radioactive labelling of N-alkylated derivatives of the Da agonist ADTN with 11C. This investigation and the results of distribution studies with these compounds in the rate are described. Another DA agonist, N-n-propylnorapomorfine (NPA) has been tested for suitability for in vivo detection of cerebral DA receptors, making use of a tritiated compound. Firstly the regional localization of 3H-NPA in the brain of the rat, after in vivo administration of this compound, has been determined and the specificity of this localization has been defined pharmacologically. Also in this study the effects of the occupation of DA receptors with NPA upon the concentrations of DA, HVA and DOPAC in a number of brain regions have been investigated, and an estimation has been made of the maximal saturable striatal NPA compounds in vivo. Next the effects of specific injuries upon the in vivo accumulation after a tracer dose, also effects upon the total saturable in vivo compound have been quantified from saturation studies. These studies have been performed with the DA agonist 3H-NPA as well as with the antagonist 3H-spiperon. In the last study the in vivo tracer binding and the maximally saturable binding of 3H-NPA and 3H-spiperon in various regions of the rat brain have been compared in view of the application of PET for in vivo DA receptor detection with these compounds. (author). 511 refs.; 20 figs.; 14 tabs

  6. Pharmacological evidence that histamine H3 receptors inhibit the vasodepressor responses by selective stimulation of the rat perivascular sensory CGRPergic outflow.

    Science.gov (United States)

    Manrique-Maldonado, Guadalupe; Altamirano-Espinoza, Alain H; Marichal-Cancino, Bruno A; Rivera-Mancilla, Eduardo; Avilés-Rosas, Victor; Villalón, Carlos M

    2015-05-01

    This study has investigated whether pharmacological activation of Gi/o coupled histamine H3/H4 receptors inhibits the rat vasodepressor sensory outflow. For this purpose, 100 male Wistar rats were pithed, artificially ventilated and pretreated (i.v.) with: 25mg/kg gallamine, 2mg/kg/min hexamethonium and 20μg/kg/min methoxamine, followed by i.v. continuous infusions of physiological saline (0.02ml/min) or immepip (3.1, 10 or 31μg/kg/min; a histamine H3/H4 receptor agonist). Under these conditions, electrical stimulation (0.56-5.6Hz; 50V and 2ms) of the spinal cord (T9-T12) resulted in frequency-dependent vasodepressor responses, which were: (i) unchanged during the infusions of saline or immepip (3.1μg/kg/min); and (ii) significantly but, surprisingly, not dose-dependently inhibited by 10 and 31μg/kg/min immepip. Moreover, the sensory-inhibition by 10μg/kg/min immepip (which failed to inhibit the vasodepressor responses by i.v. bolus injections of α-CGRP; 0.1-1µg/kg) was: (i) essentially unaltered after i.v. administration of saline (1ml/kg) or blocking doses of the antagonists ketotifen (100μg/kg; H1), ranitidine (1000μg/kg; H2) or JNJ7777120 (310μg/kg; H4); and (ii) abolished after i.v. thioperamide (310µg/kg; H3). In conclusion, our results suggest that immepip-induced inhibition of the vasodepressor sensory outflow is mainly mediated by prejunctional activation of histamine H3 receptors. PMID:25704614

  7. Cerebral vasoconstriction after subarachnoid hemorrhage--role of changes in vascular receptor phenotype

    DEFF Research Database (Denmark)

    Hansen-Schwartz, Jacob; Ansar, Saema; Edvinsson, Lars

    2008-01-01

    prominent given their ability to elicit powerful constriction of cerebral arteries. Investigating both 5-HT and ET receptors we have observed that there are distinct changes in receptor phenotype after experimental SAH, namely upregulation of the ETB and 5-HT1B receptors, and that this upregulation is...... linked to a higher sensitivity to the endogenous agonists. It has also been shown that reduction in regional cerebral blood flow (CBF) is associated with receptor upregulation and interventional animal experiments have shown a benefit from inhibiting the PKC and MAP kinase pathways on receptor...

  8. Proton pump inhibitor use and fracture risk - effect modification by histamine H1 receptor blockade. Observational case-control study using National Prescription Data

    DEFF Research Database (Denmark)

    Abrahamsen, Bo; Vestergaard, Peter

    2013-01-01

    It remains unknown why proton pump inhibitor (PPI) use may be associated with risk of osteoporotic fractures; evidence of direct effects on calcium absorption or on the osteoclast in humans is weak or absent. However, the ensuing increased gastrin levels may cause histamine production through...... hypertrophy of gastric enterochromaffin like cells, which could lead to bone loss. We speculated that H1 receptor antagonists (H1RA) used for allergies would then reduce the effect of PPI on bone. We therefore conducted a register-based case-control study comprising 124,655 patients with hospital treated...

  9. Radioprotective properties of histamine H2 receptor antagonists. Present and Future prospects

    International Nuclear Information System (INIS)

    Various chemical agents were examined for their radioprotective capability to provide partial protection against radiation injury over the past 50 years. However, no suitable drug has yet been introduced for routine clinical use. In the present study, the radioprotective potential of H2 receptor antagonists was examined in in vivo and in vitro conditions. For this purpose, an in vivo micronucleus assay and an in vitro metaphase analysis were used to test the effects of cimetidine, ranitidine, and famotidine on radiation-induced clastogenic effects. For micronuclei assay, BALB/c mice were irradiated in the presence or absence of drugs, and slides were prepared from bone marrow cells. The frequency of micronuclei was determined in bone marrow erythrocytes. For the in vitro assay, lymphocytes in whole peripheral blood were exposed to radiation in the presence or absence of drugs, and the frequency of chromosomal aberrations were determined. The results show that radiation produced a high number of micronuclei in polychromatic erythrocytes (PCE) and chromosomal aberrations in lymphocytes. All three drugs used in this study effectively reduced the frequency of radiation-induced micronuclei and chromosomal aberrations at various doses. Famotidine was found to be more effective than the other two drugs. From the results obtained, it can be concluded that H2-receptor antagonists reduced the clastogenic effects of radiation with a dose reduction factor (DRF) of 1.5-2 in vivo and in vitro. The way in which these drugs reduce the clastogenic effects of radiation might be via a radical scavenging mechanism. (author)

  10. HISTAMINE H3 RECEPTOR INVERSE AGONISTS ON COGNITIVE AND MOTOR PROCESSES: RELEVANCE TO ALZHEIMER’S DISEASE, ADHD, SCHIZOPHRENIA AND DRUG ABUSE

    Directory of Open Access Journals (Sweden)

    Divya Vohora

    2012-10-01

    Full Text Available Histamine H3 receptor antagonists/ inverse agonists possess potential to treat diverse disease states of the central nervous system (CNS. Cognitive dysfunction and motor impairments are the hallmark of multifarious neurodegenerative and/or psychiatric disorders. This review presents the various neurobiological/ neurochemical evidences available so far following H3 receptor inverse agonists/ antagonists in the pathophysiology of Alzheimer’s disease (AD, attention-deficit hyperactivity disorder (ADHD, schizophrenia and drug abuse each of which is accompanied by deficits of some aspects of cognitive and/or motor functions. Whether the H3 receptor inverse agonism modulates the neurochemical basis underlying the disease condition or affects only the cognitive/motor component of the disease process is discussed with the aim to provide a rationale for their use in diverse disease states that are interlinked and are accompanied by some common motor, cognitive and attentional deficits.

  11. Bispyrimidines as potent histamine H(4) receptor ligands: delineation of structure-activity relationships and detailed H(4) receptor binding mode.

    Science.gov (United States)

    Engelhardt, Harald; Schultes, Sabine; de Graaf, Chris; Nijmeijer, Saskia; Vischer, Henry F; Zuiderveld, Obbe P; Dobler, Julia; Stachurski, Katharina; Mayer, Moriz; Arnhof, Heribert; Scharn, Dirk; Haaksma, Eric E J; de Esch, Iwan J P; Leurs, Rob

    2013-06-13

    The basic methylpiperazine moiety is considered a necessary substructure for high histamine H4 receptor (H4R) affinity. This moiety is however also the metabolic hot spot for various classes of H4R ligands (e.g., indolcarboxamides and pyrimidines). We set out to investigate whether mildly basic 2-aminopyrimidines in combination with the appropriate linker can serve as a replacement for the methylpiperazine moiety. In the series of 2-aminopyrimidines, the introduction of an additional 2-aminopyrimidine moiety in combination with the appropriate linker lead to bispyrimidines displaying pKi values for binding the human H4R up to 8.2. Furthermore, the methylpiperazine replacement results in compounds with improved metabolic properties. The attempt to transfer the knowledge generated in the class of bispyrimidines to the indolecarboxamides failed. Combining the derived structure-activity relationships with homology modeling leads to new detailed insights in the molecular aspects of ligand-H4R binding in general and the binding mode of the described bispyrimidines in specific. PMID:23668417

  12. Fentanyl enhances the excitability of rapidly adapting receptors to cause cough via the enhancement of histamine release in the airways

    OpenAIRE

    Kamei, Junzo; Nakanishi, Yuki; ASATO, MEGUMI; Ikeda, Hiroko

    2013-01-01

    Background Although the mechanism of fentanyl-induced cough is unclear, several lines of evidence suggest that allergic mediators, such as histamine, may play a role in the production of fentanyl-induced coughs. The aim of this study was to explore the effects of fentanyl on cough sensitivity to inhaled citric acid and on histamine release in BALF in mice. Methods The cough reflex was induced by the inhalation of citric acid. Male ICR mice were exposed to a nebulized solution of citric acid a...

  13. The extracellular loop 2 (ECL2) of the human histamine H4 receptor substantially contributes to ligand binding and constitutive activity.

    Science.gov (United States)

    Wifling, David; Bernhardt, Günther; Dove, Stefan; Buschauer, Armin

    2015-01-01

    In contrast to the corresponding mouse and rat orthologs, the human histamine H4 receptor (hH4R) shows extraordinarily high constitutive activity. In the extracellular loop (ECL), replacement of F169 by V as in the mouse H4R significantly reduced constitutive activity. Stabilization of the inactive state was even more pronounced for a double mutant, in which, in addition to F169V, S179 in the ligand binding site was replaced by M. To study the role of the FF motif in ECL2, we generated the hH4R-F168A mutant. The receptor was co-expressed in Sf9 insect cells with the G-protein subunits Gαi2 and Gβ1γ2, and the membranes were studied in [3H]histamine binding and functional [35S]GTPγS assays. The potency of various ligands at the hH4R-F168A mutant decreased compared to the wild-type hH4R, for example by 30- and more than 100-fold in case of the H4R agonist UR-PI376 and histamine, respectively. The high constitutive activity of the hH4R was completely lost in the hH4R-F168A mutant, as reflected by neutral antagonism of thioperamide, a full inverse agonist at the wild-type hH4R. By analogy, JNJ7777120 was a partial inverse agonist at the hH4R, but a partial agonist at the hH4R-F168A mutant, again demonstrating the decrease in constitutive activity due to F168A mutation. Thus, F168 was proven to play a key role not only in ligand binding and potency, but also in the high constitutive activity of the hH4R. PMID:25629160

  14. The extracellular loop 2 (ECL2 of the human histamine H4 receptor substantially contributes to ligand binding and constitutive activity.

    Directory of Open Access Journals (Sweden)

    David Wifling

    Full Text Available In contrast to the corresponding mouse and rat orthologs, the human histamine H4 receptor (hH4R shows extraordinarily high constitutive activity. In the extracellular loop (ECL, replacement of F169 by V as in the mouse H4R significantly reduced constitutive activity. Stabilization of the inactive state was even more pronounced for a double mutant, in which, in addition to F169V, S179 in the ligand binding site was replaced by M. To study the role of the FF motif in ECL2, we generated the hH4R-F168A mutant. The receptor was co-expressed in Sf9 insect cells with the G-protein subunits Gαi2 and Gβ1γ2, and the membranes were studied in [3H]histamine binding and functional [35S]GTPγS assays. The potency of various ligands at the hH4R-F168A mutant decreased compared to the wild-type hH4R, for example by 30- and more than 100-fold in case of the H4R agonist UR-PI376 and histamine, respectively. The high constitutive activity of the hH4R was completely lost in the hH4R-F168A mutant, as reflected by neutral antagonism of thioperamide, a full inverse agonist at the wild-type hH4R. By analogy, JNJ7777120 was a partial inverse agonist at the hH4R, but a partial agonist at the hH4R-F168A mutant, again demonstrating the decrease in constitutive activity due to F168A mutation. Thus, F168 was proven to play a key role not only in ligand binding and potency, but also in the high constitutive activity of the hH4R.

  15. (11) C-labeled and (18) F-labeled PET ligands for subtype-specific imaging of histamine receptors in the brain.

    Science.gov (United States)

    Funke, Uta; Vugts, Danielle J; Janssen, Bieneke; Spaans, Arnold; Kruijer, Perry S; Lammertsma, Adriaan A; Perk, Lars R; Windhorst, Albert D

    2013-01-01

    The signaling molecule histamine plays a key role in the mediation of immune reactions, in gastric secretion, and in the sensory system. In addition, it has an important function as a neurotransmitter in the central nervous system, acting in pituitary hormone secretion, wakefulness, motor and cognitive functions, as well as in itch and nociception. This has raised interest in the role of the histaminergic system for the treatment and diagnosis of various pathologies such as allergy, sleeping and eating disorders, neurodegeneration, neuroinflammation, mood disorders, and pruritus. In the past 20 years, several ligands targeting the four different histamine receptor subtypes have been explored as potential radiotracers for positron emission tomography (PET). This contribution provides an overview of the developments of subtype-selective carbon-11-labeled and fluorine-18-labeled compounds for imaging in the brain. Using specific radioligands, the H1 R expression in human brain could be examined in diseases such as schizophrenia, depression, and anorexia nervosa. In addition, the sedative effects of antihistamines could be investigated in terms of H1 R occupancy. The H3 R is of special interest because of its regulatory role in the release of various other neurotransmitters, and initial H3 R PET imaging studies in humans have been reported. The H4 R is the youngest member of the histamine receptor family and is involved in neuroinflammation and various sensory pathways. To date, two H4 R-specific (11) C-labeled ligands have been synthesized, and the imaging of the H4 R in vivo is in the early stage. PMID:24285318

  16. EP4 prostanoid receptor-mediated vasodilatation of human middle cerebral arteries

    OpenAIRE

    Davis, Richard J.; Murdoch, Colin E.; Ali, Mozam; Purbrick, Stuart; Ravid, Rivka; Baxter, Gordon S; Tilford, Nick; Sheldrick, Robert L G; Clark, Kenneth L; Coleman, Robert A.

    2004-01-01

    Dilatation of the cerebral vasculature is recognised to be involved in the pathophysiology of migraine. Furthermore, elevated levels of prostaglandin E2 (PGE2) occur in the blood, plasma and saliva of migraineurs during an attack, suggestive of a contributory role. In the present study, we have characterised the prostanoid receptors involved in the relaxation and contraction of human middle cerebral arteries in vitro.In the presence of indomethacin (3 μM) and the TP receptor antagonist GR3219...

  17. Role of a histamine 4 receptor as an anti-inflammatory target in carrageenan-induced pleurisy in mice

    Science.gov (United States)

    Ahmad, Sheikh Fayaz; Zoheir, Khairy M A; Abdel-Hamied, Hala E; Alrashidi, Ibrahim; Attia, Sabry M; Bakheet, Saleh A; Ashour, Abdelkader E; Abd-Allah, Adel R A

    2014-01-01

    The histamine 4 receptor (H4R) is expressed primarily on cells involved in inflammation and immune responses. Despite much research into inflammatory diseases, no drugs with favourable safety profiles are yet available for their treatment. The aim of the present study was to determine the potential anti-inflammatory effect of 4-methylhistamine (4-MeH) or JNJ77777120 (JNJ) and to explore the role of H4R in a mouse model of carrageenan (Cg) -induced pleurisy. A single dose of 4-MeH or JNJ (30 mg/kg) was administered intraperitoneally 1 hr before Cg administration. The results illustrate that both the numbers of CD4+, CD25+, CD4+ CD25+, GITR+, GITR+ IL-17A+-expressing T cells and the levels of T helper type 1 (Th1)/Th17 cytokines were markedly increased in both the Cg-treated and 4-MeH-treated groups, whereas the cytokines produced by Th2 cells were significantly decreased in the same groups. However, JNJ treatment significantly decreased both the number of T-cell subsets and GITR+, GITR+ IL-17A+-expressing T cells, and the production of Th1/Th17 cytokines. Further, JNJ up-regulated the expression of the Th2 cytokines. RT-PCR analysis revealed an increased expression of interleukin-1β, tumour necrosis factor-α, monocyte chemoattractant protein-1 and intercellular adhesion molecule-1 in the Cg-treated and 4-MeH-treated groups, which was reduced by treatment with JNJ in lung tissues. Moreover, histological examinations revealed anti-inflammatory effects of JNJ, whereas 4-MeH worsened Cg-induced inflammation. In conclusion, the results of the present work clearly indicate that JNJ possesses important anti-inflammatory properties that are increased in 4-MeH-treated mice, suggesting that H4R are involved in pleurisy and that JNJ has an anti-inflammatory effect in associated disease conditions. PMID:24460575

  18. Histamine 2 blocker potentiates the effects of histamine 1 blocker in suppressing histamine-induced wheal

    Directory of Open Access Journals (Sweden)

    Dhanya N

    2008-01-01

    Full Text Available Background : Histamine is responsible for the wheal and flare reaction in various allergic conditions. Classical antihistamines are the drugs which block the H 1 receptors and are widely used in various allergic conditions, whereas H 2 blockers are mainly used for acid peptic disease. Although H 1 receptor-mediated actions of histamine are primarily responsible for vasodilatation, vasopermeability, and itching, it has been observed that combined blocking of both H 1 and H 2 receptors may provide better relief. Aim: To compare the efficacy of levocetirizine (H 1 blocker versus levocetirizine and ranitidine (H 2 blocker in suppressing histamine-induced wheal. Methods: Fifteen volunteers were given a single dose of levocetirizine 5 mg on day 1 and a single dose of levocetirizine 5 mg with ranitidine 150 mg twice a day on day 7. A pretest was performed by intradermal histamine prick test. After administration of the drugs, the prick test was repeated at 1 hour, 2, 3, 6, and 24 hours, and the size of the wheal measured and statistically analyzed. Results: At 1 hour, there was no statistically significant difference in the wheal size between levocetirizine alone and the combination of levocetirizine and ranitidine. Levocetirizine with ranitidine resulted in statistically significant reduction of wheal size at 2, 3, 6, and 24 hours when compared with levocetirizine alone. Conclusion: H2 blocker potentiates the effects of an H1 blocker in suppressing histamine-induced wheal.

  19. Altered endothelin receptor expression and affinity in spontaneously hypertensive rat cerebral and coronary arteries

    DEFF Research Database (Denmark)

    Cao, Lei; Cao, Yong-Xiao; Xu, Cang-Bao;

    2013-01-01

    BACKGROUND: Hypertension is associated with arterial hyperreactivity, and endothelin (ET) receptors are involved in vascular pathogenesis. The present study was performed to examine the hypothesis that ET receptors were altered in cerebral and coronary arteries of spontaneously hypertensive rats...... (SHR). METHODOLOGY/PRINCIPAL FINDINGS: Cerebral and coronary arteries were removed from SHR. Vascular contraction was recorded using a sensitive myograph system. Real-time PCR and Western blotting were used to quantify mRNA and protein expression of receptors and essential MAPK pathway molecules. The...... results demonstrated that both ETA and ETB receptor-mediated contractile responses in SHR cerebral arteries were shifted to the left in a nonparallel manner with increased maximum contraction compared with Wistar-Kyoto (WKY) rats. In SHR coronary arteries, the ETA receptor-mediated contraction curve was...

  20. Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent [3H]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata

    International Nuclear Information System (INIS)

    The release of [3H]GABA from slices of rat substantia nigra pars reticulata induced by increasing extracellular K+ from 6 to 15 mM in the presence of 10 μM sulpiride was inhibited by 73±3% by 1 μM SCH 23390, consistent with a large component of release dependent upon D1 receptor activation. The histamine H3 receptor-selective agonist immepip (1 μM) and the non-selective agonist histamine (100 μM) inhibited [3H]GABA release by 78±2 and 80±2%, respectively. The inhibition by both agonists was reversed by the H3 receptor antagonist thioperamide (1 μM). However, in the presence of 1 μM SCH 23390 depolarization-induced release of [3H]GABA was not significantly decreased by 1 μM immepip. In rats depleted of dopamine by pretreatment with reserpine, immepip no longer inhibited control release of [3H]GABA, but in the presence of 1 μM SKF 38393, which produced a 7±1-fold stimulation of release, immepip reduced the release to a level not statistically different from that in the presence of immepip alone. Immepip (1 μM) also inhibited the depolarization-induced release of [3H]dopamine from substantia nigra pars reticulata slices, by 38±3%.The evidence is consistent with the proposition that activation of histamine H3 receptors leads to the selective inhibition of the component of depolarization-induced [3H]GABA release in substantia nigra pars reticulata slices which is dependent upon D1 receptor activation. This appears to be largely an action at the terminals of the striatonigral GABA projection neurons, which may be enhanced by a partial inhibition of dendritic [3H]dopamine release. (Copyright (c) 1997 Elsevier Science B.V., Amsterdam. All rights reserved.)

  1. Agonist-induced activation of histamine H3 receptor signals to extracellular signal-regulated kinases 1 and 2 through PKC-, PLD-, and EGFR-dependent mechanisms.

    Science.gov (United States)

    Lai, Xiangru; Ye, Lingyan; Liao, Yuan; Jin, Lili; Ma, Qiang; Lu, Bing; Sun, Yi; Shi, Ying; Zhou, Naiming

    2016-04-01

    The histamine H3 receptor (H3R), abundantly expressed in the central and the peripheral nervous system, has been recognized as a promising target for the treatment of various important CNS diseases including narcolepsy, Alzheimer's disease, and attention deficit hyperactivity disorder. The H3R acts via Gi/o -proteins to inhibit adenylate cyclase activity and modulate MAPK activity. However, the underlying molecular mechanisms for H3R mediation of the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) remain to be elucidated. In this study, using HEK293 cells stably expressing human H3R and mouse primary cortical neurons endogenously expressing mouse H3R, we found that the H3R-mediated activation of ERK1/2 was significantly blocked by both the pertussis toxin and the MEK1/2 inhibitor U0126. Upon stimulation by H3R agonist histamine or imetit, H3R was shown to rapidly induce ERK1/2 phosphorylation via PLC/PKC-, PLDs-, and epidermal growth factor receptor (EGFR) transactivation-dependent pathways. Furthermore, it was also indicated that while the βγ-subunits play a key role in H3R-activated ERK1/2 phosphorylation, β-arrestins were not required for ERK1/2 activation. In addition, when the cultured mouse cortical neurons were exposed to oxygen and glucose deprivation conditions (OGD), imetit exhibited neuroprotective properties through the H3R. Treatment of cells with the inhibitor UO126 abolished these protective effects. This suggests a possible neuroprotective role of the H3R-mediated ERK1/2 pathway under hypoxia conditions. These observations may provide new insights into the pharmacological effects and the physiological functions modulated by the H3R-mediated activation of ERK1/2. Histamine H3 receptors are abundantly expressed in the brain and play important roles in various CNS physiological functions. However, the underlying mechanisms for H3R-induced activation of extracellular signal-regulated kinase (ERK)1/2 remain largely unknown. Here

  2. Dopamine receptor activation modulates GABA neuron migration from the basal forebrain to the cerebral cortex.

    Science.gov (United States)

    Crandall, James E; McCarthy, Deirdre M; Araki, Kiyomi Y; Sims, John R; Ren, Jia-Qian; Bhide, Pradeep G

    2007-04-01

    GABA neurons of the cerebral cortex and other telencephalic structures are produced in the basal forebrain and migrate to their final destinations during the embryonic period. The embryonic basal forebrain is enriched in dopamine and its receptors, creating a favorable environment for dopamine to influence GABA neuron migration. However, whether dopamine receptor activation can influence GABA neuron migration is not known. We show that dopamine D1 receptor activation promotes and D2 receptor activation decreases GABA neuron migration from the medial and caudal ganglionic eminences to the cerebral cortex in slice preparations of embryonic mouse forebrain. Slice preparations from D1 or D2 receptor knock-out mouse embryos confirm the findings. In addition, D1 receptor electroporation into cells of the basal forebrain and pharmacological activation of the receptor promote migration of the electroporated cells to the cerebral cortex. Analysis of GABA neuron numbers in the cerebral wall of the dopamine receptor knock-out mouse embryos further confirmed the effects of dopamine receptor activation on GABA neuron migration. Finally, dopamine receptor activation mobilizes striatal neuronal cytoskeleton in a manner consistent with the effects on neuronal migration. These data show that impairing the physiological balance between D1 and D2 receptors can alter GABA neuron migration from the basal forebrain to the cerebral cortex. The intimate relationship between dopamine and GABA neuron development revealed here may offer novel insights into developmental disorders such as schizophrenia, attention deficit or autism, and fetal cocaine exposure, all of which are associated with dopamine and GABA imbalance. PMID:17409246

  3. Cerebral vasoconstriction after subarachnoid hemorrhage--role of changes in vascular receptor phenotype

    DEFF Research Database (Denmark)

    Hansen-Schwartz, J.; Ansar, S.; Edvinsson, L.

    2008-01-01

    linked to a higher sensitivity to the endogenous agonists. It has also been shown that reduction in regional cerebral blood flow (CBF) is associated with receptor upregulation and interventional animal experiments have shown a benefit from inhibiting the PKC and MAP kinase pathways on receptor...

  4. C-labeled and F-labeled PET ligands for subtype-specific imaging of histamine receptors in the brain

    OpenAIRE

    Funke, Uta; Vugts, Danielle J.; Janssen, Bieneke; Spaans, Arnold; Kruijer, Perry S.; Lammertsma, Adriaan A.; Perk, Lars R.; Albert D. Windhorst

    2013-01-01

    The signaling molecule histamine plays a key role in the mediation of immune reactions, in gastric secretion, and in the sensory system. In addition, it has an important function as a neurotransmitter in the central nervous system, acting in pituitary hormone secretion, wakefulness, motor and cognitive functions, as well as in itch and nociception. This has raised interest in the role of the histaminergic system for the treatment and diagnosis of various pathologies such as allergy, sleeping ...

  5. Histamine Induces Egr-1 Expression in Human Aortic Endothelial Cells via the H1 Receptor-mediated Protein Kinase Cδ-dependent ERK Activation Pathway*

    OpenAIRE

    Hao, Feng; Tan, Mingqi; Xu, Xuemin; Cui, Mei-Zhen

    2008-01-01

    Histamine, a potent inflammatory mediator, has multiple effects on the pathogenesis of atherosclerosis. This study investigates the effect of histamine on the expression of early growth response factor 1 (Egr-1), a master transcription factor that regulates the expression of an array of atherogenic genes in atherosclerotic lesions. Histamine markedly and rapidly induces Egr-1 mRNA and protein expression in primary human aortic endothelial cells (HAECs). Histamine-induc...

  6. Cytokines increase endothelin ETB receptor contractile activity in rat cerebral artery

    DEFF Research Database (Denmark)

    Leseth, K H; Adner, M; Berg, H K;

    1999-01-01

    concentration-response curves were obtained in artery segments exposed to sarafotoxin S6c. Organ culture in the presence of either interleukin-1 beta or tumour necrosis factor-alpha, but not interleukin-2 or interleukin-6, further amplified the maximal contraction to sarafotoxin S6c. The plasticity of ETB...... receptor expression in cerebral arteries and sensitivity for pro-inflammatory cytokines, suggest a role in inflammatory cerebral diseases such as stroke....

  7. Effect of a somatostatin analogue (SMS 201-995) on antral gastrin cell hyperplasia and hypergastrinemia induced by a histamine H2-receptor antagonist.

    Science.gov (United States)

    Kimura, K

    1993-05-01

    The effect of a somatostatin analogue, SMS 201-995 (SMS), on antral gastrin cell hyperplasia (AGH) and hypergastrinemia associated with 14-day administration of the histamine H2-receptor antagonist (H2-RA) famotidine was studied in rats. When the famotidine group was compared with the control group, the antral gastrin cell (G-cell) number was significantly increased (P SMS group was compared with the famotidine group, the G-cell number was significantly decreased (P < 0.01) by approximately 30%, and the serum gastrin level was significantly decreased (P < 0.01) by approximately 40%. These findings suggest that SMS may be useful for inhibiting AGH and hypergastrinemia induced by long-term H2-RA administration. PMID:8511502

  8. Cerebral ischemia enhances vascular angiotensin AT1 receptor-mediated contraction in rats

    DEFF Research Database (Denmark)

    Stenman, Emelie; Edvinsson, Lars

    2004-01-01

    MCA occlusion (P<0.05). The angiotensin II type 1 (AT1) receptor antagonists candesartan and losartan abolished the enhanced responses to angiotensin II (P<0.05), whereas the AT2 receptor antagonist PD123319 had no effect. The amount of AT1 receptor mRNA was lower in the occluded MCAs compared with....... These results support a role for AT1 receptors in cerebral ischemia, and we think that AT1 receptors might be a future therapeutic target in ischemic stroke....

  9. Lactate transport and receptor actions in cerebral malaria

    DEFF Research Database (Denmark)

    Mariga, Shelton T; Kolko, Miriam; Gjedde, Albert;

    2014-01-01

    Cerebral malaria (CM), caused by Plasmodium falciparum infection, is a prevalent neurological disorder in the tropics. Most of the patients are children, typically with intractable seizures and high mortality. Current treatment is unsatisfactory. Understanding the pathogenesis of CM is required in...... order to identify therapeutic targets. Here, we argue that cerebral energy metabolic defects are probable etiological factors in CM pathogenesis, because malaria parasites consume large amounts of glucose metabolized mostly to lactate. Monocarboxylate transporters (MCTs) mediate facilitated transfer...

  10. MEK1/2 inhibition attenuates vascular ETA and ETB receptor alterations after cerebral ischaemia

    DEFF Research Database (Denmark)

    Henriksson, Marie; Stenman, Emelie; Vikman, Petter;

    2007-01-01

    effect of inhibition of the MAP kinase/ERK kinase (MEK)1/2 on ET receptor alteration, brain damage, and neurology in experimental cerebral ischaemia. Transient middle cerebral artery occlusion (MCAO) was induced in male Wistar rats by the intraluminal filament technique. The animals received 100 mg...... MCAO, the contractile responses of the ETA and ETB receptors were augmented in the ipsilateral MCA. U0126 decreased this alteration in ET receptor response. Furthermore, treatment with U0126 significantly decreased the brain damage and improved neurological scores. Immunohistochemistry showed that....../kg intraperitoneally of the MEK1/2 inhibitor U0126 or vehicle in conjunction with the occlusion. After 24 h, the rats were decapitated and the brains removed. The middle cerebral arteries were dissected out and examined with myographs or immunohistochemistry. The ischaemic areas of the brains were compared. After the...

  11. Development of radioiodinated receptor ligands for cerebral single photon emission tomography

    International Nuclear Information System (INIS)

    In the last decade the use of radiolabeled ligands for the imaging of cerebral receptors by emission computed tomography (ECT) has seen rapid growth. The opportunity to routinely perform cerebral single photon emission tomography (SPET) with iodine-123-labeled ligands depends on the availability of receptor ligands into which iodine can be introduced without decreasing the required high target receptor specificity. The use of iodine-123-labeled receptor-specific ligands also depends on the availability of high purity iodine-123 at reasonable costs and the necessary imaging instrumentation. In this paper, the development and current stage of evaluation of various iodine-123-labeled ligands for SPET imaging of dopaminergic, serotonergic and muscarinic acetylcholinergic receptor classes are discussed

  12. Histamine is required for IL-4-driven eosinophilic allergic responses1

    OpenAIRE

    Swartzendruber, Julie A.; Byrne, Adam J.; Bryce, Paul J.

    2011-01-01

    Histamine is an important allergic mediator and studies have defined roles for both histamine 1 and 4 receptors (H1R and H4R) in allergic airway inflammation. Here, we show that histamine is necessary to generate IL-4-driven eosinophilic inflammation, as histamine deficient mice cannot generate eosinophilic lung inflammation in response to intratracheal IL-4 and exogenous histamine restores responsiveness. This is histamine 2 receptor (H2R) dependent since H2R KO mice fail to respond to IL-4,...

  13. Cerebral ischemia upregulates vascular endothelin ET(B) receptors in rat

    DEFF Research Database (Denmark)

    Stenman, Emelie; Malmsjö, Malin; Uddman, Erik; Gidö, Gunilla; Wieloch, Tadeuz; Edvinsson, Lars

    2002-01-01

    BACKGROUND AND PURPOSE: Elevated levels of endothelin-1 (ET-1) have been reported in cerebral ischemia. A role for ET may prove more important if the vascular receptors were changed. We addressed whether there is any change in ET receptor expression in cerebral ischemia. METHODS: The right middle......, calculated as percentage of the contractile capacity of 63.5 mmol/L K+]=68+/-68%; P<0.0001), while there was no difference in the responses to ET-1 after cerebral ischemia. Real-time polymerase chain reaction revealed a significant upregulation of both the ET(A) and ET(B) receptors (both P<0.05) in the...... occluded MCA compared with the nonoccluded MCA from the same rats. CONCLUSIONS: Focal cerebral ischemia in rat induces increased transcription of both ET(A) and ET(B) receptors, which results in the appearance of a contractile response to the ET(B) receptor agonist S6c. These results suggest a role for ET...

  14. Time-dependent histamine release from stored human blood products

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Edvardsen, L; Vangsgaard, K;

    1996-01-01

    Perioperative transfusion of whole blood has been shown to amplify trauma-induced immunosuppression, which could be attenuated by perioperative administration of histamine2 receptor antagonists. Supernatants from different blood products were, therefore, analysed for histamine content during...... storage. Whole blood (six units), plasma-reduced whole blood (six units), and plasma- and buffy coat-reduced (saline-adenine-glucose-mannitol) (SAGM) blood (six units) from unpaid healthy donors were stored in the blood bank for 35 days at 4 degrees C. Plasma histamine and total cell-bound histamine...... content at donation, and histamine concentration in samples drawn from the units on days 0, 2, 5, 9, 14, 21, 28 and 35 were analysed with an enzyme-linked immunosorbent assay. Median plasma histamine concentration was 4.8 (range 1.9-14.3) nmol/l (n = 18). Median total cell-bound histamine content was 417...

  15. Histamine H4-receptors inhibit mast cell renin release in ischemia/reperfusion via protein kinase C ε-dependent aldehyde dehydrogenase type-2 activation.

    Science.gov (United States)

    Aldi, Silvia; Takano, Ken-ichi; Tomita, Kengo; Koda, Kenichiro; Chan, Noel Y-K; Marino, Alice; Salazar-Rodriguez, Mariselis; Thurmond, Robin L; Levi, Roberto

    2014-06-01

    Renin released by ischemia/reperfusion (I/R) from cardiac mast cells (MCs) activates a local renin-angiotensin system (RAS) causing arrhythmic dysfunction. Ischemic preconditioning (IPC) inhibits MC renin release and consequent activation of this local RAS. We postulated that MC histamine H4-receptors (H4Rs), being Gαi/o-coupled, might activate a protein kinase C isotype-ε (PKCε)-aldehyde dehydrogenase type-2 (ALDH2) cascade, ultimately eliminating MC-degranulating and renin-releasing effects of aldehydes formed in I/R and associated arrhythmias. We tested this hypothesis in ex vivo hearts, human mastocytoma cells, and bone marrow-derived MCs from wild-type and H4R knockout mice. We found that activation of MC H4Rs mimics the cardioprotective anti-RAS effects of IPC and that protection depends on the sequential activation of PKCε and ALDH2 in MCs, reducing aldehyde-induced MC degranulation and renin release and alleviating reperfusion arrhythmias. These cardioprotective effects are mimicked by selective H4R agonists and disappear when H4Rs are pharmacologically blocked or genetically deleted. Our results uncover a novel cardioprotective pathway in I/R, whereby activation of H4Rs on the MC membrane, possibly by MC-derived histamine, leads sequentially to PKCε and ALDH2 activation, reduction of toxic aldehyde-induced MC renin release, prevention of RAS activation, reduction of norepinephrine release, and ultimately to alleviation of reperfusion arrhythmias. This newly discovered protective pathway suggests that MC H4Rs may represent a new pharmacologic and therapeutic target for the direct alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure. PMID:24696042

  16. Effects of 3-methylhistamine and phenylethylamine on histamine action on isolated guinea-pig trachea rings

    OpenAIRE

    Gajović Olgica; Lazić Zorica; Pantović Suzana; Čolić Maja; Stojanović Jelica; Stanarčić Jelena; Rosić G.; Rosić Mirko

    2011-01-01

    It is well known that histamine produces constriction via H1 receptors and decreases tracheal smooth muscle tone via H2 and H3 receptors. In addition, it has already been reported that 3-methylhistamine and phenylethylamine are competitive antagonists of histamine N-methyl-transferase (HMT), the enzyme responsible for rapid inactivation of histamine. Our results suggest the possibility that 3- methyl-histamine and phenylethylamine as competitive antagonists...

  17. Somatostatin content and receptors in the cerebral cortex of depressed and control subjects.

    OpenAIRE

    Charlton, B G; Leake, A; Wright, C.; Fairbairn, A F; McKeith, I G; Candy, J M; Ferrier, I. N.

    1988-01-01

    Somatostatin-like immunoreactivity is reduced in the cerebrospinal fluid in depression and this is presumed to reflect alterations in cerebral somatostatinergic systems. We have examined this hypothesis by measuring this immunoreactivity and somatostatin receptors in post-mortem cortical tissue from depressed patients and control subjects. There was no significant difference in the temporal and occipital cortex in somatostatin-like immunoreactivity or in somatostatin receptor affinity and bin...

  18. Histamine H1-receptor-mediated increase in the Ca2+ transient without a change in the Ca2+ current in electrically stimulated guinea-pig atrial myocytes

    OpenAIRE

    Yoshimoto, Kimihiro; Hattori, Yuichi; Houzen, Hideki; Kanno, Morio; Yasuda, Keishu

    1998-01-01

    The effects of histamine on the intracellular Ca2+ concentration ([Ca2+]i), action potential and membrane currents were assessed in single atrial myocytes prepared from guinea-pigs.Histamine caused a concentration-dependent increase in the [Ca2+]i transient in indo1/AM loaded myocytes when stimulated electrically at 0.5 Hz. However, the maximum increase in [Ca2+]i transient produced by histamine was less than 50% of that elicited by isoprenaline. The histamine-induced increase in [Ca2+]i tran...

  19. A Milk-Free Diet Downregulates Folate Receptor Autoimmunity in Cerebral Folate Deficiency Syndrome

    Science.gov (United States)

    Ramaekers, Vincent T.; Sequeira, Jeffrey M.; Blau, Nenad; Quadros, Edward V.

    2008-01-01

    In cerebral folate deficiency syndrome, the presence of autoantibodies against the folate receptor (FR) explains decreased folate transport to the central nervous system and the clinical response to folinic acid. Autoantibody crossreactivity with milk FR from different species prompted us to test the effect of a milk-free diet. Intervention with a…

  20. Inhibition of PKC activity blocks the increase of ETB receptor expression in cerebral arteries

    DEFF Research Database (Denmark)

    Henriksson, Marie; Vikman, Petter; Stenman, Emelie;

    2006-01-01

    BACKGROUND: Previous studies have shown that there is a time-dependent upregulation of contractile endothelin B (ETB) receptors in middle cerebral arteries (MCA) after organ culture. This upregulation is dependent on mitogen-activated protein kinases and possibly protein kinase C (PKC). The aim o...

  1. Triptan-induced contractile (5-HT1B receptor) responses in human cerebral and coronary arteries

    DEFF Research Database (Denmark)

    Edvinsson, Lars; Uddman, Erik; Wackenfors, Angelica; Davenport, Anthony; Longmore, Jenny; Malmsjö, Malin

    2005-01-01

    Triptans are agonists at 5-HT1B and 5-HT1D (where 5-HT is 5-hydroxytryptamine; serotonin) receptors and cause vasoconstriction of isolated blood vessels. The aim of the present study was to determine vasoconstrictor potency (EC50) of triptans in human coronary and cerebral arteries and to examine...

  2. Subarachnoid hemorrhage enhances endothelin receptor expression and function in rat cerebral arteries

    DEFF Research Database (Denmark)

    Hansen-Schwartz, Jacob; Hoel, Natalie Løvland; Zhou, Mingfang;

    2003-01-01

    OBJECTIVE: Inspired by organ culture-induced changes in the vascular endothelin (ET) receptor population, we investigated whether such changes occur in cerebral arteries in a rat subarachnoid hemorrhage (SAH) model. METHODS: SAH was induced with injection of 250 microl of blood into the prechiasm...

  3. [Histamine intolerance--possible dermatologic sequences].

    Science.gov (United States)

    Lugović-Mihić, Liborija; Seserko, Ana; Duvancić, Tomislav; Situm, Mirna; Mihić, Josip

    2012-12-01

    Although histamine intolerance (HIT) is not very frequently encountered, it can have serious consequences. Food intolerance is a non allergic hypersensitivity to food that does not include the immune system even though the symptoms are similar to those of IgE-mediated allergic reactions. HIT apparently develops as a result of an impaired diamine oxidase (DAO) activity due to gastrointestinal disease or through DAO inhibition, as well as through a genetic predisposition which was proven in a number of patients. The intake of histamine-rich foods as well as alcohol or drugs which cause either the release of histamine or the blocking of DAO can lead to various disorders in many organs (gastrointestinal system, skin, lungs, cardiovascular system and brain), depending on the expression of histamine receptors. Dermatologic sequels can be rashes, itch, urticaria, angioedema, dermatitis, eczema and even acne, rosacea, psoriasis, and other. Recognizing the symptoms due to HIT is especially important in treating such patients. The significance of HIT in patients with atopic dermatitis in whom the benefit of a low histamine diet has been proven is becoming increasingly understood recently. Because of the possibility of symptoms affecting numerous organs, a detailed history of symptoms following the intake of histamine-rich foods or drugs that interfere with histamine metabolism is essential for making the diagnosis of HIT. Considering that such symptoms can be the result of multiple factors, the existence of HIT is usually underestimated, but considerable expectations are being made from future studies. PMID:23814966

  4. Interleukin-4 (IL-4 enhances and soluble interleukin-4 receptor (sIL-4R inhibits histamine release from peripheral blood basophils and mast cells in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    B. Niggemann

    1997-01-01

    Full Text Available The aim of the study was to analyse the effect of interleukin-4 (IL-4 on allergen and anti-IgE mediated histamine release from basophils and human skin mast cells and to assess whether soluble recombinant interleukin-4 receptor (sIL4R can inhibit these effects. Anti-IgE stimulated histamine release from peripheral blood basophils and mast cells of atopic donors was enhanced after preincubation with IL-4, whereas after preincubation with sIL-4R it was inhibited. These effects were even more pronounced when samples were stimulated with a clinically relevant allergen. In IL-4 preincubated skin mast cells, there was a similar enhancement of anti-IgE stimulated histamine release, which could again be inhibited by sIL-4R. The effects of IL-4 and sIL4R were dose- and time-dependent. Mice sensitized to ovalbumin and treated with soluble recombinant murine sIL-4R showed significantly reduced immediate-type cutaneous hypersensitivity responses compared with untreated mice. These in vivo effects were IgE independent, since there were no significant differences in total and allergen specific IgE/IgG1 antibody titres between treated and untreated mice. This indicates that IL4 exerts priming effects on histamine release by effector cells of the allergic response and that these effects are potently antagonized by soluble IL-4R both in vitro and in vivo.

  5. Antihistamines suppress upregulation of histidine decarboxylase gene expression with potencies different from their binding affinities for histamine H1 receptor in toluene 2,4-diisocyanate-sensitized rats.

    Science.gov (United States)

    Mizuguchi, Hiroyuki; Das, Asish K; Maeyama, Kazutaka; Dev, Shrabanti; Shahriar, Masum; Kitamura, Yoshiaki; Takeda, Noriaki; Fukui, Hiroyuki

    2016-04-01

    Antihistamines inhibit histamine signaling by blocking histamine H1 receptor (H1R) or suppressing H1R signaling as inverse agonists. The H1R gene is upregulated in patients with pollinosis, and its expression level is correlated with the severity of nasal symptoms. Here, we show that antihistamine suppressed upregulation of histidine decarboxylase (HDC) mRNA expression in patients with pollinosis, and its expression level was correlated with that of H1R mRNA. Certain antihistamines, including mepyramine and diphenhydramine, suppress toluene-2,4-diisocyanate (TDI)-induced upregulation of HDC gene expression and increase HDC activity in TDI-sensitized rats. However, d-chlorpheniramine did not demonstrate any effect. The potencies of antihistamine suppressive effects on HDC mRNA elevation were different from their H1R receptor binding affinities. In TDI-sensitized rats, the potencies of antihistamine inhibitory effects on sneezing in the early phase were related to H1R binding. In contrast, the potencies of their inhibitory effects on sneezing in the late phase were correlated with those of suppressive effects on HDC mRNA elevation. Data suggest that in addition to the antihistaminic and inverse agonistic activities, certain antihistamines possess additional properties unrelated to receptor binding and alleviate nasal symptoms in the late phase by inhibiting synthesis and release of histamine by suppressing HDC gene transcription. PMID:26980430

  6. Further evidence for the role of histamine H3, but not H1, H2 or H4, receptors in immepip-induced inhibition of the rat cardioaccelerator sympathetic outflow.

    Science.gov (United States)

    Pinacho-García, Manuel; Marichal-Cancino, Bruno A; Villalón, Carlos M

    2016-02-15

    Since histamine H3 and H4 receptors are coupled to heterotrimeric Gi/o proteins, a signal transduction pathway associated with inhibition of neurotransmitter release, the present study has investigated the inhibition of the rat cardioaccelerator sympathetic outflow induced by the H3/H4 receptor agonist immepip by using antagonists for histamine H1 (ketotifen), H2 (ranitidine), H3 (thioperamide) and H4 (JNJ7777120) receptors. For this purpose, 102 male Wistar rats were pithed, artificially ventilated and prepared for either preganglionic spinal (C7-T1) stimulation of the cardioaccelerator sympathetic outflow (n=90) or i.v. bolus injections of noradrenaline (n=12). This approach resulted in frequency-dependent and dose-dependent tachycardic responses, respectively. I.v. continuous infusions of immepip (3 and 10 μg/kg min), but not of saline (0.02 ml/min), dose-dependently inhibited the sympathetically-induced tachycardic responses. Moreover, the cardiac sympatho-inhibition induced by 10 μg/kg min immepip (which failed to affect the tachycardic responses to i.v. noradrenaline) was: (i) unaltered after i.v. treatment with 1 ml/kg vehicle, 100 μg/kg ketotifen, 3000 μg/kg ranitidine, 30 μg/kg thioperamide or 300 μg/kg JNJ7777120; and (ii) abolished after 100 μg/kg thioperamide (i.v.). These doses of antagonists, which did not affect per se the sympathetically-induced tachycardic responses, were high enough to block their respective receptors. In conclusion, the cardiac sympatho-inhibition induced by 10 μg/kg.min immepip involves histamine H3 receptors, with further pharmacological evidence excluding the involvement of H1, H2 and H4 receptors. PMID:26826593

  7. Trends in Oral Antibiotic, Proton Pump Inhibitor, and Histamine 2 Receptor Blocker Prescription Patterns for Children Compared With Adults: Implications for Clostridium difficile Infection in the Community.

    Science.gov (United States)

    Faden, Howard S; Ma, Chan-Xing

    2016-07-01

    The use of antibiotics, proton pump inhibitor (PPI), and histamine 2 receptor blocker (H2B) was compared between children and adults in the community from 2005 through 2011. Antibiotic prescription rates remained stable for children, but increased significantly for adults, P = .03. PPI prescription rates increased for children, P = .02 and for adults, P = .009. H2B prescription rates increased for children, P = .03, but not for adults. Antibiotic prescription rates were significantly higher in children than adults in all 7 years, P < .0001. In contrast, PPI prescription rates were significantly higher in adults than children in all 7 years, P < .0001. H2B prescription rates were significantly higher in adults than children 1 to 18 years old P < .0001; however, H2B prescription rates were highest in children <1 year old, P = .0001. The high use of oral antibiotics, PPI, and H2B among outpatients may be a contributing factor to the rise of Clostridium difficile infection in the community. PMID:26350427

  8. Lafutidine, a novel histamine H2-receptor antagonist, increases serum calcitonin gene-related peptide in rats after water immersion-restraint stress.

    Science.gov (United States)

    Sato, Hiroshi; Kawashima, Kousaku; Yuki, Mika; Kazumori, Hideaki; Rumi, Mohammad Azharul Karim; Ortega-Cava, Cesar Francisco; Ishihara, Shunji; Kinoshita, Yoshikazu

    2003-02-01

    Lafutidine is a novel histamine H(2)-receptor antagonist with a potent and long-lasting anti-acid secretory effect that has also been found to have a potent gastroprotective effect. We investigated the effect of lafutidine on gastric mucosal injury induced in rats with the use of water-immersion restraint stress (WRS) by examining serum calcitonin gene-related peptide (CGRP) concentrations, which we measured with the use of an enzyme immunometric assay. WRS-induced mucosal erosive injury in the stomach was reduced significantly by both lafutidine and famotidine pretreatment (from 7.79 +/- 2.02 mm(2) to 3.09 +/- 0.74 mm(2) and 4.05 +/- 1.18 mm(2), respectively). A single administration of lafutidine or famotidine did not change the serum CGRP concentration from the control value when these drugs were administered without WRS. Lafutidine pretreatment before WRS caused a significant increase in serum CGRP concentration compared with famotidine (lafutidine, 86.64 +/- 9.52 pg/mL; famotidine, 47.55 +/- 4.35 pg/mL; control, 58.43 +/- 6.07 pg/mL). Our results suggest that lafutidine augments CGRP release from the rat stomach when administered before the induction of WRS. PMID:12577045

  9. Reduced Numbers of Somatostatin Receptors in the Cerebral Cortex in Alzheimer's Disease

    Science.gov (United States)

    Flint Beal, M.; Mazurek, Michael F.; Tran, Vinh T.; Chattha, Geetinder; Bird, Edward D.; Martin, Joseph B.

    1985-07-01

    Somatostatin receptor concentrations were measured in patients with Alzheimer's disease and controls. In the frontal cortex (Brodmann areas 6, 9, and 10) and temporal cortex (Brodmann area 21), the concentrations of somatostatin in receptors in the patients were reduced to approximately 50 percent of control values. A 40 percent reduction was seen in the hippocampus, while no significant changes were found in the cingulate cortex, postcentral gyrus, temporal pole, and superior temporal gyrus. Scatchard analysis showed a reduction in receptor number rather than a change in affinity. Somatostatin-like immunoreactivity was significantly reduced in both the frontal and temporal cortex. Somatostatin-like immunoreactivity was linearly related to somatostatin-receptor binding in the cortices of Alzheimer's patients. These findings may reflect degeneration of postsynaptic neurons or cortical afferents in the patients' cerebral cortices. Alternatively, decreased somatostatinlike immunoreactivity in Alzheimer's disease might indicate increased release of somatostatin and down regulation of postsynaptic receptors.

  10. Time-dependent histamine release from stored human blood products

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Edvardsen, L; Vangsgaard, K; Dybkjaer, E; Skov, P S

    1996-01-01

    Perioperative transfusion of whole blood has been shown to amplify trauma-induced immunosuppression, which could be attenuated by perioperative administration of histamine2 receptor antagonists. Supernatants from different blood products were, therefore, analysed for histamine content during...... full amount of leucocytes, and this may play a significant role in detrimental effects of blood transfusion....

  11. Halogenated benzamides as ligands for cerebral dopamine receptors

    International Nuclear Information System (INIS)

    In the past several years the authors' has synthesized a series of high affinity iodine-123 and fluorine-18 labeled substituted benzamide ligands for SPECT and PET visualization of the dopamine D-2 receptors in brain regions with low receptor density outside the striatum. Radioiodination and radiofluorination in high yield and high specific activity was achieved by using the tributyltin precursor and nucleophilic displacement of the saturation analysis revealed that the optimal striatum-to-cerebellum uptake ratio in the rat brain is highly correlated with the product of Kw and KD. The authors have used [125I] and [123I] epidepride to detect extra striatal dopamine D2 receptors in vitro by saturation analysis and in vivo with high resolution SPECT imaging

  12. Luciferase reporter gene assay on human, murine and rat histamine H4 receptor orthologs: correlations and discrepancies between distal and proximal readouts.

    Directory of Open Access Journals (Sweden)

    Uwe Nordemann

    Full Text Available The investigation of the (pathophysiological role of the histamine H4 receptor (H4R and its validation as a possible drug target in translational animal models are compromised by distinct species-dependent discrepancies regarding potencies and receptor subtype selectivities of the pharmacological tools. Such differences were extremely pronounced in case of proximal readouts, e. g. [(32P]GTPase or [(35S]GTPγS binding assays. To improve the predictability of in vitro investigations, the aim of this study was to establish a reporter gene assay for human, murine and rat H4Rs, using bioluminescence as a more distal readout. For this purpose a cAMP responsive element (CRE controlled luciferase reporter gene assay was established in HEK293T cells, stably expressing the human (h, the mouse (m or the rat (r H4R. The potencies and efficacies of 23 selected ligands (agonists, inverse agonists and antagonists were determined and compared with the results obtained from proximal readouts. The potencies of the examined ligands at the human H4R were consistent with reported data from [(32P]GTPase or [(35S]GTPγS binding assays, despite a tendency toward increased intrinsic efficacies of partial agonists. The differences in potencies of individual agonists at the three H4R orthologs were generally less pronounced compared to more proximal readouts. In conclusion, the established reporter gene assay is highly sensitive and reliable. Regarding discrepancies compared to data from functional assays such as [(32P]GTPase and [(35S]GTPγS binding, the readout may reflect multifactorial causes downstream from G-protein activation, e.g. activation/amplification of or cross-talk between different signaling pathways.

  13. TASK Channels on Basal Forebrain Cholinergic Neurons Modulate Electrocortical Signatures of Arousal by Histamine

    OpenAIRE

    Vu, Michael T.; Du, Guizhi; Bayliss, Douglas A.; Horner, Richard L.

    2015-01-01

    Basal forebrain cholinergic neurons are the main source of cortical acetylcholine, and their activation by histamine elicits cortical arousal. TWIK-like acid-sensitive K+ (TASK) channels modulate neuronal excitability and are expressed on basal forebrain cholinergic neurons, but the role of TASK channels in the histamine-basal forebrain cholinergic arousal circuit is unknown. We first expressed TASK channel subunits and histamine Type 1 receptors in HEK cells. Application of histamine in vitr...

  14. Involvement of calcium-calmodulin-dependent protein kinase II in endothelin receptor expression in rat cerebral arteries

    DEFF Research Database (Denmark)

    Waldsee, Roya; Ahnstedt, Hilda; Eftekhari, Sajedeh;

    2010-01-01

    Experimental cerebral ischemia and organ culture of cerebral arteries result in the enhanced expression of endothelin ET(B) receptors in smooth muscle cells via increased transcription. The present study was designed to evaluate the involvement of calcium-calmodulin-dependent protein kinase (CAMK......(B) receptor agonist) were studied using a sensitive myograph. The mRNA levels of the ET(A) and ET(B) receptors and CAMKII were determined by real-time PCR, and their protein levels were evaluated by immunohistochemistry and Western blot. The mRNA levels of CAMKII and the ET(B) receptor increased during organ...

  15. The effects of p-chloromercuribenzoate on muscarinic receptors in the cerebral cortex.

    OpenAIRE

    Birdsall, N. J.; Burgen, A S; Hulme, E. C.; Wong, E. H.

    1983-01-01

    The action of p-chloromercuribenzoate (PCMB) on the ligand binding properties of the muscarinic receptors in the rat cerebral cortex has been examined. At low concentrations, PCMB produces a selective change in the binding of agonists without any effect on the binding of antagonists. At higher concentrations, the structure-binding profile for binding antagonists is changed. The affinity of agonists is greatly reduced and the heterogeneity of binding eliminated. The effects of both high and lo...

  16. Mechanisms of histamine stimulated secretion in rabbit ileal mucosa.

    Science.gov (United States)

    Linaker, B D; McKay, J S; Higgs, N B; Turnberg, L A

    1981-11-01

    Histamine is present in high concentrations in the intestine and we investigated the possibility that it might have a role here in intestinal transport. When added to the basal side of rabbit ileal mucosa in vitro histamine (10(-4)M) induced a short-lived increase in electrical potential difference and short circuit current. It inhibited net chloride absorption but did not influence sodium transport. Alkali secretion, measured by a pH stat technique, was inhibited, suggesting that bicarbonate secretion was reduced. Both the electrical and ion flux responses to histamine were blocked by the H1 receptor blocker diphenhydramine, but not by the H2 receptor blocker cimetidine. The presence of specific H1 histamine receptors was further supported by shifts in the dose-response curve to histamine by four different concentrations of diphenhydramine. Calculation of a pA2 value from these "Schild' plots provided a figure of 7.85, which is similar to that for H1 receptors in other tissues. Aminoguanidine, a histaminase blocker, had no electrical effects alone but shifted the histamine dose response curve to the left. These studies indicate that histamine inhibits chloride absorption and alkali secretion, possibly by influencing a chloride/bicarbonate exchange process, through specific mucosal H1 receptors. Enhancement of histamine effects by a histaminase inhibitor suggests that histaminases are present in the intestinal mucosa and supports the possibility of a role for endogenous histamine in influencing ion transport. The observations indicate a mechanism by which absorption might be impaired in diseases in which histamine is liberated locally in the intestine. PMID:7308851

  17. Computer aided drug designing of imidazole free acyl piperazine derivative as a histamine H/sub 3/ receptor antagonist

    International Nuclear Information System (INIS)

    Computer aided drug designing of 1- alkyl-4-acyl piperazine derivative was performed by Argus Lab software. The minimum potential energy is calculated by geometry convergence function by Argus lab software. The most feasible position for the drug to interact with the receptor was found to be 51.19358580 kcal/mol. (author)

  18. Cerebral serotonin 4 receptors and amyloid-β in early Alzheimer's disease

    DEFF Research Database (Denmark)

    Madsen, Karine; Neumann, Wolf-Julian; Holst, Klaus Kähler;

    2011-01-01

    The 5-HT4 receptor may play a role in memory and learning and 5-HT4 receptor activation has been suggested to modulate acetylcholine release and to reduce amyloid-ß (Aß) accumulation. The aim of this study was for the first time to investigate the in vivo cerebral 5-HT4 receptor binding in early...... Alzheimer disease (AD) patients in relation to cortical Aß burden. Eleven newly diagnosed untreated AD patients (mean MMSE 24, range 19–27) and twelve age- and gender-matched healthy controls underwent a two-hour dynamic [11C]SB207145 PET scan to measure the binding potential of the 5-HT4 receptor. All AD...

  19. Morphine analgesia and cerebral opiate receptors: a developmental study

    International Nuclear Information System (INIS)

    Development of the analgesic response to morphine and ontogenesis of central opiate receptors were analyzed in rats 5 to 120 days old. The analgesic effect of morphine increased until day 15, after which it decreased to reach a plateau at about day 30. With phenoperidine, on the other hand, the analgesic effect increased until day 15, remained constant between day 15 and day 30 after which it decreased slowly. The ratio of the amounts of morphine in blood over those in brain increased about 3 fold between day 15 and day 30. Opiate receptors were detected in the brain of newborn rats; stereospecific binding of [3H]-naloxone at 10 and 50 nM indicated the presence of low and high affinity binding sites. The number of [3H]-naloxone binding sites increased rapidly during the second and third week after birth. Their affinity for several opiates remained constant throughout development. These results indicate that the analgesic activity of opiates varies with age: until day 15, the analgesic effect of opiates increases in parallel with the number of opiate brain receptors. Then, the formation of the blood brain barrier introduces an additional step in the regulation of opiate activity. (author)

  20. Activation of histamine H4 receptors decreases epithelial-to-mesenchymal transition progress by inhibiting transforming growth factor-β1 signalling pathway in non-small cell lung cancer.

    Science.gov (United States)

    Cai, Wen-Ke; Hu, Jing; Li, Teng; Meng, Jing-Ru; Ma, Xue; Yin, Sun-Jun; Zhao, Can-Hu; He, Gong-Hao; Xu, Gui-Li

    2014-04-01

    Previous investigations found that epithelial-to-mesenchymal transition (EMT) was an important character of non-small cell lung cancer (NSCLC) and it was also suggested that histamine H4 receptors may have a role in preventing EMT progress in certain kind of tumours. However, the effect of H4 receptor activation on EMT progress of NSCLC and its potential mechanisms remain unclear. Therefore, we performed both in vitro and in vivo experiments to explore the effects of specific H4 receptor agonist 4-methylhistamine and antagonist JNJ7777120 on EMT progress. We showed the expression of H4 receptors in NSCLC and found that 4-methylhistamine increased the expression of the epithelial marker E-cadherin and decreased the expression of Vimentin, the mesenchymal marker, in both NSCLC cell lines and xenograft NSCLC tumours. Pretreatment with JNJ7777120 or H4 receptor gene silencing decreased while overexpression of H4 receptors facilitated this effect of 4-methylhistamine. Furthermore, we showed that down-regulation of cyclic adenosine monophosphate (cAMP) was the secondary signalling after H4 receptor activation, which in turn resulted in inactivation of transforming growth factor-β1 (TGF-β1) pathway and down-regulation of several important EMT inducing factors such as ZEB1, Snail and Slug. In conclusion, these findings revealed the anti-EMT effect of histamine H4 receptor activation in NSCLC, which provide novel insight into the development mechanism of NSCLC; and H4 receptors may be a new therapeutic target for NSCLC treatment. PMID:24447834

  1. Inhibitory Effect of Imiquimod-Induced Psoriasis-Like Skin Inflammation in Mice by Histamine H4 Receptor Agonist 4-Methylhistamine.

    Science.gov (United States)

    Kim, C-H; Lee, J M; Yoo, J K; Kim, J-S; Kim, S-U; Chang, K-T; Choo, Y-K

    2016-06-01

    Psoriasis is a chronic inflammatory immune-mediated autoimmune skin disorder. The histamine H4 receptor (H4R) agonist 4-methylhistamine (4-MH) plays an important role in immunomodulation of inflammatory responses associated with allergic inflammatory diseases. In this study, we investigated the effects of H4R agonist 4-MH on the development of imiquimod (IMQ)-induced psoriasis-like skin inflammation in mice and explored the immunoregulatory mechanism involved. The total clinical severity scores were significantly ameliorated by treatment with 4-MH (20 mg/kg) and 4-MH (40 mg/kg). Histological analysis of the skin revealed that 4-MH (20 mg/kg) and 4-MH (40 mg/kg) significantly attenuated the psoriatic phenotypes, including epidermal hyperplasis, hyperkeratosis and lymphocytes infiltration. Treatment with 4-MH (20 mg/kg) and 4-MH (40 mg/kg) led to reductions in the levels of Th1 cytokines (TNF-α, IFN-α, and IL-27) in the serum and dorsal skin, whereas Th17 cytokines levels (IL-17A and IL-23) did not change in response to treatment with 4-MH (20 mg/kg) and 4-MH (40 mg/kg). Furthermore, the number of CD4(+) CD25(+) FoxP3(+) regulatory T (Treg) cells was significantly increased by treatment with 4-MH (40 mg/kg). Taken together, these results imply that H4R agonist 4-MH might be an effective immunomodulatory approach for treatment of patients with psoriasis and the effects may be related to inhibited epidermal alteration, selectively reduced Th1 pro-inflammatory cytokines, and recruited CD4(+) CD25(+) FoxP3(+) Treg cells. PMID:26900758

  2. Cross sectional PET study of cerebral adenosine A1 receptors in premanifest and manifest Huntington's disease

    International Nuclear Information System (INIS)

    To study cerebral adenosine receptors (AR) in premanifest and manifest stages of Huntington's disease (HD). We quantified the cerebral binding potential (BPND) of the A1AR in carriers of the HD CAG trinucleotide repeat expansion using the radioligand [18 F]CPFPX and PET. Four groups were investigated: (i) premanifest individuals far (preHD-A; n = 7) or (ii) near (preHD-B; n = 6) to the predicted symptom onset, (iii) manifest HD patients (n = 8), and (iv) controls (n = 36). Cerebral A1AR values of preHD-A subjects were generally higher than those of controls (by up to 31 %, p 1AR BPND was observed to the levels of controls in preHD-B and undercutting controls in manifest HD by down to 25 %, p 1AR BPND and years to onset. Before onset of HD, the assumed annual rates of change of A1AR density were -1.2 % in the caudatus, -1.7 % in the thalamus and -3.4 % in the amygdala, while the corresponding volume losses amounted to 0.6 %, 0.1 % and 0.2 %, respectively. Adenosine receptors switch from supra to subnormal levels during phenoconversion of HD. This differential regulation may play a role in the pathophysiology of altered energy metabolism. (orig.)

  3. HISTAMINE BIOSENSOR: A REVIEW

    Directory of Open Access Journals (Sweden)

    Niraj*, M. M. Gupta and Shweta Pandey

    2012-11-01

    Full Text Available Some biogenic amine like Histamine, cadaverine and putrescine have been confirmed as useful chemical indicators to estimate bacterial spoilage of foods, particularly fish and fish products, cheese, meat and fermented foods. Histamine is toxic at high intakes, while cadaverine and putrescine potentiate the effects of Histamine. Histamine has regulated level of 200 mg/kg (200 ppm. Basic principle involved in Biogenic amines biosensor is the action of diamine oxidase (DAO that catalyzes the oxidative deamination of primary amines to the corresponding aldehydes, hydrogen peroxide and ammonia. Two different approaches for the histamine biosensor design were studied, i.e. the enzyme DAO was directly immobilized on the surface of the oxygen electrode membrane using glutaraldehyde or entrapped in a hydrogel film. In histamine biosensor consisting of diamine oxidase (DAO and a conventional oxygen electrode transducer was developed and applied for the determination of standard histamine solutions. For immobilisation with glutaraldehyde, the enzyme was cross-linked with glutaraldehyde as a bifunctional reagent on the electrode surface. For entrapment, DAO was entrapped in a polymeric hydrogel film, i.e. poly(hydroxyl ethyl methacrylate (pHEMA polymer and deposited onto the teflon membrane of the oxygen electrode. Good linear correlation response obtained of the histamine biosensors with immobilized DAO showed between the changes of oxygen level with changes in concentration of histamine at both high concentration ranges (200-1000 mg/L and low concentrations (20-100 mg/L. However, the sensitivity of the biosensor response decreased at high concentration range of histamine, for the direct DAO immobilisation with glutaraldehyde. Biogenic amines concentration can be measured by monitoring either the decrease in oxygen or the increase of hydrogen peroxide concentration.

  4. Comparative studies of D2 receptors and cerebral blood flow in hemi-parkinsonism rats

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Y.; Lin, X. [Shanghai Medical Univ., Shanghai (Korea, Republic of)

    2000-07-01

    To study the relationship between dopamine (DA) D{sub 2} receptors and cerebral blood flow in hemiparkinsonism rats. Hemi-parkinsonism rats were made by stereotaxic 6-hydroxy dopamine (6-OH-DA) lesions in substantia nigra and ventral tegmental area, apomorphine (Apo) which could induce the successful model rat rotates toward the intact side was used to screen that rats, {sup 125}I-IBZM in vivo autoradiography and {sup 99m}Tc-HM-PAO regional brain biodistribution were used to study D{sub 2} receptors and cerebral blood flow. The HPLC-ECD were used to measure the concentration of DA and it metabolites homovanillic acid (HVA), 3,4-dehydroxyphenyl acetic acid (DOPAC) in bilateral striatum (ST). The lesioned side ST DA and its metabolites HVA DOPAC reduced significantly than that of the intact side and pseudo-operated control group, ST/cerebellum (CB) {sup 125}I-IBZM uptake ratio was 8.04 {+-}0.71 in lesioned side of hemi-parkinsonism rats, significantly increased compared with the intact side and the pseudo-operated group (p<0.05), 30{sup 99m}Tc 30.1{+-}4.53% enhancement as compared to the intact side, and also show good correlation with 30 min Apo induced rotation numbers (r=0.98), the regional cerebral blood flow study didn't show significant difference between bilateral brain cortex area (p>0.05). The DA content decreased significantly and induced an up-regulation of ST D{sub 2} receptor binding sites in 6-OH-DA lesioned side in hemi-parkinsonism rats, the increased percentage of lesioned-intact side ST/CB {sup 125}I-IBZM uptake ratio showed good correlation with rotation behavior induced by Apo. Compare with cerebral blood flow, D{sub 2} receptor reflected by IBZM seems to be more specific and earlier to detect the cerebral functional impairment in experimental hemi-parkinsonism.

  5. SPECT imaging of GABAA/benzodiazepine receptors and cerebral perfusion in mild cognitive impairment

    International Nuclear Information System (INIS)

    The involvement of neocortical and limbic GABAA/benzodiazepine (BZD) receptors in Alzheimer's disease (AD) is controversial and mainly reported in advanced stages. The status of these receptors in the very early stages of AD is unclear and has not been explored in vivo. Our aims were to investigate in vivo the integrity of cerebral cortical GABAA/BZD receptors in subjects with amnestic mild cognitive impairment (MCI) and to compare possible receptor changes to those in cerebral perfusion. [123I]Iomazenil and [99mTc]HMPAO SPECT images were acquired in 16 patients with amnestic MCI and in 14 normal elderly control subjects (only [123I]iomazenil imaging in 5, only [99mTc]HMPAO imaging in 4, and both [123I]iomazenil and [99mTc]HMPAO imaging in 5). Region of interest (ROI) analysis and voxel-based analysis were performed with cerebellar normalization. Neither ROI analysis nor voxel-based analysis showed significant [123I]iomazenil binding changes in MCI patients compared to control subjects, either as a whole group or when considering only those patients with MCI that converted to AD within 2 years of clinical follow-up. In contrast, the ROI analysis revealed significant hypoperfusion of the precuneus and posterior cingulate cortex in the whole group of MCI patients and in MCI converters as compared to control subjects. Voxel-based analysis showed similar results. These results indicate that in the very early stages of AD, neocortical and limbic neurons/synapses expressing GABAA/BZD receptors are essentially preserved. They suggest that in MCI patients functional changes precede neuronal/synaptic loss in neocortical posterior regions and that [99mTc]HMPAO rCBF imaging is more sensitive than [123I]iomazenil GABAA/BZD receptor imaging in detecting prodromal AD. (orig.)

  6. Cerebral A{sub 1} adenosine receptors (A{sub 1}AR) in liver cirrhosis

    Energy Technology Data Exchange (ETDEWEB)

    Boy, Christian [Research Centre Juelich, Brain Imaging Centre West, Institute of Medicine, Juelich (Germany); University Hospital Essen, Department of Nuclear Medicine, Essen (Germany); Meyer, Philipp T. [Research Centre Juelich, Brain Imaging Centre West, Institute of Medicine, Juelich (Germany); University Hospital Aachen, Department of Nuclear Medicine, Aachen (Germany); Kircheis, Gerald; Haussinger, Dieter [University of Duesseldorf, Clinic for Gastroenterology, Hepatology and Infectiology, Duesseldorf (Germany); Holschbach, Marcus H.; Coenen, Heinz H. [Research Centre Juelich, Institute of Nuclear Chemistry, Juelich (Germany); Herzog, Hans; Elmenhorst, David [Research Centre Juelich, Brain Imaging Centre West, Institute of Medicine, Juelich (Germany); Kaiser, Hans J. [University Hospital Aachen, Department of Nuclear Medicine, Aachen (Germany); Zilles, Karl [Research Centre Juelich, Brain Imaging Centre West, Institute of Medicine, Juelich (Germany); C. and O. Vogt Institute of Brain Research, Duesseldorf (Germany); Bauer, Andreas [Research Centre Juelich, Brain Imaging Centre West, Institute of Medicine, Juelich (Germany); University of Duesseldorf, Department of Neurology, Duesseldorf (Germany)

    2008-03-15

    The cerebral mechanisms underlying hepatic encephalopathy (HE) are poorly understood. Adenosine, a neuromodulator that pre- and postsynaptically modulates neuronal excitability and release of classical neurotransmitters via A{sub 1} adenosine receptors (A{sub 1}AR), is likely to be involved. The present study investigates changes of cerebral A{sub 1}AR binding in cirrhotic patients by means of positron emission tomography (PET) and [{sup 18}F]CPFPX, a novel selective A{sub 1}AR antagonist. PET was performed in cirrhotic patients (n = 10) and healthy volunteers (n = 10). Quantification of in vivo receptor density was done by Logan's non-invasive graphical analysis (pons as reference region). The outcome parameter was the apparent binding potential (aBP, proportional to B{sub max}/K{sub D}). Cortical and subcortical regions showed lower A{sub 1}AR binding in cirrhotic patients than in controls. The aBP changes reached statistical significance vs healthy controls (p < 0.05, U test with Bonferroni-Holm adjustment for multiple comparisons) in cingulate cortex (-50.0%), precentral gyrus (-40.9%), postcentral gyrus (-38.6%), insular cortex (-38.6%), thalamus (-32.9%), parietal cortex (-31.7%), frontal cortex (-28.6), lateral temporal cortex (-28.2%), orbitofrontal cortex (-27.9%), occipital cortex (-24.6), putamen (-22.7%) and mesial temporal lobe (-22.4%). Regional cerebral adenosinergic neuromodulation is heterogeneously altered in cirrhotic patients. The decrease of cerebral A{sub 1}AR binding may further aggravate neurotransmitter imbalance at the synaptic cleft in cirrhosis and hepatic encephalopathy. Different pathomechanisms may account for these alterations including decrease of A{sub 1}AR density or affinity, as well as blockade of the A{sub 1}AR by endogenous adenosine or exogenous xanthines. (orig.)

  7. Histamine and the regulation of body weight

    DEFF Research Database (Denmark)

    Jørgensen, Emilie A; Knigge, Ulrich; Warberg, Jørgen;

    2007-01-01

    Energy intake and expenditure is regulated by a complex interplay between peripheral and central factors. An exhaustive list of peptides and neurotransmitters taking part in this complex regulation of body weight exists. Among these is histamine, which acts as a central neurotransmitter. In the p......Energy intake and expenditure is regulated by a complex interplay between peripheral and central factors. An exhaustive list of peptides and neurotransmitters taking part in this complex regulation of body weight exists. Among these is histamine, which acts as a central neurotransmitter...... lipolysis. Based on the current evidence of the involvement of histamine in the regulation of body weight, the histaminergic system is an obvious target for the development of pharmacological agents to control obesity. At present, H(3) receptor antagonists that stimulate the histaminergic system may...

  8. Stress-induced release of anterior pituitary hormones: Effect of H3 receptor-mediated inhibition of histaminergic activity or posterior hypothalamic lesion

    DEFF Research Database (Denmark)

    Knigge, U.; Søe-Jensen, P.; Jørgensen, Henrik; Kjær, Andreas; Møller, Morten; Warberg, Jørgen

    Histamine receptors, corticotropin, *Gb-endorphin, prolactin, adrenal steroids, stress, endotoxin, serotonin......Histamine receptors, corticotropin, *Gb-endorphin, prolactin, adrenal steroids, stress, endotoxin, serotonin...

  9. On histamine and appetites

    Directory of Open Access Journals (Sweden)

    Fernando eTorrealba

    2012-07-01

    Full Text Available Brain histamine may influence a variety of different behavioral and physiological functions, but its responsibility in waking up has casted a long shadow on other important functions of this neurotransmitter. Here we review evidence indicating a central role of brain histamine in motivation, emphasizing its differential involvement in the appetitive and consummatory phases of motivated behaviors. We discuss the inputs that control the histaminergic neurons of the tuberomamillary nucleus of the hypothalamus, which determine the distinct role of these neurons in appetitive behavior, sleep/wake cycles and in food anticipatory activity. We review evidence supporting a dysfunction of histamine neurons and its cortical input in certain forms of decreased motivation (apathy. We finally discuss the relationship between the histamine system and drug addiction as a dysfunction of motivation.

  10. Potentiodynamic formation of gold nanoparticles film on glassy carbon electrode using aminophenyl diazonium cations grafted gold nanoparticles: Determination of histamine H2 receptor antagonist

    International Nuclear Information System (INIS)

    Graphical abstract: - Highlights: • Grafting based AuNPs were synthesized in aqueous medium by spontaneous grafting. • GC/ITO electrode was modified with AuNPs film by potentiodynamic method. • AuNPs film modified electrode was characterized by XPS, AFM and CV. • Simultaneous determination of ranitidine and paracetamol was demonstrated. • Practical application was demonstrated in commercial drugs. - Abstract: The aminophenyl (AP) functionalized AuNPs (AP-AuNPs) were synthesized in aqueous medium by spontaneous grafting method and were used for the formation of AuNPs film on glassy carbon (GC) and indium tin oxide (ITO) surfaces by potentiodynamic method. The formed AP-AuNPs film modified electrodes were characterized by cyclic voltammetry (CV), atomic force microscopy (AFM), electrochemical impedance spectroscopy (EIS), and X-ray photoelectron spectroscopy (XPS). EIS studies show that the electron transfer reaction of [Fe(CN)6]3-/4− was higher at the AP-AuNPs film modified electrode (1.58 × 10−4 cm s−1) than at bare (3.78 × 10−5 cm s−1) GC electrode. The surface coverage of the AP-AuNPs film modified electrode was found to be 4.4 × 10−10 mol cm−2. The film formation takes place via -NH2 groups of AP-AuNPs, which was confirmed by XPS from the observed peaks corresponding to =N-H (396.7 eV), -N-H (399.2 eV), -N = N- (400.2 eV) and -N+-H (403.3 eV). The AP-AuNPs film modified electrode was successfully utilized for the determination of histamine H2 receptor antagonist ranitidine (RA). Further, the AP-AuNPs film modified electrode was effectively used for the selective determination of RA in the presence of 40-fold excess paracetamol. The present method was successfully used to determine the concentration of RA in commercial drugs

  11. Aldosterone and the mineralocorticoid receptor in the cerebral circulation and stroke

    Directory of Open Access Journals (Sweden)

    Dinh Quynh N

    2012-10-01

    Full Text Available Abstract Ischemic stroke is a leading cause of morbidity and mortality worldwide. Elevated plasma aldosterone levels are an independent cardiovascular risk factor and are thought to contribute to hypertension, a major risk factor for stroke. Evidence from both experimental and human studies supports a role for aldosterone and/or the mineralocorticoid receptor (MR in contributing to detrimental effects in the cerebral vasculature and to the incidence and outcome of ischemic stroke. This article reviews the evidence, including the protective effects of MR antagonism. Specifically, the effects of aldosterone and/or MR activation on cerebral vascular structure and on immune cells will be reviewed. The existing evidence suggests that aldosterone and the MR contribute to cerebral vascular pathology and to the incidence and outcome of stroke. We suggest that further research into the signaling mechanisms underlying the effects of aldosterone and MR activation in the brain and its vasculature, especially with regard to cell-specific actions, will provide important insight into causes and potential treatments for cerebrovascular disease and stroke.

  12. Effect of delta opioid receptor activation on spatial cognition and neurogenesis in cerebral ischemic rats.

    Science.gov (United States)

    Wang, Shu-Yan; Duan, Ya-Le; Zhao, Bing; Wang, Xiang-Rui; Zhao, Zheng; Zhang, Guang-Ming

    2016-05-01

    This study aimed to investigate whether a selective delta opioid receptor agonist, [D-Ala2, D-Leu5]-Enkephalin (DADLE), regulates neurogenesis in the hippocampus of ischemic rats. Using an intracerebral cannula, rats were subjected to cerebral ischemia using the standard four-vessel occlusion. DADLE (2.5nmol), DADLE (2.5nmol) with naltrindole (NAL) (2.5nmol), or vehicle was administered at the onset of reperfusion. Bromodeoxyuridine (BrdU, 100mg/kg, intraperitoneal) was used to label newly formed cells from days 1 to 7 after ischemia. Immunohistochemistry was used to evaluate cell proliferation and apoptosis and differentiation 7days 28 days, respectively, after ischemia. Morris water maze test was conducted to test spatial learning and memory 23-27 days after ischemia. We found that DADLE treatment improved performance in the Morris water maze test, promoted proliferation and differentiation of newly formed neurons, and inhibited differentiation into astrocytes in a rat model of cerebral ischemia. Furthermore, the protective effects of DADLE were significantly reversed by co-administration of NAL (Pstrategy for cerebral ischemia. PMID:27016387

  13. Higher density of serotonin-1A receptors in the hippocampus and cerebral cortex of alcohol-preferring P rats

    International Nuclear Information System (INIS)

    Saturable [3H]-80HDPAT binding to 5HT-1A receptors in membranes prepared from hippocampus and frontal cerebral cortex of alcohol-preferring (P) rats and of alcohol-nonpreferring (NP) rats has been compared. The Bmax values or densities of recognition sites for 5HT-1A receptors in both brain areas of the P rats are 38 and 44 percent lower in the P rats than in the NP rats. The corresponding KD values are 38 and 44 percent lower in the P rats than in the NP rats, indicating higher affinities of the recognition sites for the 5HT-1A receptors in hippocampus and cerebral cortex of the P rats. These findings indicate either an enrichment of 5HT-1A receptor density during selective breeding for alcohol preference or an upregulation of 5HT-1A receptors of 5HT found in these brain areas of P rats as compared with the NP rats

  14. Circadian rhythm in adenosine A1 receptor of mouse cerebral cortex

    International Nuclear Information System (INIS)

    In order to investigate diurnal variation in adenosine A1 receptors binding parameters, Bmax and Kd values of specifically bound N6-cyclohexyl-[3H]adenosine were determined in the cerebral cortex of mice that had been housed under controlled light-dark cycles for 4 weeks. Significant differences were found for Bmax values measured at 3-hr intervals across a 24-h period, with low Bmax values during the light period and high Bmax values during the dark period. The amplitude between 03.00 and 18.00 hr was 33%. No substantial rhythm was found in the Kd values. It is suggested that the changes in the density of A1 receptors could reflect a physiologically-relevant mechanism by which adenosine exerts its modulatory role in the central nervous system

  15. The effect of nitric oxide synthase inhibition on histamine induced headache and arterial dilatation in migraineurs

    DEFF Research Database (Denmark)

    Lassen, L H; Christiansen, I; Iversen, Helle Klingenberg; Jansen-Olesen, I; Olesen, J

    2003-01-01

    middle cerebral artery (MCA) (transcranial doppler) and diameters of temporal and radial arteries (high resolution ultrasound) were repeatedly measured. Pre-treatment with L-NMMA, had no effect on histamine induced headache or migraine, but also had no effect on the magnitude of histamine induced....... Our results showed for the first time a craniospecificity for the vasodilating effect of histamine and for the arterial effects of NOS inhibition.......We have previously proposed that histamine causes migraine via increased NO production. To test this hypothesis, we here examined if the NOS inhibitor, L-NG methylarginine hydrochloride (L-NMMA:546C88), could block or attenuate histamine induced migraine attacks and responses of the middle cerebral...

  16. Cytokines and growth factors modify the upregulation of contractile endothelin ET(A) and ET(B) receptors in rat cerebral arteries after organ culture

    DEFF Research Database (Denmark)

    Ahnstedt, H; Stenman, E; Cao, L; Henriksson, M; Edvinsson, L

    2012-01-01

    Experimental cerebral ischaemia and organ culture of cerebral arteries induce an increased endothelin ET(B) receptor-mediated contraction. The aim of this study was to examine whether cytokines and growth factors, known to be activated in ischaemia, can influence the expression and function of...... endothelin receptors after organ culture....

  17. Cerebral A1 adenosine receptors (A1AR) in liver cirrhosis

    International Nuclear Information System (INIS)

    The cerebral mechanisms underlying hepatic encephalopathy (HE) are poorly understood. Adenosine, a neuromodulator that pre- and postsynaptically modulates neuronal excitability and release of classical neurotransmitters via A1 adenosine receptors (A1AR), is likely to be involved. The present study investigates changes of cerebral A1AR binding in cirrhotic patients by means of positron emission tomography (PET) and [18F]CPFPX, a novel selective A1AR antagonist. PET was performed in cirrhotic patients (n = 10) and healthy volunteers (n = 10). Quantification of in vivo receptor density was done by Logan's non-invasive graphical analysis (pons as reference region). The outcome parameter was the apparent binding potential (aBP, proportional to Bmax/KD). Cortical and subcortical regions showed lower A1AR binding in cirrhotic patients than in controls. The aBP changes reached statistical significance vs healthy controls (p 1AR binding may further aggravate neurotransmitter imbalance at the synaptic cleft in cirrhosis and hepatic encephalopathy. Different pathomechanisms may account for these alterations including decrease of A1AR density or affinity, as well as blockade of the A1AR by endogenous adenosine or exogenous xanthines. (orig.)

  18. Histamine is released from skin by substance P but does not act as the final vasodilator in the axon reflex.

    OpenAIRE

    Barnes, P J; Brown, M. J.; Dollery, C. T.; Fuller, R W; Heavey, D. J.; Ind, P. W.

    1986-01-01

    We have explored in man the hypothesis that histamine released from dermal mast cells by neurotransmitters from afferent nerves contributes to vasodilatation of the axon reflex. The ability of substance P to release histamine from human skin in vivo, and the effects of a histamine H1-receptor antagonist on capsaicin-induced axon reflex flares were studied. Intradermal injections of substance P (50 pmol) produced a weal and flare response which was associated with increased histamine concentra...

  19. Different profiles of desensitization dynamics in guinea-pig jejunal longitudinal smooth muscle after stimulation with histamine and methacholine.

    OpenAIRE

    Leurs, R.; Smit, M. J.; Bast, A.; Timmerman, H.

    1990-01-01

    1. In the present study we investigated desensitization phenomena of guinea-pig jejunal longitudinal smooth muscle responses after stimulation with 100 microM histamine or methacholine, using a superfusion method. 2. Histamine H1-receptor-mediated contractions appear to be rapidly reduced after application of 100 microM histamine. Muscarinic responses were not affected following desensitization with 100 microM histamine, indicating a homologous desensitization. 3. Initial contractions to 0.3 ...

  20. Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria.

    Directory of Open Access Journals (Sweden)

    Dieudonnée Togbe

    Full Text Available BACKGROUND: TNF-related lymphotoxin alpha (LTalpha is essential for the development of Plasmodium berghei ANKA (PbA-induced experimental cerebral malaria (ECM. The pathway involved has been attributed to TNFR2. Here we show a second arm of LTalpha-signaling essential for ECM development through LTbeta-R, receptor of LTalpha1beta2 heterotrimer. METHODOLOGY/PRINCIPAL FINDINGS: LTbetaR deficient mice did not develop the neurological signs seen in PbA induced ECM but died at three weeks with high parasitaemia and severe anemia like LTalphabeta deficient mice. Resistance of LTalphabeta or LTbetaR deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and angiography, associated with lack of microvascular obstruction, while wild-type mice developed distinct microvascular pathology. Recruitment and activation of perforin(+ CD8(+ T cells, and their ICAM-1 expression were clearly attenuated in the brain of resistant mice. An essential contribution of LIGHT, another LTbetaR ligand, could be excluded, as LIGHT deficient mice rapidly succumbed to ECM. CONCLUSIONS/SIGNIFICANCE: LTbetaR expressed on radioresistant resident stromal, probably endothelial cells, rather than hematopoietic cells, are essential for the development of ECM, as assessed by hematopoietic reconstitution experiment. Therefore, the data suggest that both functional LTbetaR and TNFR2 signaling are required and non-redundant for the development of microvascular pathology resulting in fatal ECM.

  1. The effect of pK(a) on pyrimidine/pyridine-derived histamine H4 ligands.

    Science.gov (United States)

    Savall, Brad M; Meduna, Steven P; Venable, Jennifer; Wei, Jianmei; Smith, Russell C; Hack, Michael D; Thurmond, Robin L; McGovern, Patricia; Edwards, James P

    2014-12-01

    During the course of our efforts toward the discovery of human histamine H4 antagonists from a series of 2-aminiopyrimidines, it was noted that a 6-trifluoromethyl group dramatically reduced affinity of the series toward the histamine H4 receptor. This observation was further investigated by synthesizing a series of ligands that varied in pKa of the pyrimidine derived H4 ligands by over five orders of magnitude and the effect on histamine H4 affinity. This trend was then extended to the discovery of C-linked piperidinyl-2-amino pyridines as histamine H4 receptor antagonists. PMID:25455490

  2. On the role of serotonin and histamine in neurohumoral mechanisms of postirradiation diarrhea in rats

    International Nuclear Information System (INIS)

    In experiments with rats exposed to 200 Gy radiation it was shown that the diarrhea effect of serotonin under the effect of radiation is implemented via D- and M-type receptors, and that of histamine via H1 and H2 receptors. Serotonin and histamine, that were released under the effect of radiation from endocrine and mast cells of the digestive tract stimulated the propulsion activity of the intestine whereas histamine, in addition, inhibited the absorption process. It is suggested that serotonin and histamine antagonists should be used as means of preventing of radiation-induced diarrhea

  3. Conantokin probes of NMDA receptors in normal and Alzheimer disease human cerebral cortex

    International Nuclear Information System (INIS)

    Full text: The pharmacology of the N-methyl-D-aspartate (NMDA) receptor site was examined in pathologically affected and relatively spared regions of cerebral cortex tissue obtained at autopsy from Alzheimer disease cases and matched controls. The affinity and density of the [3H]MK-801 binding site were delineated along with the enhancement of [3H]MK-801 binding by glutamate and spermine. Sites with distinct pharmacologies were distributed regionally through the cortex. The differences could not be explained by variations in the parameters of [3H]MK-801 binding; rather, the data suggest that the subunit composition of NMDA receptors may be locally variable. Selective differences were also found between controls and Alzheimer disease cases in certain brain regions. The interactions of human NMDA sites with the Ala(7) and Lys(7) derivatives of conantokin-G (Con-G) were also characterized. Ala(7)-con-G showed the higher affinity of the two peptides, and also defined two distinct binding sites in controls. In distinction to the Ala(7) peptide, Lys(7)- con-G showed preferential binding to receptor sites in Alzheimer disease cf. control brain. Modified conantokins are useful for identifying differences in subunit composition of the NMDA receptors between brain areas. They may also have potential as protective agents against over-excitation mediated by specific NMDA receptors, which might contribute to localized brain damage in Alzheimer disease. For further characterization of the pharmacology of different NMDA receptor subunits, a mammalian expression system has been developed for the analysis of their responses to selected ligands, including conantokins. Copyright (2002) Australian Neuroscience Society

  4. Dynamic changes of excitatory amino acid receptors in the rat hippocampus following transient cerebral ischemia

    International Nuclear Information System (INIS)

    The changes in excitatory amino acid receptor ligand binding induced by transient cerebral ischemia were studied in the rat hippocampal subfields. Ten minutes of ischemia was induced by common carotid artery occlusion combined with hypotension, and the animals were allowed variable periods of recovery ranging from 1 day to 4 weeks. The binding of 3H-AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) to quisqualate receptors, 3H-kainic acid (KA) to kainate receptors, and 3H-glutamate to N-methyl-D-aspartate (NMDA) receptors as determined by quantitative autoradiography. One week following ischemia the CA1 region of the hippocampus displayed a severe (90%) dendrosomatic lesion with preservation of presynaptic terminals. This was associated with a 60% decrease in AMPA binding and a 25% decrease in glutamate binding to NMDA receptors. At 4 weeks postischemia, both AMPA and NMDA sites were greatly reduced. Although the dentate gyrus granule cells are resistant to an ischemic insult of this magnitude, this region showed marked changes in receptor binding. One week following ischemia, the AMPA and NMDA binding decreased by approximately 40 and 20%, respectively. Following 2 weeks of recovery, the NMDA binding was not significantly different from control level, while the AMPA binding remained depressed up to 4 weeks postischemia. The high density of KA binding sites in the inner molecular layer of the dentate gyrus was unaffected by the ischemic insult, despite an extensive degeneration of cells in the hilus of dentate gyrus which projects glutamatergic afferents to this area

  5. Histamine: an undercover agent in multiple rare diseases?

    OpenAIRE

    Pino-Ángeles, Almudena; Reyes-Palomares, Armando; Melgarejo, Esther; Sánchez-Jiménez, Francisca

    2012-01-01

    Histamine is a biogenic amine performing pleiotropic effects in humans, involving tasks within the immune and neuroendocrine systems, neurotransmission, gastric secretion, cell life and death, and development. It is the product of the histidine decarboxylase activity, and its effects are mainly mediated through four different G-protein coupled receptors. Thus, histamine-related effects are the results of highly interconnected and tissue-specific signalling networks. Consequently, alterations ...

  6. Downstream Toll-like receptor signaling mediates adaptor-specific cytokine expression following focal cerebral ischemia

    Directory of Open Access Journals (Sweden)

    Bolanle Famakin

    2012-07-01

    Full Text Available Abstract Background Deletion of some Toll-like receptors (TLRs affords protection against cerebral ischemia, but disruption of their known major downstream adaptors does not. To determine whether compensation in the production of downstream effectors by one pathway when the other is disrupted can explain these findings, we examined cytokine/chemokine expression and inflammatory infiltrates in wild-type (WT, MyD88−/− and TRIF-mutant mice following permanent middle cerebral artery occlusion (pMCAO. Methods Cytokine/chemokine expression was measured with a 25-plex bead array in the serum and brains of all three groups of mice at baseline (no surgery/naïve and at 3 hours and 24 hours following pMCAO. Brain inflammatory and neutrophil infiltrates were examined 24 hours following pMCAO. Results IL-6, keratinocyte chemoattractant (KC, granulocyte colony-stimulating factor (G-CSF and IL-10 were significantly decreased in MyD88−/− mice compared to WT mice following pMCAO. Significantly, decreased levels of the neutrophil chemoattractants KC and G-CSF corresponded with a trend toward fewer neutrophils in the brains of MyD88−/− mice. IP-10 was significantly decreased when either pathway was disrupted. MIP-1α was significantly decreased in TRIF-mutant mice, consistent with TRIF-dependent production. MyD88−/− mice showed elevations of a number of Th2 cytokines, such as IL-13, at baseline, which became significantly decreased following pMCAO. Conclusions Both MyD88 and TRIF mediate pathway-specific cytokine production following focal cerebral ischemia. Our results also suggest a compensatory Th2-type skew at baseline in MyD88−/− mice and a paradoxical switch to a Th1 phenotype following focal cerebral ischemia. The MyD88 pathway directs the expression of neutrophil chemoattractants following cerebral ischemia.

  7. Histamine inhibits differentiation of skin fibroblasts into myofibroblasts.

    Science.gov (United States)

    Lin, Lin; Yamagata, Kaoru; Nakayamada, Shingo; Sawamukai, Norifumi; Yamaoka, Kunihiro; Sakata, Kei; Nakano, Kazuhisa; Tanaka, Yoshiya

    2015-07-31

    Histamine and TGF-β, major mediators secreted by mast cells, are involved in skin inflammation and play critical roles in the pathogenesis of systemic sclerosis. However, the roles of signaling mechanisms in the development of skin fibrosis remain largely unclear. Here we show that histamine suppressed the expression of α smooth muscle actin (αSMA), a marker of myofibroblasts, induced by TGF-β1 in skin fibroblasts. Histamine H1-receptor (H1R), but not H2-receptor (H2R) or H4-receptor (H4R), was expressed on skin fibroblasts at both mRNA and protein levels. Interestingly, an H1R antagonist, but not H2R or H4R antagonists, antagonized the histamine-mediated suppression of αSMA expression by TGF-β1. Correspondingly, phosphorylated Smad2 was detected after treatment with TGF-β1, whereas the addition of histamine inhibited this phosphorylation. Taken together, histamine-H1R decreased TGF-β1-mediated Smad2 phosphorylation and inhibited differentiation of skin fibroblasts into myofibroblasts. PMID:26036574

  8. β-Receptor-mediated increase in cerebral blood flow during hypoglycemia

    International Nuclear Information System (INIS)

    The authors tested the hypothesis that β-adrenergic receptor stimulation is involved with the increase in regional cerebral blood flow (rCBF) during hypoglycemia. Rats were surgically prepared with the use of halothane-nitrous oxide anesthesia. A plaster restraining cast was placed around the hindquarters, and anesthesia was discontinued. Hypoglycemia was produced by an intravenous injection of insulin; normoglycemic control rates were given saline. Propranolol was administered to some control and some hypoglycemic rats to block the β-adrenergic receptors. Regional CBF was measured using 4-[N-methyl-14C]iodoantipyrine. Regional CBF increased during hypoglycemia in rats that were not treated with propranolol. The increase varied from ∼60 to 200% depending on the brain region. During hypoglycemia, propranolol abolished the increase in rCBF in the hypothalamus, cerebellum, and pyramidal tract. In other regions the increase in rCBF was only 33-65% of the increase in hypoglycemic rats that were not treated with propranolol. They conclude that β-receptor stimulation plays a major role in the increase in rCBF during hypoglycemia

  9. beta. -Receptor-mediated increase in cerebral blood flow during hypoglycemia

    Energy Technology Data Exchange (ETDEWEB)

    Hollinger, B.R.; Bryan, R.M. (Pennsylvania State Univ., Hershey (USA))

    1987-10-01

    The authors tested the hypothesis that {beta}-adrenergic receptor stimulation is involved with the increase in regional cerebral blood flow (rCBF) during hypoglycemia. Rats were surgically prepared with the use of halothane-nitrous oxide anesthesia. A plaster restraining cast was placed around the hindquarters, and anesthesia was discontinued. Hypoglycemia was produced by an intravenous injection of insulin; normoglycemic control rates were given saline. Propranolol was administered to some control and some hypoglycemic rats to block the {beta}-adrenergic receptors. Regional CBF was measured using 4-(N-methyl-{sup 14}C)iodoantipyrine. Regional CBF increased during hypoglycemia in rats that were not treated with propranolol. The increase varied from {approximately}60 to 200% depending on the brain region. During hypoglycemia, propranolol abolished the increase in rCBF in the hypothalamus, cerebellum, and pyramidal tract. In other regions the increase in rCBF was only 33-65% of the increase in hypoglycemic rats that were not treated with propranolol. They conclude that {beta}-receptor stimulation plays a major role in the increase in rCBF during hypoglycemia.

  10. Blockage of transient receptor potential vanilloid 4 inhibits brain edema in middle cerebral artery occlusion mice

    Directory of Open Access Journals (Sweden)

    Pinghui eJie

    2015-04-01

    Full Text Available Brain edema is an important pathological process during stroke. Activation of transient receptor potential vanilloid 4 (TRPV4 causes an up-regulation of matrix metalloproteinases (MMPs in lung tissue. MMP can digest the endothelial basal lamina to destroy blood brain barrier, leading to vasogenic brain edema. Herein, we tested whether TRPV4-blockage could inhibit brain edema through inhibiting MMPs in middle cerebral artery occlusion (MCAO mice. We found that the brain water content and Evans blue extravasation at 48 h post-MCAO were reduced by a TRPV4 antagonist HC-067047. The increased MMP-2/9 protein in hippocampus of MCAO mice was attenuated by HC-067046, but only the increased MMP-9 activity was blocked by HC-067047. The loss of zonula occluden-1 (ZO-1 and occludin protein in MCAO mice was also attenuated by HC-067047. Moreover, MMP-2/9 protein increased in mice treated with a TRPV4 agonist GSK1016790A, but only MMP-9 activity was increased by GSK1016790A. Finally, ZO-1 and occludin protein was decreased by GSK1016790A, which was reversed by an MMP-9 inhibitor. We conclude that blockage of TRPV4 may inhibit brain edema in cerebral ischemia through inhibiting MMP-9 activation and the loss of tight junction protein.

  11. Occurrence of Histamine Forming Bacteria and Histamine in Dried Fish

    Directory of Open Access Journals (Sweden)

    Devarajan Sumitha

    2014-04-01

    Full Text Available Natural spoilage of protein rich foods leads to the production of histamine, which is associated with histamine poisoning throughout the world. Fish and fish products are at times associated with major concern due to the presence of histamine, which at toxic level generates histamine or scombroid poisoning known to be contaminated with high levels of histamine leading to histamine poisoning. Histamine consumption is also considered to be of health concerns at chronic levels due to effects on the physiological functions. Dried fish are known to be one of the most popular fish products consumed in the Indian subcontinent, often prepared under unhygienic conditions. In this present study, fifteen dried fish sold in local retail markets were purchased and screened to determine the occurrence of histamine and histamine-forming bacteria. The levels of pH, salt, moisture content and Aerobic Plate Count (APC were determined in all samples and ranged from 5.46 to 7.07, 0.5 to 1.19%, 33 to 77.05% and 10.5 to 11.4 log CFU/g respectively. Two strains of Enterobactercancerogenous PUFSTFMDf01 and Enterobacter sp., PUFSTFMDf02 were identified as histamine forming bacteria in dried fish samples. All fifteen dried fish samples contained an average histamine content of 10.03 mg/100 g which is greater than the guideline value (5 mg/100 g suggested by USFDA.

  12. Benzodiazepine receptor distribution and cerebral blood flow in early blindness. A PET study

    International Nuclear Information System (INIS)

    We studied benzodiazepine receptor (BZR) distribution, which is thought to be affected by neuronal density in the cerebral cortex, and CBF using [11C]flumazenil and [15O]water PET in early blind (EB) and in blindfold sighted control (SC) subjects. PET images were co-registered to the subject's MRI. Using SPM96, MRI images were normalized in the Talairach and Tournoux coordinate system, and accordingly MRI-registered PET images were spatially normalized. Statistical parametric maps were computed on a voxel-by-voxel basis, using the general linear model. CBF for EB was significantly larger in the Brodmann area 17 and 18, especially anterior area, than that for SC, while there was no significant difference in BZR distribution. Our BZR data suggest that the amount of neurons do not change due to early visual deprivation in the visual cortex, in spite of high CBF in visual cortex of EB subjects. (author)

  13. Histamine Potentiates Cyclosomatostatin-Induced Catalepsy in Old Rats

    Directory of Open Access Journals (Sweden)

    Ionov

    2015-05-01

    Full Text Available Background The decreased level of somatostatin and increased level of histamine are detected in the Parkinsonian brain. In old Wistar rats, the brain somatostatin deficiency can initiate catalepsy that suggests the pathogenic significance of this abnormality in Parkinson’s disease (PD. The ability of histamine to affect the somatostatin deficiency action is not studied. Objectives The current study aimed to examine if histamine alters the cataleptogenic activity of the brain somatostatin deficiency in Wistar rats. Materials and Methods The animals used in the study were 100 - 110 and 736 - 767 days old. Catalepsy was evaluated by the bar test. The inhibition of the brain somatostatin activity was simulated by I.C.V. administration of cyclosomatostatin (cycloSOM, a somatostatin receptor antagonist. Results CycloSOM (0.2, 1.0, and 5.0 µg and histamine (1.0 and 10.0 µg alone were ineffective in both young and old animals. In combination, however, cycloSOM and histamine initiated cataleptic response in old rats. Effect of the combination was inhibited by H1 and H2 but not H3 antagonists. Conclusions CycloSOM and histamine synergistically exert catalepsy in old rats. In light of these data, the combination of the decreased brain level of somatostatin and increased brain level of histamine may be of pathogenic relevance for extrapyramidal signs in PD.

  14. Effects of Histamine on Cultured Interstitial Cells of Cajal in Murine Small Intestine

    OpenAIRE

    Kim, Byung Joo; Kwon, Young Kyu; Kim, Euiyong; So, Insuk

    2013-01-01

    Interstitial cells of Cajal (ICCs) are the pacemaker cells in the gastrointestinal tract, and histamine is known to regulate neuronal activity, control vascular tone, alter endothelial permeability, and modulate gastric acid secretion. However, the action mechanisms of histamine in mouse small intestinal ICCs have not been previously investigated, and thus, in the present study, we investigated the effects of histamine on mouse small intestinal ICCs, and sought to identify the receptors invol...

  15. Histamine suppresses epidermal keratinocyte differentiation and impairs skin barrier function in a human skin model

    OpenAIRE

    Gschwandtner, M; Mildner, M.; Mlitz, V; Gruber, F.; Eckhart, L; Werfel, T.; Gutzmer, R; Elias, P.M.; Tschachler, E.

    2012-01-01

    Background Defects in keratinocyte differentiation and skin barrier are important features of inflammatory skin diseases like atopic dermatitis. Mast cells and their main mediator histamine are abundant in inflamed skin and thus may contribute to disease pathogenesis. Methods Human primary keratinocytes were cultured under differentiation-promoting conditions in the presence and absence of histamine, histamine receptor agonists and antagonists. The expression of differentiation-associated gen...

  16. Alteration in contractile G-protein coupled receptor expression by moist snuff and nicotine in rat cerebral arteries

    DEFF Research Database (Denmark)

    Sandhu, Hardip; Xu, Cang-Bao; Edvinsson, Lars

    2011-01-01

    vasocontractile G-protein coupled receptors (GPCR), such as endothelin ET(B), serotonin 5-HT(1B), and thromboxane A(2) TP receptors, in rat cerebral arteries. Studies show that these vasocontractile GPCR show alterations by lipid-soluble cigarette smoke particles via activation of mitogen-activated protein...... 5-carboxamidotryptamine, and TP receptor agonist U46619 were investigated by a sensitive myograph. The expression of ET(B), 5-HT(1B), and TP receptors was studied at mRNA and protein levels using quantitative real-time PCR and immunohistochemistry, respectively. Organ culture with WSS or DSS (25ng...... kept at plasma level of snus users (25ng nicotine/ml). A high dose (250ng nicotine/ml) was also included due to the previous results showing alteration in the GPCR expression by nicotine at this concentration. Contractile responses to the ET(B) receptor agonist sarafotoxin 6c, 5-HT(1B) receptor agonist...

  17. Enhanced expressions of microvascular smooth muscle receptors after focal cerebral ischemia occur via the MAPK MEK/ERK pathway

    DEFF Research Database (Denmark)

    Maddahi, Aida; Edvinsson, Lars

    2008-01-01

    quantitative Western blot. We demonstrate that there is an increase in the number of contractile smooth muscle receptors inthe MCA and in micro- vessels within the ischemic region. The enhanced expression occurs in the smooth muscle cells as verified by co-localization studies. This receptor upregulation is...... furthermore associated with enhanced expression of pERK1/2 and of transcription factor pElk-1 in the vascular smooth muscle cells. Blockade of transcription with the MEK1 inhibitor U0126, given at the onset of reperfusion or as late as 6 hours after the insult, reduced transcription (pERK1/2 and pElk-1), the......BACKGROUND: MEK1/2 is a serine/threonine protein that phosphorylates extracellular signal-regulated kinase (ERK1/2). Cerebral ischemia results in enhanced expression of cerebrovascular contractile receptors in the middle cerebral artery (MCA) leading to the ischemic region. Here we explored the...

  18. Cytoplasmic and nuclear estradiol receptors in the hypothalamus and cerebral cortex of female rats during the neonatal period

    International Nuclear Information System (INIS)

    The content of estradifol receptors (E2) in the cytoplasmic and nuclear fractions of the hypothalamus and cerebral cortex of female rats was investigated in the course of neonatal development. In the cytosol of the hypothalamus and cortex, the E2-binding proteins, which possess high capacity, include both the true estradiol receptors and proteins identical with α-fetoprotein. True receptors E2 were detected in the nuclear fraction; in the hypothalamus their concentration was virtually unchanged, while in the cortex it decreased from the first to fifth days of postnatal development

  19. Alteration in contractile G-protein coupled receptor expression by moist snus and nicotine in rat cerebral arteries

    International Nuclear Information System (INIS)

    The cardiovascular risk for users of use of Swedish snus/American snuff (moist tobacco) has been debated for a long time. The present study was designed to examine the effects of water- or lipid-soluble (DMSO-soluble) snus and nicotine, the most important substance in tobacco, on the expression of vasocontractile G-protein coupled receptors (GPCR), such as endothelin ETB, serotonin 5-HT1B, and thromboxane A2 TP receptors, in rat cerebral arteries. Studies show that these vasocontractile GPCR show alterations by lipid-soluble cigarette smoke particles via activation of mitogen-activated protein kinases (MAPK). However, the effects of moist tobacco on the expression of GPCR are less studied. Rat middle cerebral arteries were isolated and organ cultured in serum-free medium for 24 h in the presence of water-soluble snus (WSS), DMSO-soluble snus (DSS), or nicotine. The dose of snus and nicotine was kept at plasma level of snus users (25 ng nicotine/ml). A high dose (250 ng nicotine/ml) was also included due to the previous results showing alteration in the GPCR expression by nicotine at this concentration. Contractile responses to the ETB receptor agonist sarafotoxin 6c, 5-HT1B receptor agonist 5-carboxamidotryptamine, and TP receptor agonist U46619 were investigated by a sensitive myograph. The expression of ETB, 5-HT1B, and TP receptors was studied at mRNA and protein levels using quantitative real-time PCR and immunohistochemistry, respectively. Organ culture with WSS or DSS (25 ng nicotine/ml) lowered the 5-HT1B receptor-mediated contraction. Furthermore, DSS shifted the TP receptor-mediated contraction curve left-wards with a stronger contraction. High dose of nicotine (250 ng nicotine/ml) increased the ETB receptor-mediated contraction. The combined 5-HT1B and 5-HT2A receptor-mediated contraction was increased, and both the 5-CT and TxA2 induced contractions were left-ward shifted by WSS, DSS, or nicotine (250 ng nicotine/ml). Only the DSS group showed that the

  20. Decreased GABA receptor in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A

    Directory of Open Access Journals (Sweden)

    Mathew Jobin

    2012-02-01

    Full Text Available Abstact Background Gamma amino butyric acid (GABA, the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tones that counter balances neuronal excitation. When this balance is perturbed, seizures may ensue. Methods In the present study, alterations of the general GABA, GABAA and GABAB receptors in the cerebral cortex of the epileptic rat and the therapeutic application of Bacopa monnieri were investigated. Results Scatchard analysis of [3H]GABA, [3H]bicuculline and [3H]baclofen in the cerebral cortex of the epileptic rat showed significant decrease in Bmax (P Aά1, GABAAγ, GABAAδ, GABAB and GAD where down regulated (P Aά5 subunit and Cyclic AMP responsible element binding protein were up regulated. Confocal imaging study confirmed the decreased GABA receptors in epileptic rats. Epileptic rats have deficit in radial arm and Y maze performance. Conclusions Bacopa monnieri and Bacoside-A treatment reverses epilepsy associated changes to near control suggesting that decreased GABA receptors in the cerebral cortex have an important role in epileptic occurrence; Bacopa monnieri and Bacoside-A have therapeutic application in epilepsy management.

  1. Low brain histamine content affects ethanol-induced motor impairment.

    Science.gov (United States)

    Lintunen, Minnamaija; Raatesalmi, Kristiina; Sallmen, Tina; Anichtchik, Oleg; Karlstedt, Kaj; Kaslin, Jan; Kiianmaa, Kalervo; Korpi, Esa R; Panula, Pertti

    2002-02-01

    The effect of ethanol on motor performance in humans is well established but how neural mechanisms are affected by ethanol action remains largely unknown. To investigate whether the brain histaminergic system is important in it, we used a genetic model consisting of rat lines selectively outbred for differential ethanol sensitivity. Ethanol-sensitive rats had lower levels of brain histamine and lower densities of histamine-immunoreactive fibers than ethanol-insensitive rats, although both rat lines showed no changes in histamine synthesizing neurons. Lowering the high brain histamine content of the ethanol-insensitive rats with alpha-fluoromethylhistidine before ethanol administration increased their ethanol sensitivity in a behavioral motor function test. Higher H3 receptor ligand binding and histamine-induced G-protein activation was detected in several brain regions of ethanol-naive ethanol-sensitive rats. Brain histamine levels and possibly signaling via H3 receptors may thus correlate with genetic differences in ethanol-induced motor impairment. PMID:11848689

  2. Histamine: an undercover agent in multiple rare diseases?

    Science.gov (United States)

    Pino-Ángeles, Almudena; Reyes-Palomares, Armando; Melgarejo, Esther; Sánchez-Jiménez, Francisca

    2012-09-01

    Histamine is a biogenic amine performing pleiotropic effects in humans, involving tasks within the immune and neuroendocrine systems, neurotransmission, gastric secretion, cell life and death, and development. It is the product of the histidine decarboxylase activity, and its effects are mainly mediated through four different G-protein coupled receptors. Thus, histamine-related effects are the results of highly interconnected and tissue-specific signalling networks. Consequently, alterations in histamine-related factors could be an important part in the cause of multiple rare/orphan diseases. Bearing this hypothesis in mind, more than 25 rare diseases related to histamine physiopathology have been identified using a computationally assisted text mining approach. These newly integrated data will provide insight to elucidate the molecular causes of these rare diseases. The data can also help in devising new intervention strategies for personalized medicine for multiple rare diseases. PMID:22435405

  3. The effect of the excitatory amino acid receptor antagonist dizocilipine maleate (MK-801) on hemispheric cerebral blood flow and metabolism in dogs: modification by prior complete cerebral ischemia.

    Science.gov (United States)

    Perkins, W J; Lanier, W L; Karlsson, B R; Milde, J H; Michenfelder, J D

    1989-09-25

    The effect of the N-methyl-D-aspartate (NMDA) receptor antagonist dizociplipine maleate (MK-801) on cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO2), intracranial pressure and systemic variables was examined in 6 normal dogs (Group I). In 6 additional dogs (Group II), the effects of a prior 11 min episode of complete cerebral ischemia on the response to dizocilipine was studied. CBF was measured with a sagittal sinus outflow technique and CMRO2 was calculated as the product of CBF and the arterial to sagittal sinus O2 content difference. Dizocilipine was administered as a 150 micrograms/kg i.v. bolus followed by a 75 micrograms.kg-1.h-1 infusion for 90 min. Plasma dizocilipine levels were greater than 25 ng/ml for the duration of the infusion. The CSF levels were approximately half the plasma levels. Five minutes after initiation of dizocilipine treatment, Group I dogs experienced a 63% increase in heart rate (P less than 0.01) and an 8% decrease in the mean arterial blood pressure (P less than 0.05). Over the same time interval. CBF increased by 85% (P less than 0.01) and intracranial pressure nearly doubled (P less than 0.05). In addition, dizocilipine treatment in all Group I animals resulted in EEG quasiperiodic bursts of delta-waves and polyspikes on a background of beta-activity. With the exception of the intracranial pressure, the above changes in systemic and cerebral variables persisted for the duration of the drug infusion. Intracranial pressure was no longer significantly elevated after 80 min of drug infusion. Hemispheric CMRO2 was unchanged by dizocilipine in Group I dogs. There was a decrease in the cortical glucose level at the end of the study, but no significant change in phosphocreatine, ATP, lactate, or energy charge when compared with 6 laboratory normals. An identical dose of dizocilipine administered after an 11 min episode of complete cerebral ischemia resulted in no significant changes in either cerebral or systemic

  4. Central Effect of Exogenous Histamine on Pain Induced by Sub-Plantar Injection of Formalin in Rabbits

    OpenAIRE

    Esmaeal Tamaddonfard

    2010-01-01

    In the present study, the effects of intracerebroventricular (ICV) administration of normal saline (control), histamine, mepyramine (a histamine H1-receptor antagonist) and ranitidine (a histamine H2-receptor antagonist) were investigated on the formalin-induced pain in rabbits. Subcutaneous (SC) injection of a formalin (100 μl, 5%) solution into the ventral surface of the right hind paw was performed, and the time durations spent licking and biting the injected paw were measured in 10 min bl...

  5. Binding pathway of histamine to the hH4R, observed by unconstrained molecular dynamics.

    Science.gov (United States)

    Wittmann, Hans-Joachim; Strasser, Andrea

    2015-03-15

    Histamine binds with high affinity to the human histamine H4 receptor (hH4R). We are the first to examine the complete binding pathway of histamine from the extracellular side to the orthosteric binding site of the hH4R by means of unconstrained molecular dynamic simulation. Furthermore, the simulations show that the positively charged amine moiety of the histamine interacts electrostatically with the highly conserved Asp(3.32), while the imidazole moiety forms a hydrogen bond interaction with Glu(5.46) and Gln(7.42). PMID:25677665

  6. Organic cation transporter 3 modulates murine basophil functions by controlling intracellular histamine levels

    OpenAIRE

    Schneider, Elke; Machavoine, François; Pléau, Jean-Marie; Bertron, Anne-France; Thurmond, Robin L.; Ohtsu, Hiroshi; Watanabe, Takehiko; Schinkel, Alfred H; Dy, Michel

    2005-01-01

    In this study, we identify the bidirectional organic cation transporter 3 (OCT3/Slc22a3) as the molecule responsible for histamine uptake by murine basophils. We demonstrate that OCT3 participates in the control of basophil functions because exogenous histamine can inhibit its own synthesis—and that of interleukin (IL)-4, IL-6, and IL-13—through this means of transport. Furthermore, ligands of H3/H4 histamine receptors or OCT3 inhibit histamine uptake, and outward transport of newly synthesiz...

  7. Occupancy of pramipexole (Sifrol) at cerebral dopamine D2/3 receptors in Parkinson's disease patients.

    Science.gov (United States)

    Deutschländer, Angela; la Fougère, Christian; Boetzel, Kai; Albert, Nathalie L; Gildehaus, Franz-Josef; Bartenstein, Peter; Xiong, Guoming; Cumming, Paul

    2016-01-01

    Whereas positron emission tomography (PET) with the antagonist ligand [(18)F]fallypride reveals the composite of dopamine D2 and D3 receptors in brain, treatment of Parkinson's disease (PD) patients with the D3-prefering agonist pramipexole should result in preferential occupancy in the nucleus accumbens, where the D3-subtype is most abundant. To test this prediction we obtained pairs of [(18)F]fallypride PET recordings in a group of nine PD patients, first in a condition of treatment as usual with pramipexole (ON-Sifrol; 3 × 0.7 mg p.d.), and again at a later date, after withholding pramipexole 48-72 h (OFF-Sifrol); in that condition the serum pramipexole concentration had declined by 90% and prolactin levels had increased four-fold, in conjunction with a small but significant worsening of PD motor symptoms. Exploratory comparison with historical control material showed 14% higher dopamine D2/3 availability in the more-affected putamen of patients OFF medication. On-Sifrol there was significant (p ˂ 0.01) occupancy at [(18)F]fallypride binding sites in globus pallidus (8%) thalamus (9%) and substantia nigra (19%), as well as marginally significant occupancy in frontal and temporal cortex of patients. Contrary to expectation, comparison of ON- and OFF-Sifrol results did not reveal any discernible occupancy in nucleus accumbens, or elsewhere in the extended striatum; present methods should be sensitive to a 10% change in dopamine D2/3 receptor availability in striatum; the significant findings elsewhere in the basal ganglia and in cerebral cortex are consistent with a predominance of D3 receptors in those structures, especially in substantia nigra, and imply that therapeutic effects of pramipexole may be obtained at sites outside the extended striatum. PMID:27408789

  8. Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

    DEFF Research Database (Denmark)

    Færch, Louise H; Thorsteinsson, Birger; Tarnow, Lise;

    2015-01-01

    INTRODUCTION: High spontaneous activity of the renin-angiotensin system (RAS) results in more pronounced cognitive impairment and more prolonged QTc interval during hypoglycaemia in type 1 diabetes. We tested whether angiotensin II receptor blockade improves cerebral and cardiovascular function...

  9. Glyburide in Treating Malignant Cerebral Edema. Blocking Sulfonyl Urea One (SUR1) Receptors

    OpenAIRE

    Pallan, Tony V; Ahmed, Iftekhar

    2014-01-01

    Cerebral edema is a serious side effect of malignant stroke. On average 70,000 patients are diagnosed with malignant cerebral edema every year, of those patients, approximately 60-80% results in fatalities. The treatment of cerebral edema includes multimodality approaches.

  10. Roles of histamine on the expression of aldehyde dehydrogenase 1 in endometrioid adenocarcinoma cell line

    International Nuclear Information System (INIS)

    Cancer-initiating cells (CICs) are a limited number of cells that are essential for maintenance, recurrence, and metastasis of tumors. Aldehyde dehydrogenase 1 (ALDH1) has been recognized as a marker of CICs. We previously reported that ALDH1-high cases of uterine endometrioid adenocarcinoma showed poor prognosis, and that ALDH1 high population was more tumorigenic, invasive, and resistant to apoptosis than ALDH1 low population. Histamine plays a critical role in cancer cell proliferation, migration, and invasion. Here, we examined the effect of histamine on ALDH1 expression in endometrioid adenocarcinoma cell line. The addition of histamine increased ALDH1 high population, which was consistent with the result that histamine enhanced the invasive ability and the resistance to anticancer drug. Among 4 types of histamine receptors, histamine H1 and H2 receptor (H1R and H2R) were expressed in endometrioid adenocarcinoma cell line. The addition of H1R agonist but not H2R agonist increased ALDH1. The antagonist H1R but not H2R inhibited the effect of histamine on ALDH1 expression. These results indicated that histamine increased the expression of ALDH1 via H1R but not H2R. These findings may provide the evidence for exploring a new strategy to suppress CICs by inhibiting ALDH1 expression with histamine

  11. Htr2a gene and 5-HT2A receptor expression in the cerebral cortex studied using genetically modified mice

    Directory of Open Access Journals (Sweden)

    Rodrigo Andrade

    2010-08-01

    Full Text Available Serotonin receptors of the 5-HT2A subtype are robustly expressed in the cerebral cortex where they have been implicated in the pathophysiology and therapeutics of mental disorders and the actions of hallucinogens. Much less is known, however, about the specific cell types expressing 5-HT2A receptors in cortex. In the current study we use immunohistochemical and electrophysiological approaches in genetically modified mice to address the expression of the Htr2a gene and 5-HT2A receptors in cortex. We first use an EGFP expressing BAC transgenic mice and identify three main Htr2A gene expressing neuronal populations in cortex. The largest of these cell populations corresponds to layer V pyramidal cells of the anterior cortex, followed by GABAergic interneurons of the middle layers, and nonpyramidal cells of the subplate/Layer VIb. We then use 5-HT2A receptor knockout mice to identify an antibody capable of localizing 5-HT2A receptors in brain and use it to map these receptors. We find strong laminar expression of 5-HT2A receptors in cortex, especially along a diffuse band overlaying layer Va. This band exhibits a strong anteroposterior gradient that closely matches the localization of Htr2A expressing pyramidal cells of layer V. Finally we use electrophysiological and immunohistochemical approaches to show that most, but not all, GABAergic interneurons of the middle layers are parvalbumin expressing Fast-spiking interneurons and that these cells are depolarized and excited by serotonin, most likely through the activation of 5-HT2A receptors. These results clarify and extend our understanding of the cellular distribution of 5-HT2A receptors in the cerebral cortex.

  12. Recombinant T cell receptor ligands improve outcome after experimental cerebral ischemia.

    Science.gov (United States)

    Akiyoshi, Kozaburo; Dziennis, Suzan; Palmateer, Julie; Ren, Xuefang; Vandenbark, Arthur A; Offner, Halina; Herson, Paco S; Hurn, Patricia D

    2011-09-01

    A key target for novel stroke therapy is the regulation of post-ischemic inflammatory mechanisms. Recent evidence emphasizes the role of T lymphocytes of differing subtypes in the evolution is ischemic brain damage. We have recently demonstrated the benefit of myelin antigen-specific immunodulatory agents known as recombinant T cell receptor ligands (RTLs) in a standard murine model of focal stroke. The aim of the current study was to extend this initial observation to RTL treatment in a therapeutically relevant timing after middle cerebral artery occlusion (MCAO) and verify functional benefit to complement histological outcome measures. We observed that the administration of mouse-specific RTL551 reduced infarct size and improved sensorimotor outcome when administered within a 3 h post-ischemic therapeutic window. RTL551 treatment reduced cortical, caudate putamen, and total infarct volume as compared to vehicle-treated mice. Using a standard behavioral testing repertoire, we observed that RTL551 reduced sensorimotor impairment 3 days after MCAO. Humanized RTL1000 (HLA-DR2 moiety linked to hMOG-35-55 peptide) also reduced infarct size in HLA-DR2 transgenic mice. These data indicate that this neuroantigen-specific immunomodulatory agent reduces damage when administered in a therapeutically relevant reperfusion timeframe. PMID:21961027

  13. Neuronal histamine and cognitive symptoms in Alzheimer's disease.

    Science.gov (United States)

    Zlomuzica, Armin; Dere, Dorothea; Binder, Sonja; De Souza Silva, Maria Angelica; Huston, Joseph P; Dere, Ekrem

    2016-07-01

    Alzheimer's disease is a neurodegenerative disorder characterized by extracellular amyloid plaque deposits, mainly composed of amyloid-beta peptide and intracellular neurofibrillary tangles consisting of aggregated hyperphosphorylated tau protein. Amyloid-beta represents a neurotoxic proteolytic cleavage product of amyloid precursor protein. The progressive cognitive decline that is associated with Alzheimer's disease has been mainly attributed to a deficit in cholinergic neurotransmission due to the continuous degeneration of cholinergic neurons e.g. in the basal forebrain. There is evidence suggesting that other neurotransmitter systems including neuronal histamine also contribute to the development and maintenance of Alzheimer's disease-related cognitive deficits. Pathological changes in the neuronal histaminergic system of such patients are highly predictive of ensuing cognitive deficits. Furthermore, histamine-related drugs, including histamine 3 receptor antagonists, have been demonstrated to alleviate cognitive symptoms in Alzheimer's disease. This review summarizes findings from animal and clinical research on the relationship between the neuronal histaminergic system and cognitive deterioration in Alzheimer's disease. The significance of the neuronal histaminergic system as a promising target for the development of more effective drugs for the treatment of cognitive symptoms is discussed. Furthermore, the option to use histamine-related agents as neurogenesis-stimulating therapy that counteracts progressive brain atrophy in Alzheimer's disease is considered. This article is part of a Special Issue entitled 'Histamine Receptors'. PMID:26025658

  14. An interspecies comparison of mercury inhibition on muscarinic acetylcholine receptor binding in the cerebral cortex and cerebellum

    International Nuclear Information System (INIS)

    Mercury (Hg) is a ubiquitous pollutant that can disrupt neurochemical signaling pathways in mammals. It is well documented that inorganic Hg (HgCl2) and methyl Hg (MeHg) can inhibit the binding of radioligands to the muscarinic acetylcholine (mACh) receptor in rat brains. However, little is known concerning this relationship in specific anatomical regions of the brain or in other species, including humans. The purpose of this study was to explore the inhibitory effects of HgCl2 and MeHg on [3H]-quinuclidinyl benzilate ([3H]-QNB) binding to the mACh receptor in the cerebellum and cerebral cortex regions from human, rat, mouse, mink, and river otter brain tissues. Saturation binding curves were obtained from each sample to calculate receptor density (B max) and ligand affinity (K d). Subsequently, samples were exposed to HgCl2 or MeHg to derive IC50 values and inhibition constants (K i). Results demonstrate that HgCl2 is a more potent inhibitor of mACh receptor binding than MeHg, and the receptors in the cerebellum are more sensitive to Hg-mediated mACh receptor inhibition than those in the cerebral cortex. Species sensitivities, irrespective of Hg type and brain region, can be ranked from most to least sensitive: river otter > rat > mink > mouse > humans. In summary, our data demonstrate that Hg can inhibit the binding [3H]-QNB to the mACh receptor in a range of mammalian species. This comparative study provides data on interspecies differences and a framework for interpreting results from human, murine, and wildlife studies

  15. Biosensor cell assay for measuring real-time aldosterone-induced release of histamine from mesenteric arteries

    DEFF Research Database (Denmark)

    Dalgaard, Emil G; Andersen, Kenneth; Svenningsen, Per; Hansen, Pernille B L

    2016-01-01

    AIMS: The aims were to develop a method for real-time detection of histamine release and to test if incubation with aldosterone induces histamine release from isolated, perfused mice mesenteric arteries. METHODS: Fura-2 loaded HEK-293 cells transfected with the histamine H1 receptor was used as a...... sensitive biosensor assay for histamine release from isolated mouse mesenteric arteries. Activation of the H1 receptor by histamine was measured as an increased number of intracellular Ca(2+) transient peaks using fluorescence imaging RESULTS: The developed biosensor was sensitive to histamine in...... physiological relevant concentrations and responded to substances released by the artery preparation. Aldosterone treatment of mesenteric arteries from wild type mice for 50 minutes resulted in an increased number of intracellular Ca(2+) transient peaks in the biosensor cells, which was significantly inhibited...

  16. Influence of histamine of precursors of granulocytic leukocytes in murine bone marrow

    International Nuclear Information System (INIS)

    The effect of histamine on granulocytic progenitor cells in murine bone marrow was studied in vitro. When bone marrow cells were cultured for three days with the drug, 10-8 M to 10-5 M of histamine stimulated differentiation and proliferation of myeloid precursor cells. Subsequently, the number of descendant cells, such as metamyelocytes and neutrophils, increased dose-dependently. Co-existence of equimolar H2 blockers such as cimetidine and ranitidine completely suppressed this effect of histamine, though this was not the case with an H1 blocker/histamine combination. Significant increase in 3H-thymidine incorporation was observed almost exclusively in myeloblasts, promyelocytes and myelocytes after exposure to histamine at concentrations higher than 10-8 M. Also, selective incorporation of 3H-histamine into bone marrow cells was observed in myeloblasts and promyelocytes, but histamine incorporation was not influenced by the presence of either of histamine agonists of antagonists. While histamine, via H2 receptors, selectively increased the number of granulocytic colony forming units in culture (CFU-C), it had no such effect on macrophage colonies. 22 references, 5 figures, 4 tables

  17. The effects of crocin and safranal on the yawning induced by intracerebroventricular injection of histamine in rats

    Science.gov (United States)

    Taati, Mina; Tamaddonfard, Esmaeal; Erfanparast, Amir; Ghasemi, Hamid

    2016-01-01

    Objective: Crocin and safranal, as the major constituents of saffron, have many biological activities. This study investigated the effects of crocin and safranal on yawning response induced by intracerebroventricular (i.c.v.) injection of histamine in rats. Materials and Methods: In ketamine/xylazine-anesthetized rats, a guide cannula was implanted in the right ventricle of the brain and yawning induced by i.c.v. injection of histamine. Crocin and safranal were intraperitoneally (i.p.) injected alone and before i.c.v. injection of histamine. Results: Histamine at the doses of 10 and 20 µg/rat produced yawning. Mepyramine (a histamine H1 receptor antagonist) 40 µg/rat significantly (p<0.05) prevented histamine (20 µg/rat)-induced yawning. Crocin (30 mg/kg) and safranal (1 mg/kg) significantly (p<0.05) increased histamine (10 µg/rat)-induced yawning. Crocin and safranal also induced yawning when injected before mepyramine plus histamine administration. Conclusion: The results of the present study showed a yawning-inducing effect for central histamine, which was inhibited by mepyramine. Crocin and safranal increased histamine-induced yawning, and also produced yawning when the histamine action is blocked.

  18. Lactobacillus reuteri-Specific Immunoregulatory Gene rsiR Modulates Histamine Production and Immunomodulation by Lactobacillus reuteri

    OpenAIRE

    Hemarajata, P; Gao, C; Pflughoeft, K. J.; Thomas, C M; Saulnier, D. M.; Spinler, J. K.; Versalovic, J

    2013-01-01

    Human microbiome-derived strains of Lactobacillus reuteri potently suppress proinflammatory cytokines like human tumor necrosis factor (TNF) by converting the amino acid l-histidine to the biogenic amine histamine. Histamine suppresses mitogen-activated protein (MAP) kinase activation and cytokine production by signaling via histamine receptor type 2 (H2) on myeloid cells. Investigations of the gene expression profiles of immunomodulatory L. reuteri ATCC PTA 6475 highlighted numerous genes th...

  19. SPECT imaging of GABA{sub A}/benzodiazepine receptors and cerebral perfusion in mild cognitive impairment

    Energy Technology Data Exchange (ETDEWEB)

    Pappata, Sabina; Varrone, Andrea; Vicidomini, Caterina; Sansone, Valeria; Comerci, Marco; Panico, Maria Rosaria; Quarantelli, Mario [CNR, Institute of Biostructure and Bioimaging, Naples (Italy); Milan, Graziella; De Falco, Caterina; Lore, Elisa; Postiglione, Alfredo [University ' ' Federico II' ' , Department of Clinical and Experimental Medicine, Naples (Italy); Iavarone, Alessandro [Neurologic and Stroke Unit, CTO Hospital, Naples (Italy); Salvatore, Marco [CNR, Institute of Biostructure and Bioimaging, Naples (Italy); University ' ' Federico II' ' , Department of Biomorphological and Functional Sciences, Naples (Italy)

    2010-06-15

    The involvement of neocortical and limbic GABA{sub A}/benzodiazepine (BZD) receptors in Alzheimer's disease (AD) is controversial and mainly reported in advanced stages. The status of these receptors in the very early stages of AD is unclear and has not been explored in vivo. Our aims were to investigate in vivo the integrity of cerebral cortical GABA{sub A}/BZD receptors in subjects with amnestic mild cognitive impairment (MCI) and to compare possible receptor changes to those in cerebral perfusion. [{sup 123}I]Iomazenil and [{sup 99m}Tc]HMPAO SPECT images were acquired in 16 patients with amnestic MCI and in 14 normal elderly control subjects (only [{sup 123}I]iomazenil imaging in 5, only [{sup 99m}Tc]HMPAO imaging in 4, and both [{sup 123}I]iomazenil and [{sup 99m}Tc]HMPAO imaging in 5). Region of interest (ROI) analysis and voxel-based analysis were performed with cerebellar normalization. Neither ROI analysis nor voxel-based analysis showed significant [{sup 123}I]iomazenil binding changes in MCI patients compared to control subjects, either as a whole group or when considering only those patients with MCI that converted to AD within 2 years of clinical follow-up. In contrast, the ROI analysis revealed significant hypoperfusion of the precuneus and posterior cingulate cortex in the whole group of MCI patients and in MCI converters as compared to control subjects. Voxel-based analysis showed similar results. These results indicate that in the very early stages of AD, neocortical and limbic neurons/synapses expressing GABA{sub A}/BZD receptors are essentially preserved. They suggest that in MCI patients functional changes precede neuronal/synaptic loss in neocortical posterior regions and that [{sup 99m}Tc]HMPAO rCBF imaging is more sensitive than [{sup 123}I]iomazenil GABA{sub A}/BZD receptor imaging in detecting prodromal AD. (orig.)

  20. Upregulation of contractile endothelin type B receptors by lipid-soluble cigarette smoking particles in rat cerebral arteries via activation of MAPK

    International Nuclear Information System (INIS)

    Cigarette smoke exposure increases the risk of stroke. However, the underlying molecular mechanisms are poorly understood. Endothelin system plays key roles in the pathogenesis of stroke. The present study was designed to examine if lipid-soluble (dimethyl sulfoxide-soluble) cigarette smoke particles (DSP) induces upregulation of contractile endothelin type B (ETB) receptors in rat cerebral arteries and if activation of mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) mediate the upregulation of contractile endothelin receptors in the cerebral arteries. Rat middle cerebral arteries were isolated and organ cultured in serum free medium for 24 h in the presence of DSP with or without specific inhibitors: MEK specific (U0126), p38 specific (SB202190), JNK specific (SP600125), NF-κB specific (BMS-345541) or (IMD-0354), transcription inhibitor (actinomycin D), or translation blocker (cycloheximide). Contractile responses to the ETB receptor agonist sarafotoxin 6c were investigated by a sensitive myograph. The expression of the ETB receptors were studied at mRNA and protein levels using quantitative real time PCR and immunohistochemistry, respectively. Results show that organ culture per se induced transcriptional upregulation of contractile ETB receptors in the cerebral vascular smooth muscle cells. This upregulation was further increased at the translational level by addition of DSP to the organ culture, but this increase was not seen by addition of nicotine or water-soluble cigarette smoke particles to the organ culture. The increased upregulation of contractile ETB receptors by DSP was abrogated by U0126, SP600125, actinomycin D, and cycloheximide, suggesting that the underlying molecular mechanisms involved in this process include activation of MEK and JNK MAPK-mediated transcription and translation of new contractile ETB receptors. Thus, the MAPK-mediated upregulation of contractile ETB receptors in cerebral arteries might be a

  1. Angiotensin II type-2 receptor stimulation induces neuronal VEGF synthesis after cerebral ischemia.

    Science.gov (United States)

    Mateos, Laura; Perez-Alvarez, Maria Jose; Wandosell, Francisco

    2016-07-01

    Intense efforts are being undertaken to understand the pathobiology of ischemia and to develop novel and effective treatments. Angiotensin II type 2 receptor (AT2R) is related with a beneficial role in neurodegenerative disorders, including ischemia. However, the underlying molecular mechanism remains elusive. In this study, we have established that AT2R stimulation by C21 compound, a specific AT2R agonist, caused a VEGF upregulation. Using mouse primary cortical neurons exposed to oxygen-glucose deprivation (OGD), we established that this effect was mediated by a mechanism dependent of mTORC1 signaling since mTOR inhibition abolished the C21-induced VEGF upregulation. Also, we have temporally characterized the changes on VEGF levels after ischemia induction in rats using two different approaches: transient and permanent middle cerebral artery occlusion (tMCAO and pMCAO). VEGF levels were permanently augmented after reperfusion (tMCAO) whereas lower levels of VEGF were found after pMCAO, remarkably at 21days. Therefore, C21 compound accelerated the recovery of the neurological status of pMCAO rats, reduced the ischemic damage area and abolished pMCAO-induced VEGF downregulation at 21days. This effect of C21 compound was mainly observed in neurons of the peri-infarct area. Our results suggest that a C21-induced VEGF upregulation may be crucial after an ischemic neuronal insult in both of our experimental approaches. This upregulation was mediated by a mechanism dependent of Akt/mTOR signaling pathway, since mTOR inhibition abolished the VEGF upregulation induced by C21. Considering that VEGF is involved in regenerative processes, we propose that AT2R activation could be used as a potential pharmacological strategy after ischemic stroke. PMID:27045356

  2. Hypersensitivity to thromboxane receptor mediated cerebral vasomotion and CBF oscillations during acute NO-deficiency in rats.

    Directory of Open Access Journals (Sweden)

    Béla Horváth

    Full Text Available BACKGROUND: Low frequency (4-12 cpm spontaneous fluctuations of the cerebrovascular tone (vasomotion and oscillations of the cerebral blood flow (CBF have been reported in diseases associated with endothelial dysfunction. Since endothelium-derived nitric oxide (NO suppresses constitutively the release and vascular effects of thromboxane A(2 (TXA(2, NO-deficiency is often associated with activation of thromboxane receptors (TP. In the present study we hypothesized that in the absence of NO, overactivation of the TP-receptor mediated cerebrovascular signaling pathway contributes to the development of vasomotion and CBF oscillations. METHODOLOGY/PRINCIPAL FINDINGS: Effects of pharmacological modulation of TP-receptor activation and its downstream signaling pathway have been investigated on CBF oscillations (measured by laser-Doppler flowmetry in anesthetized rats and vasomotion (measured by isometric tension recording in isolated rat middle cerebral arteries, MCAs both under physiological conditions and after acute inhibition of NO synthesis. Administration of the TP-receptor agonist U-46619 (1 µg/kg i.v. to control animals failed to induce any changes of the systemic or cerebral circulatory parameters. Inhibition of the NO synthesis by nitro-L-arginine methyl ester (L-NAME, 100 mg/kg i.v. resulted in increased mean arterial blood pressure and a decreased CBF accompanied by appearance of CBF-oscillations with a dominant frequency of 148±2 mHz. U-46619 significantly augmented the CBF-oscillations induced by L-NAME while inhibition of endogenous TXA(2 synthesis by ozagrel (10 mg/kg i.v. attenuated it. In isolated MCAs U-46619 in a concentration of 100 nM, which induced weak and stable contraction under physiological conditions, evoked sustained vasomotion in the absence of NO, which effect could be completely reversed by inhibition of Rho-kinase by 10 µM Y-27632. CONCLUSION/SIGNIFICANCE: These results suggest that hypersensitivity of the TP-receptor

  3. Curcumin modulates dopaminergic receptor, CREB and phospholipase c gene expression in the cerebral cortex and cerebellum of streptozotocin induced diabetic rats

    Directory of Open Access Journals (Sweden)

    George Naijil

    2010-05-01

    Full Text Available Abstract Curcumin, an active principle component in rhizome of Curcuma longa, has proved its merit for diabetes through its anti-oxidative and anti-inflammatory properties. This study aims at evaluating the effect of curcumin in modulating the altered dopaminergic receptors, CREB and phospholipase C in the cerebral cortex and cerebellum of STZ induced diabetic rats. Radioreceptor binding assays and gene expression was done in the cerebral cortex and cerebellum of male Wistar rats using specific ligands and probes. Total dopaminergic receptor binding parameter, Bmax showed an increase in cerebral cortex and decrease in the cerebellum of diabetic rats. Gene expression studies using real time PCR showed an increased expression of dopamine D1 and D2 receptor in the cerebral cortex of diabetic rats. In cerebellum dopamine D1 receptor was down regulated and D2 receptor showed an up regulation. Transcription factor CREB and phospholipase C showed a significant down regulation in cerebral cortex and cerebellum of diabetic rats. We report that curcumin supplementation reduces diabetes induced alteration of dopamine D1, D2 receptors, transcription factor CREB and phospholipase C to near control. Our results indicate that curcumin has a potential to regulate diabetes induced malfunctions of dopaminergic signalling, CREB and Phospholipase C expression in cerebral cortex and cerebellum and thereby improving the cognitive and emotional functions associated with these regions. Furthermore, in line with these studies an interaction between curcumin and dopaminergic receptors, CREB and phospholipase C is suggested, which attenuates the cortical and cerebellar dysfunction in diabetes. These results suggest that curcumin holds promise as an agent to prevent or treat CNS complications in diabetes.

  4. Effects of histamine and antihistamines on the kinetics of carbon dioxide in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Russell, J.C.; Chambers, M.M.

    1981-01-01

    We have investigated the effects of chlorpheniramine (an H1 histamine inhibitor) and metiamide (an H2 inhibitor) on response to 14C pulse-labeling of carbon dioxide in the rat in the presence and absence of histamine. Neither chlorpheniramine nor metiamide alone had any effect upon the gastric venous/arterial ratio (VG/A) or the peripheral venous/arterial ratio (Vp/A). As in the case with no drug present, Vp/A rose with time following pulse-labeling to a value of 1.15-1.20. The presence of a preexisting steady-state infusion of histamine caused no changes in the ratios in the presence or absence of the inhibitors. The inhibitors did completely abolish the oscillations of both VG/A and Vp/A caused by initiation of histamine infusion coincident with the pulse-labeling. The results suggest that the histamine effects are largely mediated through H1 receptors.

  5. Effects of histamine and antihistamines on the kinetics of carbon dioxide in the rat

    International Nuclear Information System (INIS)

    We have investigated the effects of chlorpheniramine (an H1 histamine inhibitor) and metiamide (an H2 inhibitor) on response to 14C pulse-labeling of carbon dioxide in the rat in the presence and absence of histamine. Neither chlorpheniramine nor metiamide alone had any effect upon the gastric venous/arterial ratio (VG/A) or the peripheral venous/arterial ratio (Vp/A). As in the case with no drug present, Vp/A rose with time following pulse-labeling to a value of 1.15-1.20. The presence of a preexisting steady-state infusion of histamine caused no changes in the ratios in the presence or absence of the inhibitors. The inhibitors did completely abolish the oscillations of both VG/A and Vp/A caused by initiation of histamine infusion coincident with the pulse-labeling. The results suggest that the histamine effects are largely mediated through H1 receptors

  6. In depth pharmacological characterization of endothelin B receptors in the rat middle cerebral artery

    DEFF Research Database (Denmark)

    Szok, D; Hansen-Schwartz, J; Edvinsson, L

    2001-01-01

    middle cerebral artery were cannulated with micropipettes, pressurized and luminally perfused. Vessel diameters were evaluated using a microscope equipped with an imaging system. Both intra- and extraluminal applications of endothelin-1 produced constriction. Intraluminal administration of a selective...

  7. Compound 48/80, a histamine-depleting agent, blocks the protective effect of morphine against electroconvulsive shock in mice

    OpenAIRE

    Karadag C.H.; Dokmeci D.; Dost T.; Ulugol A.; Dokmeci I.

    2000-01-01

    We have shown that morphine has an anticonvulsive effect against maximal electroconvulsive shock (MES) in mice, and this effect is antagonized by histamine H1-receptor antagonists. Brain histamine is localized both in neurons and in mast cells, and morphine is known to enhance the turnover of neuronal histamine and to release histamine from mast cells. In the present experiments, compound 48/80 was injected chronically (0.5 mg/kg on day 1, 1 mg/kg on day 2, 2 mg/kg on day 3, 3 mg/kg on day 4,...

  8. Enhanced expressions of microvascular smooth muscle receptors after focal cerebral ischemia occur via the MAPK MEK/ERK pathway

    DEFF Research Database (Denmark)

    Maddahi, A.; Edvinsson, L.

    2008-01-01

    furthermore associated with enhanced expression of pERK1/2 and of transcription factor pElk-1 in the vascular smooth muscle cells. Blockade of transcription with the MEK1 inhibitor U0126, given at the onset of reperfusion or as late as 6 hours after the insult, reduced transcription (pERK1/2 and pElk-1), the...... enhanced vascular receptor expression, and attenuated the cerebral infarct and improved neurology score. CONCLUSION: Our results show that MCAO results in upregulation of cerebrovascular ETB, AT1 and 5-HT1B receptors. Blockade of this event with a MEK1 inhibitor as late as 6 h after the insult reduced the...

  9. Specific cerebral heat shock proteins and histamine receptor cross-talking mechanisms promote distinct lead-dependent neurotoxic responses in teleosts

    International Nuclear Information System (INIS)

    Recent interests are beginning to be directed towards toxic neurobiological dysfunctions caused by lead (Pb) in aquatic vertebrates. In the present work, treatment with a maximum acceptable toxic concentration of this heavy metal was responsible for highly significant (p 2R) antagonist cimetidine (Cim), as shown by the very robust (p 3R) thioperamide (Thio), instead, blocked Pb-dependent up-regulatory trends of both chaperones in mostly hypothalamic areas. Moreover, intense neuronal damages of the above brain regions coincided with altered expressions of HSP70 and HSP90 when treated only with Cim. Overall these first results show that distinct HnR are able to exert a net neuroprotective role arising from their interaction with chaperones in fish exposed to Pb-dependent stressful conditions making this a potentially key interaction especially for T. pavo, aquatic species which plays an important ecological role towards the survival of other commercially vital fishes

  10. Cutting edge: histamine is required for IL-4-driven eosinophilic allergic responses.

    Science.gov (United States)

    Swartzendruber, Julie A; Byrne, Adam J; Bryce, Paul J

    2012-01-15

    Histamine is an important allergic mediator, and studies have defined roles for both histamine 1 and 4 receptors in allergic airway inflammation. In this study, we show that histamine is necessary to generate IL-4-driven eosinophilic inflammation, as histamine-deficient mice cannot generate eosinophilic lung inflammation in response to intratracheal IL-4 and exogenous histamine restores responsiveness. This is histamine 2 receptor (H2R) dependent because H2R knockout mice fail to respond to IL-4, and a H2R agonist restores inflammation in histidine decarboxylase knockout. Furthermore, alveolar epithelial cells require H2R to produce CCL24, an eosinophil recruitment factor, whereas H2R blockade reduces CCL24 production from wild-type cells. In an allergic inflammation model, H2R knockout mice show significantly reduced eosinophilic inflammation and CCL24 expression. These data demonstrate a previously unidentified role for H2R in allergic inflammation and establishes a synergy between endogenous histamine and IL-4 that supports eosinophilic recruitment to the lung. PMID:22156496

  11. Histamine is required for IL-4-driven eosinophilic allergic responses1

    Science.gov (United States)

    Swartzendruber, Julie A.; Byrne, Adam J.; Bryce, Paul J.

    2011-01-01

    Histamine is an important allergic mediator and studies have defined roles for both histamine 1 and 4 receptors (H1R and H4R) in allergic airway inflammation. Here, we show that histamine is necessary to generate IL-4-driven eosinophilic inflammation, as histamine deficient mice cannot generate eosinophilic lung inflammation in response to intratracheal IL-4 and exogenous histamine restores responsiveness. This is histamine 2 receptor (H2R) dependent since H2R KO mice fail to respond to IL-4, and a H2R agonist restores inflammation in HDC KO. Furthermore, alveolar epithelial cells require H2R in order to produce CCL24, an eosinophil recruitment factor, while H2R blockade reduces CCL24 production from WT cells. In an allergic inflammation model, H2R KO mice show significantly reduced eosinophilic inflammation and CCL24 expression. These data demonstrate a previously unidentified role for H2R in allergic inflammation and establishes a synergy between endogenous histamine and IL-4 that supports eosinophilic recruitment to the lung. PMID:22156496

  12. Histamine and neuroinflammation: insights from mouse experimental autoimmune encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Maria Beatrice ePassani

    2012-05-01

    Full Text Available Multiple sclerosis (MS is a chronic inflammatory, neurodegenerative disease of the CNS whose pathogenesis remains largely unknown, and available therapies are rarely successful in reversing neurological deficits or stopping disease progression. Ongoing studies on MS and the widely used murine model experimental autoimmune encephalomyelitis (EAE are trying to dissect out the many components of this complex and heterogeneous neurodegenerative disease in the hope of providing a mechanism-based characterization of MS that will afford successful strategies to limit and repair the neuronal damage. Recently, histamine has been postulated to have a key regulatory role in EAE and in MS pathogenesis. Histamine is a mediator of inflammation and immune responses, it explicates its many actions through four G protein-coupled receptors (H1,2,3,4R that signal through distinct intracellular pathways and have different therapeutic potentials as they vary in expression, distribution of isoforms, signaling properties and function. Immune cells involved in MS/EAE, including dendritic cells and T lymphocytes, express H1R, H2R and H4R, and histamine may have varying and counteracting effects on a particular cell type depending on the receptor subtypes being activated. Here, we review evidence of the complex and controversial role of histamine in MS/EAE pathogenesis and evaluate the therapeutic potential of histaminergic ligands to treat autoimmune diseases.

  13. Cerebral muscarinic acetylcholinergic receptor measurement in Alzheimer`s disease patients on {sup 11}C-N-methyl-4-piperidyl benzilate. Comparison with cerebral blood flow and cerebral glucose metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Yoshida, Tsuyoshi; Kuwabara, Yasuo; Ichiya, Yuichi; Sasaki, Masayuki; Fukumura, Toshimitsu; Ichimiya, Atsushi; Takita, Masashi; Ogomori, Koji; Masuda, Kouji [Kyushu Univ., Fukuoka (Japan). Faculty of Medicine

    1998-02-01

    We studied the cerebral muscarinic acetylcholinergic receptor (mACh-R) by means of {sup 11}C-N-methyl-4-piperidyl benzilate ({sup 11}C-NMPB) and positron emission tomography (PET) in Alzheimer`s disease (AD) cases, and the findings were compared with the cerebral blood flow (CBF) and the glucose metabolism (CMRGlc) to evaluate the relationship between the mACh-R and the CBF or the CMRGlc. The subjects consisted of 18 patients with AD and 18 age and sex matched normal volunteers. The patients were clinically diagnosed according to the criteria of the NINDS-ADRDA as having ``probable AD`` and were thus classified into two groups (mild and moderate AD) according to the severity of dementia determined by DSM-III-R. The CBF was measured by {sup 99m}Tc-HMPAO SPECT, and the CMRGlc was measured by {sup 18}FDG PET. The {sup 11}C-NMPB uptake was evaluated by the graphical method and the ratio method (ROIs/Cerebellum). A significant mACh-R decrease and more severe CMRGlc decrease in the cortical region was seen in mild and moderate AD. The decrease in the CBF was not as obvious as that in the mACh-R and the CMRGlc. Our study thus suggested that the mACh-R decreased in patients with AD, and that the {sup 18}FDG PET was the most sensitive method for detecting the degenerative regions in patients with AD. (author)

  14. Effect of propofol on the reactivity of acetylcholinesterase, N-methyl-D-aspartate receptors, and gamma-aminobutyric acid receptors in the hippocampus of aged rats after chronic cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Gang Chen; Jiangbei Cao; Weidong Mi

    2011-01-01

    We induced ischemic brain injury in aging rats to examine the effects of varying doses of propofol on hippocampal activities of acetylcholinesterase, N-methyl-D-aspartate receptors, and γ-aminobutyric acid receptors. Propofol exhibited no obvious impact on acetylcholinesterase activity, but directly activated the γ-aminobutyric acid receptor. The neuroprotective function of propofol on the hippocampus of aging rats following cerebral ischemic injury may be related to altered activities of γ-aminobutyric acid receptors and N-methyl-D-aspartate receptors.

  15. Mechanism of the inhibitory effect of endogenous histamine on epilepsy in rats

    Institute of Scientific and Technical Information of China (English)

    ChenZhong

    2004-01-01

    Clinical data demonstrated that long-term epilepsy, especially among children, or ingesting anticonvulsant drugs over time are likely to result in cognitive deficits (e. g. memory or attention problems as well as other CNS side effects such as psychomotor speed abnormalities, somnolence, asthenia, and dizziness. New drug therapy has been expected. The histaminergic neuron system seems to be involved in various physiological and behavioral functions including sleep - wake cycles, stress behavior, neuroendocrine, learning and memory through histamine HI, H2 and H3 receptors. The role of brain histamine in regulating seizure susceptibility has been studied, and a possible anticonvulsant action of endogenous histamine has been postulated

  16. Involvement of histamine released from mast cells in acute radiation dermatitis in mice

    International Nuclear Information System (INIS)

    A possible involvement of histamine in acute radiation dermatitis in mice was investigated. The dose of 40 Gy of gamma irradiation induced erythema and edema in C57BL/6 mice treated with vehicle. However, in C57BL/6 mice treated with chlorpheniramine and WBB6F1-W/WV mice, erythema and edema were not observed. In all of these mice, epilation and dry desquamation were induced, but bepotastine significantly reduced the extent of these areas. These results suggest that gamma irradiation-induced erythema and edema were caused by histamine released from mast cells via histamine H1 receptor, and epilation was induced by other inflammatory mediators. (author)

  17. Reduced Mechanical Stretch Induces Enhanced Endothelin B Receptor-mediated Contractility via Activation of Focal Adhesion Kinase and Extra Cellular-regulated Kinase 1/2 in Cerebral Arteries from Rat

    DEFF Research Database (Denmark)

    Rasmussen, Marianne N P; Spray, Stine; Skovsted, Gry F;

    2016-01-01

    Cerebral ischaemia results in enhanced endothelin B (ETB ) receptor-mediated contraction and receptor protein expression in the affected cerebrovascular smooth muscle cells (SMC). Organ culture of cerebral arteries is a method to induce similar alterations in ETB receptor expression. We hypothesize......-mediated contractility via triggering of an early mechanosensitive signalling pathway involving ERK1/2 and FAK signalling. A mechanism likely to be an initiating factor for the increased ETB receptor-mediated contractility found after cerebral ischaemia. This article is protected by copyright. All rights reserved....

  18. Dexmedetomidine Modulates Histamine-induced Ca2+ Signaling and Pro-inflammatory Cytokine Expression

    OpenAIRE

    Yang, Dongki; Hong, Jeong Hee

    2015-01-01

    Dexmedetomidine is a sedative and analgesic agent that exerts its effects by selectively agonizing α2 adrenoceptor. Histamine is a pathophysiological amine that activates G protein-coupled receptors, to induce Ca2+ release and subsequent mediate or progress inflammation. Dexmedetomidine has been reported to exert inhibitory effect on inflammation both in vitro and in vivo studies. However, it is unclear that dexmedetomidine modulates histamine-induced signaling and pro-inflammatory cytokine e...

  19. Signaling mechanism underlying the histamine-modulated action of hypoglossal motoneurons.

    Science.gov (United States)

    Liu, Zi-Long; Wu, Xu; Luo, Yan-Jia; Wang, Lu; Qu, Wei-Min; Li, Shan-Qun; Huang, Zhi-Li

    2016-04-01

    Histamine, an important modulator of the arousal states of the central nervous system, has been reported to contribute an excitatory drive at the hypoglossal motor nucleus to the genioglossus (GG) muscle, which is involved in the pathogenesis of obstructive sleep apnea. However, the effect of histamine on hypoglossal motoneurons (HMNs) and the underlying signaling mechanisms have remained elusive. Here, whole-cell patch-clamp recordings were conducted using neonatal rat brain sections, which showed that histamine excited HMNs with an inward current under voltage-clamp and a depolarization membrane potential under current-clamp via histamine H1 receptors (H1 Rs). The phospholipase C inhibitor U-73122 blocked H1 Rs-mediated excitatory effects, but protein kinase A inhibitor and protein kinase C inhibitor did not, indicating that the signal transduction cascades underlying the excitatory action of histamine on HMNs were H1 R/Gq/11 /phospholipase C/inositol-1,4,5-trisphosphate (IP3 ). The effects of histamine were also dependent on extracellular Na(+) and intracellular Ca(2+) , which took place via activation of Na(+) -Ca(2+) exchangers. These results identify the signaling molecules associated with the regulatory effect of histamine on HMNs. The findings of this study may provide new insights into therapeutic approaches in obstructive sleep apnea. We proposed the post-synaptic mechanisms underlying the modulation effect of histamine on hypoglossal motoneuron. Histamine activates the H1 Rs via PLC and IP3 , increases Ca(2+) releases from intracellular stores, promotes Na(+) influx and Ca(2+) efflux via the NCXs, and then produces an inward current and depolarizes the neurons. Histamine modulates the excitability of HMNs with other neuromodulators, such as noradrenaline, serotonin and orexin. We think that these findings should provide an important new direction for drug development for the treatment of obstructive sleep apnea. PMID:26811198

  20. In Vivo Imaging of Cerebral Serotonin Transporter and Serotonin(2A) Receptor Binding in 3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") and Hallucinogen Users

    DEFF Research Database (Denmark)

    Erritzoe, David; Frokjaer, Vibe G.; Holst, Klaus K.;

    2011-01-01

    assess the differential effects of MDMA and hallucinogen use on cerebral serotonin transporter (SERT) and serotonin(2A) receptor binding.Design: A positron emission tomography study of 24 young adult drug users and 21 nonusing control participants performed with carbon 11 (C-11)-labeled 3-amino-4-[2-[(di(methyl...

  1. Physiological significance of ECL-cell histamine.

    OpenAIRE

    Andersson, K.; Chen, D; Mattsson, H.; Sundler, F; Håkanson, R

    1998-01-01

    In the oxyntic mucosa of the mammalian stomach, histamine is stored in ECL cells and in mucosal mast cells. In the rat, at least 80 percent of oxyntic mucosal histamine resides in the ECL cells. Histamine is a key factor in the regulation of gastric acid secretion. Following depletion of ECL-cell histamine by treatment with alpha-fluoromethylhistidine (alpha-FMH), basal acid secretion was reduced, and gastrin-stimulated acid secretion was abolished. Vagally-induced acid secretion (by insulin ...

  2. Histamine, mast cells, and the enteric nervous system in the irritable bowel syndrome, enteritis, and food allergies

    OpenAIRE

    J D Wood

    2006-01-01

    There is altered expression of histamine H1 and H2 receptor subtypes in mucosal biopsies from the terminal ileum and large intestine of patients with symptoms of food allergy and/or irritable bowel syndrome

  3. Mass dose effects and in vivo affinity in brain PET receptor studies — a study of cerebral 5-HT4 receptor binding with [11C]SB207145

    International Nuclear Information System (INIS)

    Attention to tracer dose principles is crucial in positron emission tomography (PET), and deviations can induce serious errors. In this study, we devise a method for determining receptor occupancy of the mass dose of the radioligand itself and the in vivo affinity. Methods: The approach was used for [11C]SB207145, a new PET radioligand for imaging the cerebral 5-HT4 receptors in humans. Test–retest PET studies with varying specific activities of [11C]SB207145 were conducted in seven healthy subjects, and the output parameter regional BPND was modeled. Individual occupancy plots were first computed to estimate the mass dose that saturates 50% of receptors (ID50), and subsequently, the maximal mass dose that can be injected (arbitrarily set at an occupancy D. Results: Increasing the mass dose resulted in a decrease in BPND, whilst the relative cerebellar uptake was unchanged. The ID50 was 85.4±30.2 μg, and the upper mass dose limit was 4.5±1.6 μg, which does not require ultrahigh specific activity. The estimated in vivo KD was 2.8 nM (range 1.0–4.8), without any regional differences. Conclusion: The presented method for estimating the upper mass dose limit is suggested as part of validation of PET radioligands.

  4. Influence of apolipoprotein E and its receptors on cerebral amyloid precursor protein metabolism following traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    ZHOU Shuai; SUN Xiao-chuan

    2012-01-01

    Traumatic brain injury (TBI) is the leading cause of mortality and disability among young individuals in our society,and globally the incidence of TBI is rising sharply.Mounting evidence has indicated that apolipoprotein E (apoE:protein; APOE:gene) genotype influences the outcome after TBI.The proposed mechanism by which APOE affects the clinicopathological consequences of TBI is multifactorial and includes amyloid deposition,disruption of lipid distribution,dysfunction of mitochondrial energy production,oxidative stress and increases intracellular calcium in response to injury.This paper reviews the current state of knowledge regarding the influence of apoE and its receptors on cerebral amyloid betaprotein precursor metabolism following TBI.

  5. Mast cell-derived histamine mediates cystitis pain.

    Directory of Open Access Journals (Sweden)

    Charles N Rudick

    Full Text Available BACKGROUND: Mast cells trigger inflammation that is associated with local pain, but the mechanisms mediating pain are unclear. Interstitial cystitis (IC is a bladder disease that causes debilitating pelvic pain of unknown origin and without consistent inflammation, but IC symptoms correlate with elevated bladder lamina propria mast cell counts. We hypothesized that mast cells mediate pelvic pain directly and examined pain behavior using a murine model that recapitulates key aspects of IC. METHODS AND FINDINGS: Infection of mice with pseudorabies virus (PRV induces a neurogenic cystitis associated with lamina propria mast cell accumulation dependent upon tumor necrosis factor alpha (TNF, TNF-mediated bladder barrier dysfunction, and pelvic pain behavior, but the molecular basis for pelvic pain is unknown. In this study, both PRV-induced pelvic pain and bladder pathophysiology were abrogated in mast cell-deficient mice but were restored by reconstitution with wild type bone marrow. Pelvic pain developed normally in TNF- and TNF receptor-deficient mice, while bladder pathophysiology was abrogated. Conversely, genetic or pharmacologic disruption of histamine receptor H1R or H2R attenuated pelvic pain without altering pathophysiology. CONCLUSIONS: These data demonstrate that mast cells promote cystitis pain and bladder pathophysiology through the separable actions of histamine and TNF, respectively. Therefore, pain is independent of pathology and inflammation, and histamine receptors represent direct therapeutic targets for pain in IC and other chronic pain conditions.

  6. On the clinical impact of cerebral dopamine D2 receptor scintigraphy

    International Nuclear Information System (INIS)

    The present review describes findings and clinical indications for the dopamine D2 receptor scintigraphy. Methods for the examination of D2 receptors are positron emission tomography (PET) using 11C- or 18F-labelled butyrophenones or benzamides or single photon emission tomography (SPECT) using 123I-iodobenzamide (IBZM) respectively. The most important indication in neurology is the differential diagnosis of Parkinsonism: Patients with early Parkinson's disease show an increased D2 receptor binding (D2-RB) compared to control subjects. However, patients suffering from Steele-Richardson-Olszewski-Syndrome or Multiple System Atrophy show a decreased D2-RB and are generally non-responsive to treatment. Postsynaptic blockade of D2 receptors results in a drug induced Parkinsonian syndrome, which can be diagnosed by D2 scintigraphy. Further possible indications occur in psychiatry: The assessment of receptor occupancy is useful in schizophrenic patients treated with neuroleptics. Additionally, D2 receptor scintigraphy might help to clarify the differential diagnosis between neuroleptic malignant syndrome and lethal catatonia. The method might be useful for supervising neurobiochemical changes in drug dependency and during withdrawal. Assessment of dopamine D2 receptor binding can simplify the choice of therapy in depressive disorder: Patients showing a low D2 binding are likely to improve following an antidepressive drug treatment whereas sleep deprivation is promising in patients with high D2 binding. (orig.)

  7. Chemical neuroanatomy and in vitro receptor autoradiography: A basis for cerebral positron emission tomography

    International Nuclear Information System (INIS)

    We review chemical neuroanatomy and in vitro receptor (IVG) autoradiography as tools for the development of methods suitable for positron emission tomography (PET) studies. The organizations of monoaminergic, cholinergic, γ-aminobutyric acidergic (GABA), and excitatory amino acidergic (EAA) pathways within the central nervous system are summarized, as is the presently accepted classification of GABA and EAA receptors. We describe the technique of IVG and discuss its unique advantages for the selection of possible PET methods. Finally, we discuss receptor changes in Huntington's disease and olivopontocerebellar atrophy, two human diseases for which IVG has suggested possible targets for PET imaging

  8. PCP-induced alterations in cerebral glucose utilization in rat brain: blockade by metaphit, a PCP-receptor-acylating agent

    Energy Technology Data Exchange (ETDEWEB)

    Tamminga, C.A.; Tanimoto, K.; Kuo, S.; Chase, T.N.; Contreras, P.C.; Rice, K.C.; Jackson, A.E.; O' Donohue, T.L.

    1987-01-01

    The effects of phencyclidine (PCP) on regional cerebral glucose utilization was determined by using quantitative autoradiography with (/sup 14/C)-2-deoxyglucose. PCP increased brain metabolism in selected areas of cortex, particularly limbic, and in the basal ganglia and thalamus, whereas the drug decreased metabolism in areas related to audition. These results are consistent with the known physiology of central PCP neurons and may help to suggest brain areas involved in PCP-mediated actions. Moreover, based on the behavioral similarities between PCP psychosis and an acute schizophrenic episode, these data may be relevant to the understanding of schizophrenia. The PCP-receptor-acylating agent, metaphit, blocked most of these PCP actions. In addition, metaphit by itself was found to diminish glucose utilization rather uniformly throughout brain. These results indicate an antagonist effect of metaphit on the PCP system and suggest a widespread action of metaphit, putatively at a PCP-related site, possibly in connection with the N-methyl-D-aspartate (NMDA) receptor.

  9. Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3.

    Science.gov (United States)

    Dang, Jason; Tiwari, Shashi Kant; Lichinchi, Gianluigi; Qin, Yue; Patil, Veena S; Eroshkin, Alexey M; Rana, Tariq M

    2016-08-01

    Emerging evidence from the current outbreak of Zika virus (ZIKV) indicates a strong causal link between Zika and microcephaly. To investigate how ZIKV infection leads to microcephaly, we used human embryonic stem cell-derived cerebral organoids to recapitulate early stage, first trimester fetal brain development. Here we show that a prototype strain of ZIKV, MR766, efficiently infects organoids and causes a decrease in overall organoid size that correlates with the kinetics of viral copy number. The innate immune receptor Toll-like-Receptor 3 (TLR3) was upregulated after ZIKV infection of human organoids and mouse neurospheres and TLR3 inhibition reduced the phenotypic effects of ZIKV infection. Pathway analysis of gene expression changes during TLR3 activation highlighted 41 genes also related to neuronal development, suggesting a mechanistic connection to disrupted neurogenesis. Together, therefore, our findings identify a link between ZIKV-mediated TLR3 activation, perturbed cell fate, and a reduction in organoid volume reminiscent of microcephaly. PMID:27162029

  10. Centrally injected histamine increases posterior hypothalamic acetylcholine release in hemorrhage-hypotensive rats.

    Science.gov (United States)

    Altinbas, Burcin; Yilmaz, Mustafa S; Savci, Vahide; Jochem, Jerzy; Yalcin, Murat

    2015-01-01

    Histamine, acting centrally as a neurotransmitter, evokes a reversal of hemorrhagic hypotension in rats due to the activation of the sympathetic and the renin-angiotensin systems as well as the release of arginine vasopressin and proopiomelanocortin-derived peptides. We demonstrated previously that central nicotinic cholinergic receptors are involved in the pressor effect of histamine. The aim of the present study was to examine influences of centrally administrated histamine on acetylcholine (ACh) release at the posterior hypothalamus-a region characterized by location of histaminergic and cholinergic neurons involved in the regulation of the sympathetic activity in the cardiovascular system-in hemorrhage-hypotensive anesthetized rats. Hemodynamic and microdialysis studies were carried out in Sprague-Dawley rats. Hemorrhagic hypotension was induced by withdrawal of a volume of 1.5 ml blood/100 g body weight over a period of 10 min. Acute hemorrhage led to a severe and long-lasting decrease in mean arterial pressure (MAP), heart rate (HR), and an increase in extracellular posterior hypothalamic ACh and choline (Ch) levels by 56% and 59%, respectively. Intracerebroventricularly (i.c.v.) administered histamine (50, 100, and 200 nmol) dose- and time-dependently increased MAP and HR and caused an additional rise in extracellular posterior hypothalamic ACh and Ch levels at the most by 102%, as compared to the control saline-treated group. Histamine H1 receptor antagonist chlorpheniramine (50 nmol; i.c.v.) completely blocked histamine-evoked hemodynamic and extracellular posterior hypothalamic ACh and Ch changes, whereas H2 and H3/H4 receptor blockers ranitidine (50 nmol; i.c.v.) and thioperamide (50 nmol; i.c.v.) had no effect. In conclusion, centrally administered histamine, acting via H1 receptors, increases ACh release at the posterior hypothalamus and causes a pressor and tachycardic response in hemorrhage-hypotensive anesthetized rats. PMID:25468497

  11. The effects of crocin and safranal on the yawning induced by intracerebroventricular injection of histamine in rats

    Directory of Open Access Journals (Sweden)

    Mina Taati

    2016-06-01

    Full Text Available Objective: Crocin and safranal, as the major constituents of saffron, have many biological activities. This study investigated the effects of crocin and safranal on yawning response induced by intracerebroventricular (i.c.v. injection of histamine in rats. Materials and Methods: In ketamine/xylazine-anesthetized rats, a guide cannula was implanted in the right ventricle of the brain and yawning induced by i.c.v. injection of histamine. Crocin and safranal were intraperitoneally (i.p. injected alone and before i.c.v. injection of histamine. Results: Histamine at the doses of 10 and 20 µg/rat produced yawning. Mepyramine (a histamine H1 receptor antagonist 40 µg/rat significantly (p

  12. Gender and the use of hormonal contraception in women are not associated with cerebral cortical 5-HT 2A receptor binding

    DEFF Research Database (Denmark)

    Frokjaer, V G; Erritzoe, D; Madsen, J; Paulson, O B; Knudsen, G M

    2009-01-01

    Gender influences brain function including serotonergic neurotransmission, which may play a role in the well-known gender variations in vulnerability to mood and anxiety disorders. Even though hormonal replacement therapy in menopause is associated with globally increased cerebral 5-HT(2A) receptor...... binding it is not clear if gender or use of hormonal contraception exhibits associations with 5-HT(2A) receptor binding. We found no significant effect of gender on cortical 5-HT(2A) receptor binding (P=0.15, n=132). When adjusting for the personality trait neuroticism, known to be positively correlated...... to frontolimbic 5-HT(2A) receptor binding and to be more pronounced in women, again, the effect of gender was not significant (P=0.42, n=127). Also, the use of hormonal contraception (n=14) within the group of pre-menopausal women (total n=29) was not associated with cortical 5-HT(2A) receptor...

  13. In vivo experimental stroke and in vitro organ culture induce similar changes in vasoconstrictor receptors and intracellular calcium handling in rat cerebral arteries

    DEFF Research Database (Denmark)

    Povlsen, Gro Klitgaard; Waldsee, Roya; Ahnstedt, Hilda;

    2012-01-01

    and extracellular sources, whereas 5-HT(1B) receptor-mediated contraction was solely dependent on extracellular calcium. Organ culture and stroke increased basal intracellular calcium levels in MCA smooth muscle cells and decreased the expression of inositol triphosphate receptor and transient......)) receptors has been demonstrated after subarachnoid hemorrhage and global ischemic stroke, but the situation is less clear after focal ischemic stroke. Changes in smooth muscle calcium handling have been implicated in different vascular diseases but have not hitherto been investigated in cerebral arteries....... Intracellular calcium was measured by FURA-2. Expression and contractile functions of ET(B) and 5-HT(1B) receptors were strongly upregulated and slightly downregulated, respectively, 24 h after experimental stroke or organ culture. ET(B) receptor-mediated contraction was mediated by calcium from intracellular...

  14. Radioimmunometric analysis of histamine in myeloproliferative syndromes

    International Nuclear Information System (INIS)

    Quantitative analysis of histamine is increasingly used in clinical haematology. The present study demonstrates the properties of and potential indication for a novel histamine radioimmunoassay (RIA) in clinical haematology. The sensitivity of this test assay corresponds to a histamine level of 0,1 to 0,5 nM, the non-specific cross reaction with endogeneous histamine metabolites appears to be less than 0,1%. The total histamine levels in the peripheral blood of healthy donors (n = 10) ranged from 10 to 100 ng/ml, the plasma histamine values from 0,02 to 0,6 ng/ml blood. Increased levels of total histamine were measured in myeloproliferative syndromes, i.e. in patients with chronic myeloid leukemia (CML)(8 of 9), myelofibrosis (OMS)(2 of 4), and polycythaemia vera (PCV)(1 of 2). An excessive increase in total histamine was observed in healthy rhesus monkeys (n = 10) treated with recombinant human interleukin-3 (rhIL-3). The total histamine value correlated with the absolute number of circulating blood basophils (correlation coefficient: 0,9). The calculated content of histamine per basophil was found to be 0,5 to 1,5 pg. Plasma histamine values in patients suffering from myeloproliferative syndromes were within the normal range. In contrast, a moderate to marked increase in plasma histamine values was observed in monkeys during IL-3 treatment. The radioimmunometric analysis of histamine clearly represents a useful new test system in clinical haematology, especially in the follow up of malignant as well as IL-3-induced myeloproliferation. (Authors)

  15. Evaluation of radioiodinated C6-O- and N-iodoallyl analogues of diprenorphine as ligands for cerebral opioid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Lever, J.R.; Scheffel, U.; Stathis, M. [The Johns Hopkins Medical Institutions, Baltimore, MD (United States)] [and others

    1994-05-01

    Analogues of diprenorphine (DPN) having C6-O-iodoallyl (O-IA-DPN) and N-iodoallyl (N-IA-DPN) substituents can be I-125 labeled in good yield with high specific activity by radioiododestannylation. When tested in vitro against [H-3]-DPN in rat brain membranes, the apparent affinity (Ki) of O-IA-DPN (1.35 nM) proved 17-fold stronger than that of N-IA-DPN (23.4 nM). Against selective [H-3]-ligands, O-IA-DPN showed high apparent affinities for {mu}(1.9 nM), {gamma}(1.1 nM) and {kappa}(0.9 nM) sites. Consistent with the low apparent affinity in vitro, [I-125]-N-IA- DPN did not allow localization of cerebral opioid receptors after i.v. administration to mice. By contrast, [I-125]-O-IA-DPN exhibited a regional brain distribution which reflects binding to multiple opioid receptors. The highest radioactivity concentrations were in superior colliculi, hypothalamus, olfactory tubercles, thalamus and striatum. Peak levels (2.5-3.5 %ID/g) were maintained over the first 60 min. At all times, the lowest levels of radioactivity were in the cerebellum. Binding in vivo was saturable by O-IA-DPN, was blocked by (-)- but not by (+)-naloxone, and was inhibited by naltrexone in dose-dependent fashion. Specific binding was 83-93% for all tissues except cerebellum, where 50% blockade was noted with naltrexone (5.0 mg/kg). Using naltrexone blockade to define non-specific binding, the highest ratio of specific to non-specific binding (> 14 to 1) was noted for superior colliculi at 60 min. Inhibition studies with drugs selective for {mu}, {gamma} or {kappa} sites established that multiple opioid receptors are labeled. [123I]-O-IA-DPN has been prepared (84%, >2400 mCi/{mu}mol), and allows visualization of opioid receptors in mouse brain by ex vivo autoradiography. Together, these results suggest that [123I]-O-IA-DPN is suitable for SPECT studies of multiple opioid receptors.

  16. Electroacupuncture-Induced Neuroprotection against Cerebral Ischemia in Rats: Role of the Dopamine D2 Receptor

    Directory of Open Access Journals (Sweden)

    Ming-Shu Xu

    2013-01-01

    Full Text Available Background. Cerebral ischemia is known to produce brain damage and related behavioural deficits, including memory deficits and motor disorders. Evidence shows that EA significantly promotes recovery of neurological function and thus improves quality of life. Objective. Evidence exists for the involvement of catecholamines in human neuroplasticity. A better understanding of dopaminergic (DAergic modulation in this process will be important. Methods. A total of 72 adult male Sprague-Dawley (SD rats were divided into 6 groups: normal, model, EA, spiperone group, EA + spiperone group, and pergolide. The middle cerebral artery occlusion (MCAO model was used in all 6 groups except the normal group. A behavioural assessment was conducted at 1, 3, 5, and 7 days after MCAO. The percent of brain infarct area was also determined 7 days after MCAO. Tyrosine hydroxylase (TH and growth-associated protein 43 (GAP-43 fluorescence double labeling was performed in the striatum. Results. In this study, we found that EA at Fengchi (GB20 acupoints resulted in marked improvements based on a behavioural assessment. Both TTC staining and GAP-43 immunofluorescence labeling results showed that EA treatment reduced ischemia injury and promoted neuroplasticity compared with the model group. The D2R-selective agonist, pergolide, showed similar results, but these results were reversed by the D2R-selective antagonist, spiperone. We also found that there were more colocalization and expression of GAP-43 and TH in the EA and pergolide groups than those in the other groups. Conclusion. These results suggest that the neuroplasticity induced by EA was mediated by D2 autoreceptors in DAergic neurons.

  17. Epidermal growth factor-like repeats of tenascin-C-induced constriction of cerebral arteries via activation of epidermal growth factor receptors in rats.

    Science.gov (United States)

    Fujimoto, Masashi; Shiba, Masato; Kawakita, Fumihiro; Liu, Lei; Nakasaki, Asuka; Shimojo, Naoshi; Imanaka-Yoshida, Kyoko; Yoshida, Toshimichi; Suzuki, Hidenori

    2016-07-01

    Tenascin-C (TNC), one of matricellular proteins, has been suggested to be involved in cerebral vasospasm after aneurysmal subarachnoid hemorrhage. However, the mechanisms of how TNC constricts cerebral arteries remain unclear. The aim of this study was to examine if epidermal growth factor (EGF)-like repeats of TNC is involved in TNC-induced constriction of cerebral arteries in rats via EGF receptor (EGFR) activation. Two dosages of recombinant TNC (r-TNC) consisting of the EGF-like repeats was administered intracisternally to healthy rats, and its vasoconstrictor effects were evaluated by neurobehavioral tests and India-ink angiography at 24, 48, and 72 hours after the administration. Western blotting and immunohistochemistry were performed to explore the underlying mechanisms on constricted cerebral arteries after 24 hours. The effects of a selective EGFR tyrosine kinase inhibitor (AG1478) on r-TNC-induced vasoconstriction were evaluated by neurobehavioral tests, India-ink angiography and immunohistochemistry at 24 hours after the administration. A higher dosage of r-TNC induced cerebral arterial constriction more severely, which continued for 48 hours. The effects were associated with the activation of EGFR and extracellular signal-regulated kinase (ERK)1/2 in the smooth muscle cell layer of the constricted cerebral artery, while c-Jun N-terminal kinase and p38 were not activated. AG1478 blocked r-TNC-induced vasoconstrictive effects, as well as activation of EGFR and ERK1/2. These findings demonstrate that TNC induces constriction of cerebral arteries via activation of EGFR and ERK1/2. PMID:27086972

  18. Protective effect of delta opioid receptor agonist (D-Ala2, D-Leu5) enkephalin on permanent focal cerebral ischemia in rats.

    Science.gov (United States)

    Fu, Danyun; Liu, Haitong; Zhu, Hui; Li, Shitong; Yao, Junyan

    2016-07-01

    To investigate the effect of delta opioid receptor agonist (D-Ala, D-Leu) enkephalin (DADLE) on the permanent focal cerebral ischemia in rats. Thirty four male Sprague-Dawley rats were assigned randomly into three groups: sham group (group Sham, n=10), artificial cerebrospinal fluid group (group ACSF, n=12), and DADLE group (group DADLE, n=12). Permanent middle cerebral artery occlusion was performed to induce permanent focal cerebral ischemia in rats. Then, the animals in group DADLE and group ACSF were treated with DADLE or ACSF by an intracerebroventricular injection at 45 min after ischemia. Neurologic deficit scores were assessed according to the Garcia criterion at 24 h after ischemia. Infarct volume was determined using the 2,3,5-triphenyltetrazolium chloride staining method. The histological analysis was used to evaluate the extent of cerebral injury. Compared with the control group, the Garcia scores were significantly higher (P=0.000) and the infarct volumes (P=0.018) were significantly smaller in the DADLE treatment group at 24 h after ischemia. These neurologic changes were closely correlated with the outcome of the infarct volumes. In addition, the histological examination showed more intact neurons in rats treated with DADLE than those treated with ACSF at 24 h after ischemia (P=0.000). DADLE by intracerebroventricular administration at 45 min after ischemia can improve neurologic outcome and mitigate cortical neuronal injury induced by permanent focal cerebral ischemia in rats. PMID:27232517

  19. Histidine provides long-term neuroprotection after cerebral ischemia through promoting astrocyte migration

    OpenAIRE

    Ru-jia Liao; Lei Jiang; Rong-rong Wang; Hua-wei Zhao; Ying Chen; Ya Li; Lu Wang; Li-Yong Jie; Yu-dong Zhou; Xiang-nan Zhang; Zhong Chen; Wei-wei Hu

    2015-01-01

    The formation of glial scar impedes the neurogenesis and neural functional recovery following cerebral ischemia. Histamine showed neuroprotection at early stage after cerebral ischemia, however, its long-term effect, especially on glial scar formation, hasn’t been characterized. With various administration regimens constructed for histidine, a precursor of histamine, we found that histidine treatment at a high dose at early stage and a low dose at late stage demonstrated the most remarkable l...

  20. Effects of histamine and the histamine antagonists mepyramine and cimetidine on human coronary arteries in vitro.

    OpenAIRE

    Godfraind, Theophile; Miller, R C

    1983-01-01

    The effects of histamine have been studied on human isolated coronary artery preparations taken from hearts ranging in age from 9 to 73 years. Histamine in large concentrations (100 microM) contracted arteries which were without tone or spontaneous activity and sometimes induced rhythmic contractile activity. If spontaneous rhythmic activity was present it was enhanced by histamine. The contractile effects of histamine were inhibited by mepyramine but not by cimetidine. Arteries which were co...

  1. Histamine and duodenal ulcer: effect of omeprazole on gastric histamine in patients with duodenal ulcer.

    OpenAIRE

    Man, W K; Thompson, J. N.; Baron, J. H.; Spencer, J

    1986-01-01

    Gastric mucosal concentrations of histamine and of its metabolic enzyme, histamine methyltransferase activity, were measured in patients with duodenal ulcer disease and patients with an apparently normal stomach and duodenum. Patients with duodenal ulcer had significantly less (p less than 0.05) mucosal histamine (median 204 nmol/g) than control subjects (median 252 nmol/g). There was no significant difference between the two groups in their histamine methyltransferase activity values. Omepra...

  2. Effects of lead and mercury on histamine uptake by glial and endothelial cells

    International Nuclear Information System (INIS)

    The effects of lead and mercury on [3H]-histamine uptake by cultured astroglial and endothelial cells of rat brain were studied. Experimental data showed that both metal ions inhibited the uptake in both cell types of concentrations as low as 1-10 μM. The effects were consistent with non/competitive inhibitions. With either lead or mercury exposure, the inhibition of the uptake was greater in astroglial than in cerebral endothelial cells. Contrary to the above finding, 100 μM of mercuric chloride produced stimulation of histamine uptake and this stimulation was much more pronounced in cultured cerebral endothelial cells than in astroglial cells. Inhibition of [3H]-histamine uptake by lead acetate and mercuric chloride was considered to be association with a loss of the transmembrane Na+ and/or K+ gradient while stimulation of the uptake by high concentration of mercury might be related to a direct effect on histamine transporter. It is note-worthy, that cultured astroglial cells, derived from neonatal rat brain, are much more sensitive to the toxic effects of these heavy metal ions than cultured endothelial cells derived from the brain capillaries often same species of animals. (au) 18 refs

  3. Neuronal histamine decreases fat accumulation and up-regulates UCP family in db/db obese mice

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    To examine anti-obesity and-diabetic effects of neuronal histamine especially in leptin resistant states, we investigated the effects of chronic central treatment with histamine on lipid, glucose and energy metabolism of db/db obese mice, which are genetically leptin receptor mutated mice. Chronic centrally treatment with histamine (0.05 μmol*g-1 body weight*d-1 for 7 days) decreased body weight, food intake in db/db obese mice, and decreased body fat weight, serum concentration of glucose compared with pair-fed db/db obese mice. Neuronal histamine also suppressed ob mRNA in the white adipose tissue (WAT), serum leptin and increased UCPs mRNA expression in brown adipose tissue (BAT) and in WAT compared with pair-fed controls. These above effects of the histamine were attenuated in these mice with combination of targeted disruption of the histamine H1 receptor gene. In conclusion, neuronal histamine can regulate body fat deposition, serum glucose, leptin, BAT and WAT UCPs expression even in leptin insensitive db/db obese mice.

  4. The role of histamine in neurogenic inflammation

    OpenAIRE

    Rosa, A. C.; Fantozzi, R

    2013-01-01

    The term ‘neurogenic inflammation’ has been adopted to describe the local release of inflammatory mediators, such as substance P and calcitonin gene-related peptide, from neurons. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established. The aim of this review is to...

  5. Utilization of Superfused Cerebral Slices in Probing Muscarinic Receptor Autoregulation of Acetylcholine Release

    Czech Academy of Sciences Publication Activity Database

    Alquicer, Glenda; Doležal, Vladimír; El-Fakahany, E. E.

    New York: Springer, 2016 - (Mysliveček, J.; Jakubík, J.), s. 221-233. (Neuromethods. 107). ISBN 978-1-4939-2857-6 R&D Projects: GA ČR(CZ) GA14-05696S; GA MŠk(CZ) EE2.3.30.0025 Institutional support: RVO:67985823 Keywords : muscarinic receptors * acetylcholine release * autoregulation * superfusion Subject RIV: FH - Neurology

  6. Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits

    OpenAIRE

    Ramaekers, Vincent; Blau, N.; Sequeira, J.M.; Nassogne, M.-C.; Quadros, E.V.

    2007-01-01

    Reduced folate transport to the CNS was identified in two autism spectrum disorders, i.e., Rett syndrome and infantile low-functioning autism with neurological abnormalities. Twenty-five patients with early-onset low-functioning autism with or without neurological deficits, were evaluated for serum folate, cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF), and serum FR autoantibodies of the blocking type to determine the significance of folate receptor (FR) autoantibodies with respec...

  7. Recombinant T Cell Receptor Ligands Improve Outcome After Experimental Cerebral Ischemia

    OpenAIRE

    Akiyoshi, Kozaburo; Dziennis, Suzan; Palmateer, Julie; Ren, Xuefang; Vandenbark, Arthur A.; Offner, Halina; Herson, Paco S; Hurn, Patricia D.

    2011-01-01

    A key target for novel stroke therapy is the regulation of post-ischemic inflammatory mechanisms. Recent evidence emphasizes the role of T lymphocytes of differing subtypes in the evolution is ischemic brain damage. We have recently demonstrated the benefit of myelin antigen-specific immunodulatory agents known as recombinant T cell receptor ligands (RTLs) in a standard murine model of focal stroke. The aim of the current study was to extend this initial observation to RTL treatment in a ther...

  8. NK cell-mediated killing of AML blasts. Role of histamine, monocytes and reactive oxygen metabolites

    International Nuclear Information System (INIS)

    Blasts recovered from patients with acute myelogenous leukaemia (AML) were lysed by heterologeous natural killer (NK) cells treated with NK cell-activating cytokine-induced killing of AML blasts was inhibited by monocytes, recovered from peripheral blood by counterflow centrifugal elutriation. Histamine, at concentrations exceeding 0.1 μM, abrogated the monocyte-induced inhibition of NK cells; thereby, histamine and IL-2 or histamine and IFN-α synergistically induced NK cell-mediated destruction of AML blasts. The effect of histamine was completely blocked by the histamine H2-receptor (H2R) antagonist ranitidine but not by its chemical control AH20399AA. Catalase, a scavenger of reactive oxygen metabolites (ROM), reversed the monocyte-induced inhibition of NK cell-mediated killing of blast cells, indicating that the inhibitory signal was mediated by products of the respiratory burst of monocytes. It is concluded that (i) monocytes inhibit anti-leukemic properties of NK cells, (ii) the inhibition is conveyed by monocyte-derived ROM, and (iii) histamine reverses the inhibitory signal and, thereby, synergizes with NK cell-activating cytokines to induce killing of AML blasts. (au) 19 refs

  9. NK cell-mediated killing of AML blasts. Role of histamine, monocytes and reactive oxygen metabolites

    Energy Technology Data Exchange (ETDEWEB)

    Brune, M.; Mellqvist, U.H. [Sahlgren`s Univ. Hospital, Dept. of Medicine, Haematology Section, Goeteborg (Sweden); Hansson, M.; Hermodsson, S.; Hellstrand, K. [Sahlgren`s Univ. Hospital, Dept. of Virology, Goeteborg (Sweden)

    1996-10-01

    Blasts recovered from patients with acute myelogenous leukaemia (AML) were lysed by heterologeous natural killer (NK) cells treated with NK cell-activating cytokine-induced killing of AML blasts was inhibited by monocytes, recovered from peripheral blood by counterflow centrifugal elutriation. Histamine, at concentrations exceeding 0.1 {mu}M, abrogated the monocyte-induced inhibition of NK cells; thereby, histamine and IL-2 or histamine and IFN-{alpha} synergistically induced NK cell-mediated destruction of AML blasts. The effect of histamine was completely blocked by the histamine H2-receptor (H2R) antagonist ranitidine but not by its chemical control AH20399AA. Catalase, a scavenger of reactive oxygen metabolites (ROM), reversed the monocyte-induced inhibition of NK cell-mediated killing of blast cells, indicating that the inhibitory signal was mediated by products of the respiratory burst of monocytes. It is concluded that (i) monocytes inhibit anti-leukemic properties of NK cells, (ii) the inhibition is conveyed by monocyte-derived ROM, and (iii) histamine reverses the inhibitory signal and, thereby, synergizes with NK cell-activating cytokines to induce killing of AML blasts. (au) 19 refs.

  10. Immune-related intestinal Cl- secretion. I. Effect of histamine on the T84 cell line

    International Nuclear Information System (INIS)

    The mast cell mediator, histamine, induces a rapid and transient increase in chloride secretion across monolayers of the human colonic epithelial cell line, T84. Threshold stimulation occurred at 3 x 10-6 M histamine and a maximal effect at 10-4 M. The effect was reproduced by the H1 agonists 2-methylhistamine and 2-pyridylethylamine, but not by the H2 agonists 4-methylhistamine and dimaprit, suggesting the involvement of an H1 receptor. Additionally, histamine's action was inhibited by an H1 antagonist, diphenhydramine, but not by an H2 antagonist, cimetidine. Histamine treatment increased free cytosolic calcium levels, but not those of adenosine 3',5'-cyclic monophosphate (cAMP) or guanosine 3',5'-cyclic monophosphate (cGMP). The mechanism of chloride secretion induced by histamine resembled that of carbachol, in that both (1) were associated with an increase in free cytosolic calcium, (2) had a site of activation at a basolaterally localized K+ channel, and (3) were potentiated by both cAMP- and cGMP-mediated secretagogues. These results suggest that histamine may act as an intestinal secretagogue via direct interactions with epithelial cells

  11. Absence of histamine-induced itch in the African naked mole-rat and "rescue" by Substance P

    Directory of Open Access Journals (Sweden)

    Lewin Gary R

    2010-05-01

    Full Text Available Abstract Recent research has proposed a pathway in which sensory neurons expressing the capsaicin activated ion channel TRPV1 are required for histamine-induced itch and subsequent scratching behavior. We examined histamine-induced itch in the African naked mole-rat (Heterocephalus glaber and found that although naked mole-rats display innate scratching behavior, histamine was unable to evoke increased scratching as is observed in most mouse strains. Using calcium imaging, we examined the histamine sensitivity of naked mole-rat dorsal root ganglia (DRG neurons and identified a population of small diameter neurons activated by histamine, the majority of which are also capsaicin-sensitive. This suggested that naked mole-rat sensory neurons are activated by histamine, but that spinal dorsal horn processing of sensory information is not the same as in other rodents. We have previously shown that naked mole-rats naturally lack substance P (SP in cutaneous C-fibers, but that the neurokinin-1 receptor is expressed in the superficial spinal cord. This led us to investigate if SP deficiency plays a role in the lack of histamine-induced scratching in this species. After intrathecal administration of SP into the spinal cord we observed robust scratching behavior in response to histamine injection. Our data therefore support a model in which TRPV1-expressing sensory neurons are important for histamine-induced itch. In addition, we demonstrate a requirement for active, SP-induced post-synaptic drive to enable histamine sensitive afferents to drive itch-related behavior in the naked mole-rat. These results illustrate that it is altered dorsal horn connectivity of nociceptors that underlies the lack of itch and pain-related behavior in the naked mole-rat.

  12. Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling.

    Science.gov (United States)

    Thomas, Carissa M; Hong, Teresa; van Pijkeren, Jan Peter; Hemarajata, Peera; Trinh, Dan V; Hu, Weidong; Britton, Robert A; Kalkum, Markus; Versalovic, James

    2012-01-01

    Beneficial microbes and probiotic species, such as Lactobacillus reuteri, produce biologically active compounds that can modulate host mucosal immunity. Previously, immunomodulatory factors secreted by L. reuteri ATCC PTA 6475 were unknown. A combined metabolomics and bacterial genetics strategy was utilized to identify small compound(s) produced by L. reuteri that were TNF-inhibitory. Hydrophilic interaction liquid chromatography-high performance liquid chromatography (HILIC-HPLC) separation isolated TNF-inhibitory compounds, and HILIC-HPLC fraction composition was determined by NMR and mass spectrometry analyses. Histamine was identified and quantified in TNF-inhibitory HILIC-HPLC fractions. Histamine is produced from L-histidine via histidine decarboxylase by some fermentative bacteria including lactobacilli. Targeted mutagenesis of each gene present in the histidine decarboxylase gene cluster in L. reuteri 6475 demonstrated the involvement of histidine decarboxylase pyruvoyl type A (hdcA), histidine/histamine antiporter (hdcP), and hdcB in production of the TNF-inhibitory factor. The mechanism of TNF inhibition by L. reuteri-derived histamine was investigated using Toll-like receptor 2 (TLR2)-activated human monocytoid cells. Bacterial histamine suppressed TNF production via activation of the H(2) receptor. Histamine from L. reuteri 6475 stimulated increased levels of cAMP, which inhibited downstream MEK/ERK MAPK signaling via protein kinase A (PKA) and resulted in suppression of TNF production by transcriptional regulation. In summary, a component of the gut microbiome, L. reuteri, is able to convert a dietary component, L-histidine, into an immunoregulatory signal, histamine, which suppresses pro-inflammatory TNF production. The identification of bacterial bioactive metabolites and their corresponding mechanisms of action with respect to immunomodulation may lead to improved anti-inflammatory strategies for chronic immune-mediated diseases. PMID:22384111

  13. Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling.

    Directory of Open Access Journals (Sweden)

    Carissa M Thomas

    Full Text Available Beneficial microbes and probiotic species, such as Lactobacillus reuteri, produce biologically active compounds that can modulate host mucosal immunity. Previously, immunomodulatory factors secreted by L. reuteri ATCC PTA 6475 were unknown. A combined metabolomics and bacterial genetics strategy was utilized to identify small compound(s produced by L. reuteri that were TNF-inhibitory. Hydrophilic interaction liquid chromatography-high performance liquid chromatography (HILIC-HPLC separation isolated TNF-inhibitory compounds, and HILIC-HPLC fraction composition was determined by NMR and mass spectrometry analyses. Histamine was identified and quantified in TNF-inhibitory HILIC-HPLC fractions. Histamine is produced from L-histidine via histidine decarboxylase by some fermentative bacteria including lactobacilli. Targeted mutagenesis of each gene present in the histidine decarboxylase gene cluster in L. reuteri 6475 demonstrated the involvement of histidine decarboxylase pyruvoyl type A (hdcA, histidine/histamine antiporter (hdcP, and hdcB in production of the TNF-inhibitory factor. The mechanism of TNF inhibition by L. reuteri-derived histamine was investigated using Toll-like receptor 2 (TLR2-activated human monocytoid cells. Bacterial histamine suppressed TNF production via activation of the H(2 receptor. Histamine from L. reuteri 6475 stimulated increased levels of cAMP, which inhibited downstream MEK/ERK MAPK signaling via protein kinase A (PKA and resulted in suppression of TNF production by transcriptional regulation. In summary, a component of the gut microbiome, L. reuteri, is able to convert a dietary component, L-histidine, into an immunoregulatory signal, histamine, which suppresses pro-inflammatory TNF production. The identification of bacterial bioactive metabolites and their corresponding mechanisms of action with respect to immunomodulation may lead to improved anti-inflammatory strategies for chronic immune-mediated diseases.

  14. The effect of intracerebroventricular injection of histamine in visceral nociception induced by acetic acid in rats

    Directory of Open Access Journals (Sweden)

    Zanboori Ali

    2010-01-01

    Full Text Available Objective : This study was designed to investigate the role of brain histamine and H1 and H2 receptors in mediating the central perception of visceral pain in rats. Materials and Methods : In conscious rats implanted with a lateral brain ventricle cannula, the effect of intracerebroventricular (i.c.v. injection of histamine (2.5, 10, and 40 μg, and chlorpheniramine and ranitidine at the same doses of 5, 20, and 80 μg were investigated on visceral pain. Visceral nociception induced by intraperitoneal (i.p. injection of acetic acid (1 mL, 1%, and the number of complete abdominal wall muscle contractions accompanied with stretching of hind limbs (writhes were counted for 1 h. Results : Histamine at doses of 10 and 40 μg and chlorpheniramine and ranitidine at the same doses of 20 and 80 μg, significantly decreased the numbers of writhes (P < 0.05. Pretreatment with chlorpheniramine and ranitidine at the same dose of 80 μg, significantly prevented histamine (40 μg-induced antinociception (P < 0.05. Conclusion : The results of this study suggest that brain histamine may be involved in modulation of visceral antinociception through both central H 1 and H 2 receptors.

  15. ERK1/2 inhibition attenuates cerebral blood flow reduction and abolishes ET(B) and 5-HT(1B) receptor upregulation after subarachnoid hemorrhage in rat

    DEFF Research Database (Denmark)

    Beg, Saema A S; Hansen-Schwartz, Jacob A; Vikman, Petter J;

    2006-01-01

    Upregulation of endothelin B (ET(B)) and 5-hydroxytryptamine 1B (5-HT(1B)) receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulate......Upregulation of endothelin B (ET(B)) and 5-hydroxytryptamine 1B (5-HT(1B)) receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular signal......-regulated kinase (ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ET(B) and 5-HT(1B) receptor upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in...... with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ET(B) and 5-HT(1B) receptor messenger ribonucleic acid and protein levels compared with the SAH...

  16. Benzodiazepine receptor and cerebral blood flow in early Alzheimer's disease. SPECT study using 123I-Iomazenil and 123I-IMP

    International Nuclear Information System (INIS)

    This study was designed to investigate benzodiazepine receptors (BZR) and cerebral blood flow (CBF) in patients with early Alzheimer's disease. Imaging of BZR and measurement of CBF were performed by SPECT using 123I-Iomazenil (IMZ) and 123I-IMP respectively, in seven patients with early Alzheimer's disease and five patients with unilateral left cerebral infarction as controls. The values for the normal cerebral hemisphere (ratio to the contralateral cerebellum) in patients with cerebral infarction were adopted as control values. In patients with Alzheimer's disease, the CBF (ratio to cerebellum) decreased significantly in the frontal cortex and the parietal cortex compared with the control values. There was no significant difference in late IMZ SPECT counts (ratio to cerebellum) and washout (the ratio of late-to-early IMZ SPECT counts) between patients with Alzheimer's disease and the controls. However, the late IMZ SPECT counts and washout decreased in one patient with moderate dementia. There was a significant correlation between the severity of dementia and the late IMZ SPECT counts in the temporal cortex and the parietal cortex. These results suggest that benzodiazepine binding sites are relatively well preserved in patients with early Alzheimer's disease, and reduction of the CBF is caused by neuronal dysfunction rather than by neuronal loss. IMZ SPECT study is useful and necessary for clarifying the pathophysiological state in Alzheimer's disease. (author)

  17. Benzodiazepine receptor and cerebral blood flow in early Alzheimer`s disease. SPECT study using {sup 123}I-Iomazenil and {sup 123}I-IMP

    Energy Technology Data Exchange (ETDEWEB)

    Kitamura, Shin; Koshi, Yasuhiko; Komiyama, Tasuku; Sakayori, Osamu; Komaba, Yuichi; Ohyama, Masashi; Mishina, Masahiro; Tsuganesawa, Toshikazu; Terashi, Akiro [Nippon Medical School, Tokyo (Japan). First Hospital

    1996-01-01

    This study was designed to investigate benzodiazepine receptors (BZR) and cerebral blood flow (CBF) in patients with early Alzheimer`s disease. Imaging of BZR and measurement of CBF were performed by SPECT using {sup 123}I-Iomazenil (IMZ) and {sup 123}I-IMP respectively, in seven patients with early Alzheimer`s disease and five patients with unilateral left cerebral infarction as controls. The values for the normal cerebral hemisphere (ratio to the contralateral cerebellum) in patients with cerebral infarction were adopted as control values. In patients with Alzheimer`s disease, the CBF (ratio to cerebellum) decreased significantly in the frontal cortex and the parietal cortex compared with the control values. There was no significant difference in late IMZ SPECT counts (ratio to cerebellum) and washout (the ratio of late-to-early IMZ SPECT counts) between patients with Alzheimer`s disease and the controls. However, the late IMZ SPECT counts and washout decreased in one patient with moderate dementia. There was a significant correlation between the severity of dementia and the late IMZ SPECT counts in the temporal cortex and the parietal cortex. These results suggest that benzodiazepine binding sites are relatively well preserved in patients with early Alzheimer`s disease, and reduction of the CBF is caused by neuronal dysfunction rather than by neuronal loss. IMZ SPECT study is useful and necessary for clarifying the pathophysiological state in Alzheimer`s disease. (author).

  18. Cerebral 5-HT2A receptor binding is increased in patients with Tourette's syndrome

    DEFF Research Database (Denmark)

    Haugbøl, Steven; Pinborg, Lars H.; Regeur, Lisbeth; Hansen, Elsebet S.; Bolwig, Tom G.; Nielsen, Finn Årup; Svarer, Claus; Skovgaard, Lene T.; Knudsen, Gitte Moos

    2007-01-01

    Experimental and clinical data have suggested that abnormalities in the serotonergic neurotransmissions in frontal-subcortical circuits are involved in Tourette's syndrome. To test the hypothesis that the brain's 5-HT2A receptor binding is increased in patients with Tourette's syndrome, PET imaging...... was performed. Twenty adults with Tourette's syndrome and 20 healthy control subjects were investigated with PET-[18F]altanserin using a bolus-infusion protocol. Regions of interest were delineated automatically on co-registered MRI images, and partial volume-corrected binding parameters were...... extracted from the PET images. Comparison between control subjects and Tourette's syndrome patients showed increased specific [18F]altanserin binding, not only in the a-priori selected brain regions hypothesized to be involved in Tourette's syndrome, but also post-hoc analysis showed a global up...

  19. Inhaled histamine increases human lung mucociliary transport

    International Nuclear Information System (INIS)

    Histamine, a mediator of airways constriction, alters ciliary beat frequency, bronchial mucus production, and epithelial ion transport; and in dogs, increases mucociliary transport. To evaluate the effect of inhaled histamine on human tracheobronchial mucociliary clearance, the authors measured lung mucociliary clearance (LMC) and tracheal mucociliary transport rate (TMTR) in 5 healthy, nonsmoking subjects in a randomized, double-blind, cross-over study. The concentration of inhaled histamine which produced a 20% fall in FEV1 was established for each subject. On a separate day the subjects inhaled a 9 μm MMAD /sup 99m/Tc-Fe2O3 aerosol. LMC and TMTR were then measured for 2.5h using a gamma camera and a tracheal multidetector probe. Simultaneously, the subjects were challenged every 26 +/- 4 min with either PBS or histamine in PBS. The Fe2O3 retained after 24h for histamine (14.4 +/- 7.6%) and PBS studies (13.1 +/- 8.6%) indicated no difference in deposition of Fe2O3 (ANOVA). Fe2O3 clearance at 30 min was increased in the histamine studies (61 +/- 21% compared to the PBS studies (44 +/- 29%; p < 0.02, ANOVA)). TMTR was also increased with histamine (7.6 +/- 3.4 mm/min) compared to PBS (4.6 +/- 1.7 mm/min; p < 0.001, ANOVA). Results indicate an acute stimulatory effect of inhaled histamine on mucous transport in humans

  20. Histamine Immunoreactive Elements in the Central and Peripheral Nervous Systems of the Snail, Biomphalaria spp., Intermediate Host for Schistosoma mansoni.

    Directory of Open Access Journals (Sweden)

    Mohamed R Habib

    Full Text Available Histamine appears to be an important transmitter throughout the Animal Kingdom. Gastropods, in particular, have been used in numerous studies establishing potential roles for this biogenic amine in the nervous system and showing its involvement in the generation of diverse behaviours. And yet, the distribution of histamine has only previously been described in a small number of molluscan species. The present study examined the localization of histamine-like immunoreactivity in the central and peripheral nervous systems of pulmonate snails of the genus Biomphalaria. This investigation demonstrates immunoreactive cells throughout the buccal, cerebral, pedal, left parietal and visceral ganglia, indicative of diverse regulatory functions in Biomphalaria. Immunoreactivity was also present in statocyst hair cells, supporting a role for histamine in graviception. In the periphery, dense innervation by immunoreactive fibers was observed in the anterior foot, perioral zone, and other regions of the body wall. This study thus shows that histamine is an abundant transmitter in these snails and its distribution suggest involvement in numerous neural circuits. In addition to providing novel subjects for comparative studies of histaminegic neurons in gastropods, Biomphalaria is also the major intermediate host for the digenetic trematode parasite, which causes human schistosomiasis. The study therefore provides a foundation for understanding potential roles for histamine in interactions between the snail hosts and their trematode parasites.

  1. Inhibition of P2X7 receptor ameliorates transient global cerebral ischemia/reperfusion injury via modulating inflammatory responses in the rat hippocampus

    Directory of Open Access Journals (Sweden)

    Chu Ketan

    2012-04-01

    Full Text Available Abstract Background Neuroinflammation plays an important role in cerebral ischemia/reperfusion (I/R injury. The P2X7 receptor (P2X7R has been reported to be involved in the inflammatory response of many central nervous system diseases. However, the role of P2X7Rs in transient global cerebral I/R injury remains unclear. The purpose of this study is to determine the effects of inhibiting the P2X7R in a rat model of transient global cerebral I/R injury, and then to explore the association between the P2X7R and neuroinflammation after transient global cerebral I/R injury. Methods Immediately after infusion with the P2X7R antagonists Brilliant blue G (BBG, adenosine 5′-triphosphate-2′,3′-dialdehyde (OxATP or A-438079, 20 minutes of transient global cerebral I/R was induced using the four-vessel occlusion (4-VO method in rats. Survival rate was calculated, neuronal death in the hippocampal CA1 region was observed using H & E staining, and DNA cleavage was observed by deoxynucleotidyl transferase-mediated UTP nick end labeling TUNEL. In addition, behavioral deficits were measured using the Morris water maze, and RT-PCR and immunohistochemical staining were performed to measure the expression of IL-1β, TNF-α and IL-6, and to identify activated microglia and astrocytes. Results The P2X7R antagonists protected against transient global cerebral I/R injury in a dosage-dependent manner. A high dosage of BBG (10 μg and A-0438079 (3 μg, and a low dosage of OxATP (1 μg significantly increased survival rates, reduced I/R-induced learning memory deficit, and reduced I/R-induced neuronal death, DNA cleavage, and glial activation and inflammatory cytokine overexpression in the hippocampus. Conclusions Our study indicates that inhibiting P2X7Rs protects against transient global cerebral I/R injury by reducing the I/R-induced inflammatory response, which suggests inhibition of P2X7Rs may be a promising therapeutic strategy for clinical treatment of

  2. Cerebrovascular endothelin-1 hyper-reactivity is associated with transient receptor potential canonical channels 1 and 6 activation and delayed cerebral hypoperfusion after forebrain ischaemia in rats

    DEFF Research Database (Denmark)

    Johansson, S E; Andersen, X E D R; Hansen, R H;

    2015-01-01

    the vascular smooth muscle cells was enhanced and correlated with decreased cerebral blood flow two days after forebrain ischaemia. Furthermore, under conditions when voltage-dependent calcium channels were inhibited, endothelin-1-induced cerebrovascular contraction was enhanced and this enhancement......AIM: In this study, we aimed to investigate whether changes in cerebrovascular voltage-dependent calcium channels and non-selective cation channels contribute to the enhanced endothelin-1-mediated vasoconstriction in the delayed hypoperfusion phase after experimental transient forebrain ischaemia...... arteries from ischaemic or sham-operated rats to evaluate changes in vascular voltage-dependent calcium channels, transient receptor potential canonical channels as well as endothelin-1 receptor function and expression. RESULTS: The expression of transient receptor potential canonical channels 1 and 6 in...

  3. Cerebral 5-HT2A receptor and serotonin transporter binding in humans are not affected by the val66met BDNF polymorphism status or blood BDNF levels

    DEFF Research Database (Denmark)

    Klein, Anders Bue; Trajkovska, Viktorija; Erritzoe, David; Haugbol, Steven; Madsen, Jacob; Baaré, William; Aznar, Susana; Knudsen, Gitte M

    2010-01-01

    Recent studies have proposed an interrelation between the brain-derived neurotrophic factor (BDNF) val66met polymorphism and the serotonin system. In this study, we investigated whether the BDNF val66met polymorphism or blood BDNF levels are associated with cerebral 5-hydroxytryptamine 2A (5-HT(2A...... BDNF polymorphism status is not associated with changes in the serotonergic system. Moreover, BDNF levels in blood do not correlate with either 5-HT(2A) or SERT binding.......)) receptor or serotonin transporter (SERT) binding in healthy subjects. No statistically significant differences in 5-HT(2A) receptor or SERT binding were found between the val/val and met carriers, nor were blood BDNF values associated with SERT binding or 5-HT(2A) receptor binding. In conclusion, val66met...

  4. Effect of histamine and H1- and H2-agonists on the fractional outflow of radioactivity from the rat vas deferens and preloaded with [3H]-noradrenaline

    International Nuclear Information System (INIS)

    Histamine and relatively selective H1- and H2-receptor agonists caused a concentration-dependent increase in the fractional outflow of radioactivity from the rat isolated vas deferens preloaded with labelled noradrenaline. The evoked fractional outflow of radioactivity was not preferentially associated with either H1- or H2-selective agonists, nor was it related to the known potencies of the agonists within each group. The evoked fractional outflow caused by all compounds studied was independent of the extracellular Ca2+ concentration. The study cautions against ascribing all the effects of histamine analogs to their respective histamine receptor stimulation

  5. The effects of histamine and prostaglandin D2 on rat mast-cell cyclic AMP and mediator release

    International Nuclear Information System (INIS)

    The possibility that histamine may play a functional role in modulating mast-cell secretion, as has been suggested for basophil degranulation, has both physiologic and pharmacologic implications. Therefore the capacity of histamine to influence rat peritoneal mast-cell (RPMC) cyclic AMP levels and reversed anaphylatic degranulation as reflected in the release of 3H-serotonin (5-HT) was examined. To ascertain that RPMC were functionally responsive to exogenous hormonal stimulation, assessment of prostaglandin (PG) D2 effects on cyclic AMP and 5-HT release were determined in parallel. Although PGD2 (100 microM) increased cyclic AMP and inhibited 5-HT release in the presence of 50 microM aminophylline, histamine (up to 1000 microM) was ineffective was ineffective in both. However, 1000 microM histamine in the presence of 500 microM aminophylline was capable of transiently increasing RPMC cyclic AMP (for 15 to 30 sec) and under these conditions of suppressing 5-HT release. The receptor subtype involved in the suppressive actions of histamine appeared to be of the H-1 type as reflected in the capacity of specific H-1 agonists to reproduce the inhibition of 5-HT release, whereas neither H-2 agonists nor H-2 antagonists had any influence. Thus, under conditions in which phosphodiesterase enzymatic action is impaired, histamine in extremely high concentrations is able to modulate mast-cell secretion. However, it seems very unlikely that this action of histamine has any physiologic significance

  6. Behavioural activation system sensitivity is associated with cerebral μ-opioid receptor availability.

    Science.gov (United States)

    Karjalainen, Tomi; Tuominen, Lauri; Manninen, Sandra; Kalliokoski, Kari K; Nuutila, Pirjo; Jääskeläinen, Iiro P; Hari, Riitta; Sams, Mikko; Nummenmaa, Lauri

    2016-08-01

    The reinforcement-sensitivity theory proposes that behavioural activation and inhibition systems (BAS and BIS, respectively) guide approach and avoidance behaviour in potentially rewarding and punishing situations. Their baseline activity presumably explains individual differences in behavioural dispositions when a person encounters signals of reward and harm. Yet, neurochemical bases of BAS and BIS have remained poorly understood. Here we used in vivo positron emission tomography with a µ-opioid receptor (MOR) specific ligand [(11)C]carfentanil to test whether individual differences in MOR availability would be associated with BAS or BIS. We scanned 49 healthy subjects and measured their BAS and BIS sensitivities using the BIS/BAS scales. BAS but not BIS sensitivity was positively associated with MOR availability in frontal cortex, amygdala, ventral striatum, brainstem, cingulate cortex and insula. Strongest associations were observed for the BAS subscale 'Fun Seeking'. Our results suggest that endogenous opioid system underlies BAS, and that differences in MOR availability could explain inter-individual differences in reward seeking behaviour. PMID:27053768

  7. Effect of antihistamines, disodium cromoglycate (DSCG) or methysergide on post-irradiation cerebral blood flow and mean systemic arterial blood pressure in primates after 25 Gy, whole-body, gamma irradiation

    International Nuclear Information System (INIS)

    Exposure to ionizing radiation causes hypotension, cerebral ischemia and release of histamine (HA) and serotonin (5-HT). To investigate the relationship among these responses, rhesus monkeys (Macaca mulatta) received physiological saline (i.v.), disodium cromoglycate (DSCG), antihistamines (AH, mepyramine and cimetidine), or methysergide (METH), then were given 25 Gy whole-body irradiation. Monkeys receiving DSCG, AH or METH had higher post-irradiation mean arterial blood pressure (MBP) than saline-treated controls. Compared to levels in controls, post-irradiation hippocampal blood flow (rCBF) levels were higher in monkeys receiving DSCG, AH or METH. Treatment with the 5-HT2 receptor antagonist methysergide was the most effective in maintaining both rCBF and MBP after irradiation. Results support the hypothesis that the irradiation-induced cerebral ischemia and, to some extent, the hypotension is mediated by serotonin through 5-HT2 receptor sites. (author) 72 refs

  8. Effect of antihistamines, disodium cromoglycate (DSCG) or methysergide on post-irradiation cerebral blood flow and mean systemic arterial blood pressure in primates after 25 Gy, whole-body, gamma irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Cockerham, L.G.; Forcino, C.D. [Armed Forces Radiobiology Research Inst., Bethesda, MD (United States)

    1995-06-01

    Exposure to ionizing radiation causes hypotension, cerebral ischemia and release of histamine (HA) and serotonin (5-HT). To investigate the relationship among these responses, rhesus monkeys (Macaca mulatta) received physiological saline (i.v.), disodium cromoglycate (DSCG), antihistamines (AH, mepyramine and cimetidine), or methysergide (METH), then were given 25 Gy whole-body irradiation. Monkeys receiving DSCG, AH or METH had higher post-irradiation mean arterial blood pressure (MBP) than saline-treated controls. Compared to levels in controls, post-irradiation hippocampal blood flow (rCBF) levels were higher in monkeys receiving DSCG, AH or METH. Treatment with the 5-HT{sub 2} receptor antagonist methysergide was the most effective in maintaining both rCBF and MBP after irradiation. Results support the hypothesis that the irradiation-induced cerebral ischemia and, to some extent, the hypotension is mediated by serotonin through 5-HT{sub 2} receptor sites. (author) 72 refs.

  9. Gastrointestinal histamine and histamine formation capacity after gastric irradiation in mice

    International Nuclear Information System (INIS)

    Mice were exposed to a single dose of 9 or 15 Gy of X rays directed to the stomach. After 9 Gy, mean gastric mural histamine fell to 61% of the control value 7 days after irradiation while HFC rose to 172%. Histamine and HFC returned to control values within 2 weeks of irradiation. With 15 Gy, on Day 7, histamine fell to 46%, HFC rose to 260%. Histamine concentration remained low (less than half control value) while HFC returned to normal. These dose-dependent changes in histamine were observed neither elsewhere in the gut nor in circulating blood. Further groups were exposed to 3, 6, 9 or 15 Gy to the stomach, with gastric histamine and HFC assayed on Day 7. Histamine concentration was inversely related to dose and HFC was directly dose dependent. These results suggest that irradiation of the stomach may reduce gastric histamine without inducing a general histamine release. Depletion of the gastric histamine store may explain the inhibitory effect of irradiation of the stomach on gastric acid secretion. (author)

  10. Demethylation of Circulating Estrogen Receptor Alpha Gene in Cerebral Ischemic Stroke.

    Directory of Open Access Journals (Sweden)

    Hsiu-Fen Lin

    Full Text Available Estrogen is involved in neuron plasticity and can promote neuronal survival in stroke. Its actions are mostly exerted via estrogen receptor alpha (ERα. Previous animal studies have shown that ERα is upregulated by DNA demethylation following ischemic injury. This study investigated the methylation levels in the ERα promoter in the peripheral blood of ischemic stroke patients.The study included 201 ischemic stroke patients, and 217 age- and sex-comparable healthy controls. The quantitative methylation level in the 14 CpG sites of the ERα promoter was measured by pyrosequencing in each participant. Multivariate regression model was used to adjust for stroke traditional risk factors. Stroke subtypes and sex-specific analysis were also conducted.The results demonstrated that the stroke cases had a lower ERα methylation level than controls in all 14 CpG sites, and site 13 and site 14 had significant adjusted p-values of 0.035 and 0.026, respectively. Stroke subtypes analysis showed that large-artery atherosclerosis and cardio-embolic subtypes had significantly lower methylation levels than the healthy controls at CpG site 5, site 9, site 12, site 13 and site 14 with adjusted p = 0.039, 0.009, 0.025, 0.046 and 0.027 respectively. However, the methylation level for the patients with small vessel subtype was not significant. We combined the methylation data from the above five sites for further sex-specific analysis. The results showed that the significant association only existed in women (adjusted p = 0.011, but not in men (adjusted p = 0.300.Female stroke cases have lower ERα methylation levels than those in the controls, especially in large-artery and cardio-embolic stroke subtypes. The study implies that women suffering from ischemic stroke of specific subtype may undergo different protective mechanisms to reduce the brain injury.

  11. UVB-induced systemic immunosuppression: role of mast cells and histamine

    International Nuclear Information System (INIS)

    Full text: UVB radiation (290-320 nm) is immunosuppressive by multiple mechanisms allowing the outgrowth of UV-induced tumours in both mouse and man. Furthermore, patients with non-melanoma skin cancers have a higher risk of death from other cancers which could be explained by UV-induced immunomodulation. The mechanism(s) of suppression by UVB depend on whether the sensitising antigen is applied to the irradiated site ('local') or to non-irradiated sites ('systemic'). In the former, the activity of UV-induced TNFα is important as it affects the migration of Langerhans cells to draining lymph nodes. In contrast, histamine from dermal mast cells is critical to the early events by which UVB can suppress systemic immune responses. The prevalence of dermal mast cells in 7 strains and substrains of mice correlates directly with their susceptibility to UVB-induced systemic immunosuppression. Furthermore, mast cell depleted mice (Wf/Wf) are resistant to UVB-induced systemic immunomodulation. However, they become susceptible after reconstitution of the site to be irradiated with bone marrow derived mast cell precursors. The mice also gain susceptibility to cis-urocanic acid-induced systemic immunomodulation. There is considerable evidence that histamine is the mast cell product critical to downstream immunosuppressive events. Firstly, physiological concentrations of histamine suppress contact hypersensitivity responses. Secondly, histamine receptor antagonists halve UVB-induced systemic immunosuppression. Thirdly, mice with different UVB-susceptibilities are equally susceptible to histamine-induced immunosuppression, and finally, histamine can suppress contact hypersensitivity responses in Wf/Wf mice. We suggest that histamine may be immunomodulatory by multiple pathways. Histamine can induce the production of immunosuppressive prostanoids from keratinocytes. A lymphocyte-derived, histamine-induced suppressor factor was reported in the 1970's. More recently histamine has

  12. Functional modulation of cerebral gamma-aminobutyric acidA receptor/benzodiazepine receptor/chloride ion channel complex with ethyl beta-carboline-3-carboxylate: Presence of independent binding site for ethyl beta-carboline-3-carboxylate

    Energy Technology Data Exchange (ETDEWEB)

    Taguchi, J.; Kuriyama, K. (Kyoto Prefectural Univ. of Medicine (Japan))

    1990-05-01

    Effect of ethyl beta-carboline-3-carboxylate (beta-CCE) on the function of gamma-aminobutyric acid (GABA)A receptor/benzodiazepine receptor/chloride ion channel complex was studied. Beta-CCE noncompetitively and competitively inhibited (3H)flunitrazepam binding to benzodiazepine receptor, but not (3H)muscimol binding to GABAA receptor as well as t-(3H)butylbicycloorthobenzoate (( 3H) TBOB) binding to chloride ion channel, in particulate fraction of the mouse brain. Ro15-1788 also inhibited competitively (3H) flunitrazepam binding. On the other hand, the binding of beta-(3H)CCE was inhibited noncompetitively and competitively by clonazepam and competitively by Ro15-1788. In agreement with these results, benzodiazepines-stimulated (3H)muscimol binding was antagonized by beta-CCE and Ro15-1788. Gel column chromatography for the solubilized fraction from cerebral particulate fraction by 0.2% sodium deoxycholate (DOC-Na) in the presence of 1 M KCl indicated that beta-(3H)CCE binding site was eluted in the same fraction (molecular weight, 250,000) as the binding sites for (3H)flunitrazepam, (3H)muscimol and (3H)TBOB. GABA-stimulated 36Cl- influx into membrane vesicles prepared from the bovine cerebral cortex was stimulated and attenuated by flunitrazepam and beta-CCE, respectively. These effects of flunitrazepam and beta-CCE on the GABA-stimulated 36Cl- influx were antagonized by Ro15-1788. The present results suggest that the binding site for beta-CCE, which resides on GABAA receptor/benzodiazepine receptor/chloride ion channel complex, may be different from that for benzodiazepine. Possible roles of beta-CCE binding site in the allosteric inhibitions on benzodiazepine binding site as well as on the functional coupling between chloride ion channel and GABAA receptor are also suggested.

  13. Functional modulation of cerebral gamma-aminobutyric acidA receptor/benzodiazepine receptor/chloride ion channel complex with ethyl beta-carboline-3-carboxylate: Presence of independent binding site for ethyl beta-carboline-3-carboxylate

    International Nuclear Information System (INIS)

    Effect of ethyl beta-carboline-3-carboxylate (beta-CCE) on the function of gamma-aminobutyric acid (GABA)A receptor/benzodiazepine receptor/chloride ion channel complex was studied. Beta-CCE noncompetitively and competitively inhibited [3H]flunitrazepam binding to benzodiazepine receptor, but not [3H]muscimol binding to GABAA receptor as well as t-[3H]butylbicycloorthobenzoate [( 3H] TBOB) binding to chloride ion channel, in particulate fraction of the mouse brain. Ro15-1788 also inhibited competitively [3H] flunitrazepam binding. On the other hand, the binding of beta-[3H]CCE was inhibited noncompetitively and competitively by clonazepam and competitively by Ro15-1788. In agreement with these results, benzodiazepines-stimulated [3H]muscimol binding was antagonized by beta-CCE and Ro15-1788. Gel column chromatography for the solubilized fraction from cerebral particulate fraction by 0.2% sodium deoxycholate (DOC-Na) in the presence of 1 M KCl indicated that beta-[3H]CCE binding site was eluted in the same fraction (molecular weight, 250,000) as the binding sites for [3H]flunitrazepam, [3H]muscimol and [3H]TBOB. GABA-stimulated 36Cl- influx into membrane vesicles prepared from the bovine cerebral cortex was stimulated and attenuated by flunitrazepam and beta-CCE, respectively. These effects of flunitrazepam and beta-CCE on the GABA-stimulated 36Cl- influx were antagonized by Ro15-1788. The present results suggest that the binding site for beta-CCE, which resides on GABAA receptor/benzodiazepine receptor/chloride ion channel complex, may be different from that for benzodiazepine. Possible roles of beta-CCE binding site in the allosteric inhibitions on benzodiazepine binding site as well as on the functional coupling between chloride ion channel and GABAA receptor are also suggested

  14. A mixture of anatase and rutile TiO2 nanoparticles induces histamine secretion in mast cells

    Directory of Open Access Journals (Sweden)

    Chen Eric Y

    2012-01-01

    Full Text Available Abstract Background Histamine released from mast cells, through complex interactions involving the binding of IgE to FcεRI receptors and the subsequent intracellular Ca2+ signaling, can mediate many allergic/inflammatory responses. The possibility of titanium dioxide nanoparticles (TiO2 NPs, a nanomaterial pervasively used in nanotechnology and pharmaceutical industries, to directly induce histamine secretion without prior allergen sensitization has remained uncertain. Results TiO2 NP exposure increased both histamine secretion and cytosolic Ca2+ concentration ([Ca2+]C in a dose dependent manner in rat RBL-2H3 mast cells. The increase in intracellular Ca2+ levels resulted primarily from an extracellular Ca2+ influx via membrane L-type Ca2+ channels. Unspecific Ca2+ entry via TiO2 NP-instigated membrane disruption was demonstrated with the intracellular leakage of a fluorescent calcein dye. Oxidative stress induced by TiO2 NPs also contributed to cytosolic Ca2+ signaling. The PLC-IP3-IP3 receptor pathways and endoplasmic reticulum (ER were responsible for the sustained elevation of [Ca2+]C and histamine secretion. Conclusion Our data suggests that systemic circulation of NPs may prompt histamine release at different locales causing abnormal inflammatory diseases. This study provides a novel mechanistic link between environmental TiO2 NP exposure and allergen-independent histamine release that can exacerbate manifestations of multiple allergic responses.

  15. Effects of histamine and its antagonists on murine T-cells and bone marrow-derived dendritic cells

    Directory of Open Access Journals (Sweden)

    Hu XF

    2015-08-01

    Full Text Available Xiufen Hu,1,* Mohammad Ishraq Zafar,2,* Feng Gao2 1Department of Paediatrics, Tongji Hospital, 2Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China *These authors contributed equally to this work Abstract: We determined the effects of histamine and its antagonists on the surface marker expression of dendritic cells (DCs and the influence of lipopolysaccharide (LPS, histamine, and histamine receptor antagonists on DCs and T-cells. The bone marrow was extracted from the femurs and tibiae of 6- to 8-week-old female Balb/c mice and cultured in medium containing penicillin, streptomycin, L-glutamine, fetal calf serum, or granulocyte macrophage colony-stimulating factor (GM-CSF alone or with interleukin (IL-4. The cells received three different doses of LPS and histamine, plus three different doses of descarboethoxyloratadine (DCL. We assayed the supernatant for various cytokines. The spleen cells of DO11.10 mice were examined by flow cytometry, which included labeling and sorting CD4+ T-cells, as well as coculture of DCs and T-cells with ovalbumin (OVA323–339 peptide. Histamine or histamine plus DCL did not affect the expression of major histocompatibility complex class II, CD11c, CD11b, CD86, and CD80. However, GM-CSF increased the expression of all markers except CD80. Histamine increased interferon-γ production in GM-CSF + IL-4-cultured cells; it also enhanced IL-10 production, but suppressed IL-12 production in LPS-stimulated DCs with no DCL. Cimetidine inhibited IL-10 production and restored IL-12 secretion in LPS-treated DCs. LPS increased IL-10 and decreased IL-12 levels. GM-CSF + IL-4-generated DCs had a stronger stimulatory effect on DO11.10 T-cell proliferation than GM-CSF-generated DCs. Inducible costimulator ligand expression was higher in GM-CSF + IL-4- than in GM-CSF-generated DC groups after 2 days of coculture, but decreased 4 days

  16. Involvement of δ-and μ-opioid receptors in the delayed cerebral ischemic tolerance induced by repeated electroacupuncture preconditioning in rats

    Institute of Scientific and Technical Information of China (English)

    XIONG Li-ze; YANG Jing; WANG Qiang; LU Zhi-hong

    2007-01-01

    Background Preconditioning with repeated electroacupuncture (EA) could mimic ischemic preconditioning to induce cerebral ischemic tolerance in rats. The present study was designed to investigate whether mu(μ)-, delta(δ)- or kappa(κ)-opioid receptors are involved in the neuroprotection induced by repeated EA preconditioning.Methods The rats were pretreated with naltrindole (NTI), nor-binaltorphimine (nor-BNI) or D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), which is a highly selective δ-, κ- or μ-opioid receptor antagonist respectively, before each EA preconditioning (30 minutes per day, 5 days). Twenty-four hours after the last EA treatment, the middle cerebral artery occlusion (MCAO) was induced for 120 minutes. The brain infarct volume was determined with 2,3,5-triphenyltetrazolium chloride staining at 24 hours after MCAO and compared with that in rats which only received EA preconditioning. In another experiment, the met-enkephalin-like immunoreactivity in rat brain was investigated by immunohistochemistry in both EA preconditioning and control rats.Results The EA preconditioning reduced brain infarct volume compared with the control rats (P=0.000). Administration of both NTI and CTOP attenuated the brain infarct volume reduction induced by EA preconditioning, presenting with larger infarct volume than that in the EA preconditioning rats (P<0.001). But nor-BNI administration did not block the infarct volume reduction induced by EA preconditioning, presenting with smaller infarct volume than the control group rats(P=0.000). The number of met-enkephalin-like immunoreactivity positive neurons in the EA preconditioning rats was more than that of the control rats (P=0.000).Conclusion Repeated EA preconditioning stimulates the release of enkephalins, which may bind δ- and μ-opioid receptors to induce the tolerance against focal cerebral ischemia.

  17. Implicación del sistema cerebral del estrés en la dependencia de morfina: papel de los receptores de CRF y glucocorticoides

    OpenAIRE

    Navarro Zaragoza, Javier

    2012-01-01

    El síndrome de abstinencia a sustancias de abuso activa el sistema cerebral del estrés, que está formado por el eje hipotálamo-hipófisis-adrenal (HHA) y por la amígdala extendida. Ambas estructuras tienen como neurotransmisor principal el factor liberador de corticotropina (CRF). El CRF se une a los receptores CRF1 y CRF2 en la adenohipófisis y provoca la liberación de ACTH que produce liberación de glucocorticoides desde las adrenales. Es conocido que durante el síndrome de abstinencia a mor...

  18. Increased concentrations of interleukin-6 and interleukin-1 receptor antagonist and decreased concentrations of beta-2-glycoprotein I in Gambian children with cerebral malaria

    DEFF Research Database (Denmark)

    Jakobsen, P H; McKay, V; Morris-Jones, S D; McGuire, W; van Hensbroek, M B; Meisner, S; Bendtzen, K; Schousboe, I; Bygbjerg, I C; Greenwood, B M

    1994-01-01

    To investigate the pathogenic versus the protective role of cytokines and toxin-binding factors in Plasmodium falciparum infections, we measured the concentrations of tumor necrosis factor alpha, interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-1 receptor antagonist, and IL-6, as well as soluble...... concentrations of anti-PI antibodies and the PI-binding serum protein beta-2-glycoprotein I. We found increased concentrations of IL-6, sIL-6R, IL-1ra, and some immunoglobulin M antibodies against PI in children with cerebral malaria, but those who died had decreased concentrations of beta-2-glycoprotein I. We...

  19. Growth of cultured human glioma tumour cells can be regulated with histamine and histamine antagonists.

    OpenAIRE

    Van der Ven, L. T.; Prinsen, I. M.; Jansen, G H; Roholl, P.J.; Defferrari, R.; Slater, R.; DEN OTTER;, W.

    1993-01-01

    The 50% survival time for low grade astrocytomas is 50 months and for high grade astrocytomas it is 13 months, underlining the need for new therapies. Several reports show that in vivo histamine antagonists cause retardation of tumour growth in some animal models and prolonged survival in cancer patients. Therefore we have tested the growth modulating effects of histamine and histamine antagonists on human glioma cultures. Twelve freshly excised human gliomas were cultured and tested for thei...

  20. Anti-obesity and anti-diabetic actions of histamine neurons

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The present study aimed to examine roles of histamine neurons in leptin signaling pathways and leptin resistant states. H1-receptor knockout (H1KO) mice showed no change in daily food intake, adiposity, growth curve, basal expression of hypothalamic neuropeptides, uncoupling proteins (UCPs) or ob gene. However, H1KO mice fed with high fat diet increased fat deposition and ob gene expression more excessively. Leptin-induced feeding suppression was attenuated in H1KO mice. Chronic leptin treatment decreased visceral fat and up-regulated UCPs expression in brown and white fat. These effects of leptin were attenuated in pair-fed H1KO mice. Chronic histamine or histidine treatment decreased body weight, body fat deposition, and serum glucose and insulin in diet-induced obese, ob/ob and db/db mice. Activation of histamine neurons suppressed ob gene expression in the fat tissue together with elevation of seurm leptin and UCPs mRNA. These actions of neuronal histamine were attenuated in the double knockout mice, i.e., db/db mice with H1KO. Taken together, H1KO mice, a novel leptin resistant model, elucidate essential roles of H1-R in energy intake and expenditure as a down-stream-signaling message of leptin actions in the brain. The anti-obesity and anti-diabetic effects of histamine neurons provide a new insight into therapeutic strategies on human obesity and diabetes with leptin resistance.

  1. Role of histamine in the regulation of intestinal immunity in fish.

    Science.gov (United States)

    Galindo-Villegas, Jorge; Garcia-Garcia, Erick; Mulero, Victoriano

    2016-11-01

    In mammals, during the acute inflammatory response, the complex interrelationship and cross-talk among histamine and the immune system has been fairly well characterized. There is a substantial body of information on its structure, metabolism, receptors, signal transduction, physiologic and pathologic effects. However, for early vertebrates, there is little such knowledge. In the case of teleost fish, this lack of knowledge has been due to the widely held belief that histamine is not present in this phylogenetic group. However, it has been recently demonstrated, that granules of mast cells in perciforms contain biologically active histamine. More importantly, the inflammatory response was clearly demonstrated to be regulated by the direct action of histamine on professional phagocytes. Nevertheless, the molecular basis and exact role of this biogenic amine in perciforms is still a matter of speculation. Therefore, this review intends to summarize recent experimental evidence regarding fish mast cells and correlate the same with their mammalian counterparts to establish the possible role of histamine in the fish intestinal inflammatory response. PMID:26872545

  2. Pharmacological investigation into the effects of histamine and histamine analogues on guinea-pig and rat colon in vitro.

    OpenAIRE

    M. J. Aguilar; Morales-Olivas, F. J.; Rubio, E.

    1986-01-01

    The effects of histamine and specific histamine agonists has been examined on isolated longitudinal colon strips of guinea-pig and rat. Histamine and 2-pyridyl-ethylamine but not 4 methylhistamine produced a concentration-related contractile response in the guinea-pig colon. The H1-antagonist clemizole antagonized competitively the effect of histamine but the H2-antagonist ranitidine did not modify the dose-response curve to histamine in the guinea-pig colon. Atropine, hexamethonium, prazosin...

  3. Measurement of cerebral nicotine receptor by positron-CT aiming at early diagnosis of Alzheimer`s disease

    Energy Technology Data Exchange (ETDEWEB)

    Hayashida, Kohei; Miyake, Yoshinori; Ishida, Yoshio; Hirose, Yoshiaki [National Cardiovascular Center, Suita, Osaka (Japan)

    1997-02-01

    Cerebral circulation of the patients with cerebrovascular disease were investigated using PET (Headtome-4, Shimadzu Seisakusho Ltd.) with an aim to detect dementia at an early stage and to evaluate its degree accurately. Cerebral circulation was assessed with the following indicators; cerebral blood flow (CBF), oxygen enhancement ratio (OER), cerebral metabolic rate for O{sub 2} (CMRO), ratio of CBF to cerebral blood volume (CBV). On the PET images, respective 16 regions were chosen to investigate the correlation between resting CBV and Diamox loading CBV as well as the correlation between resting OER and Diamox loading OER. Based on the values of DEF and CBF/CBV, 194 regions concerned were divided into 3 groups; 61 regions for normal group, 113 for group stage 1 and 20 for group 2. CBV was significantly different between normal and stage 1-groups, and stage 1- and stage 2-groups. And CBV decreased depending on the severity of the disease. Further, the correlation coefficients for DEF and CBV increase due to Diamox loading were 0.33, 0.050 and 0.680 for normal, stage 1- and stage 2- group, showing significance only in stage 2-group, showing significance only in stage 2-group. Thus, evaluation of the degree of cerebrovascular disease was found possible up to the moderate degree by cerebral SPECT. (M.N.)

  4. Cerebral kinetics of the dopamine D{sub 2} receptor ligand [{sup 123}I]IBZM in mice

    Energy Technology Data Exchange (ETDEWEB)

    Meyer, Philipp T. [Department of Neurology, University Hospital Aachen, 52074 Aachen (Germany); Department of Nuclear Medicine, University Hospital Aachen, 52074 Aachen (Germany)], E-mail: pmeyer@ukaachen.de; Salber, Dagmar [C. and O. Vogt Institute of Brain Research, University Hospital Duesseldorf, 40225 Duesseldorf (Germany); Schiefer, Johannes [Department of Neurology, University Hospital Aachen, 52074 Aachen (Germany); Cremer, Markus [Institute of Neurosciences and Biophysics, Research Center Juelich, 52425 Juelich (Germany); Schaefer, Wolfgang M. [Department of Nuclear Medicine, University Hospital Aachen, 52074 Aachen (Germany); Kosinski, Christoph M. [Department of Neurology, University Hospital Aachen, 52074 Aachen (Germany); Langen, Karl-Josef [Institute of Neurosciences and Biophysics, Research Center Juelich, 52425 Juelich (Germany)

    2008-05-15

    Introduction: In vivo small animal imaging of the dopaminergic system is of great interest for basic and applied neurosciences, especially in transgenic mice. Small animal SPECT is particularly attractive because of its superior spatial resolution and tracer availability. We investigated the kinetics of the commercial dopamine D{sub 2} receptor (DZR) ligand [{sup 123}I]IBZM in mice as a prerequisite for an appropriate design of translational SPECT imaging between mice and humans. Methods: Cerebral kinetics of [{sup 123}I]IBZM under isoflurane anaesthesia were assessed by autoradiography in mice sacrificed at 30, 60, 120 and 200 min after iv injection. To explore the possible effects of isoflurane anaesthesia, an additional mice group was only anaesthetized for 20 min before being sacrificed at 140 min (putative time of single-scan SPECT analysis). Results: Maximum [{sup 123}I]IBZM uptake in the striatum (D{sub 2}R-rich; 10.5{+-}2.7 %ID/g) and cerebellum (D{sub 2}R-devoid; 2.4{+-}0.7 %ID/g) was observed at 30 min after injection. Thereafter, [{sup 123}I]IBZM uptake decreased slowly in striatum and rapidly in the cerebellum (200 min: 5.3{+-}1.9 and 0.4{+-}0.2 %ID/g, respectively). The striatum-to-cerebellum (S/C) [{sup 123}I]IBZM uptake ratio increased from 4.6{+-}1.2 at 30 min to 11.6{+-}2.6 at 120 min. The S/C ratio at 200 min was highly variable (17.8{+-}10.1), possibly indicating pseudo-equilibration in some animals. In mice, which were only anaesthetized between 120 and 140 min, a higher S/C ratio of 17.0{+-}5.1 was observed. Conclusions: The present study suggests that [{sup 123}I]IBZM is a suitable ligand for D{sub 2}R-SPECT in mice. Although a single-scan analysis may be a pragmatic semi-quantitative approach, tracer kinetic analyses on dynamic SPECT data should be pursued. The interfering effects of isoflurane anaesthesia need to be considered.

  5. Montelukast, a cysteinyl leukotriene receptor-1 antagonist protects against hippocampal injury induced by transient global cerebral ischemia and reperfusion in rats.

    Science.gov (United States)

    Saad, M A; Abdelsalam, R M; Kenawy, S A; Attia, A S

    2015-01-01

    Cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory and immune modulating lipid mediators involved in inflammatory diseases and were boosted in human brain after acute phase of cerebral ischemia. The antagonism of CysLTs receptors may offer protection against ischemic damage. Therefore it seemed interesting to study the possible neuroprotective effect of Montelukast, a CysLTR1 antagonist in global cerebral ischemia/reperfusion (IR) injury in rats. Global cerebral ischemia-reperfusion was induced by bilateral carotid artery occlusion for 15 min followed by 60 min reperfusion period. Animals were randomly allocated into three groups (n = 30 per group): Sham operated, I/R control and rats treated with montelukast (0.5 mg/kg, po) daily for 7 days then I/R was induced 1 h after the last dose of montelukast. After reperfusion rats were killed by decapitation, brains were removed and both hippocampi separated and the following biochemical parameters were estimated; lactate dehydrogenase activity, oxidative stress markers (lipid peroxides, nitric oxide and reduced glutathione), inflammatory markers (myeloperoxidase, tumor necrosis factor-alpha, nuclear factor kappa-B, interleukin-6 and interleukin-10), apoptotic biomarkers (caspase 3 and cytochrome C), neurotransmitters (glutamate, gamma aminobutyric acid), Cys-LTs contents and CysLT1 receptor expression; as well as total brain infarct size and histopathological examination of the hippocampus were assessed. Montelukast protected hippocampal tissue by reducing oxidative stress, inflammatory and apoptotic markers. Furthermore, it reduced glutamate and lactate dehydrogenase activity as well as infarct size elevated by I/R. These results were consistent with the histopathological findings. Montelukast showed a neuroprotective effects through antioxidant, anti-inflammatory and antiapoptotic mechanisms. PMID:25403620

  6. Cross sectional PET study of cerebral adenosine A{sub 1} receptors in premanifest and manifest Huntington's disease

    Energy Technology Data Exchange (ETDEWEB)

    Matusch, Andreas; Elmenhorst, David [Institute of Neuroscience and Medicine (INM-2), Juelich (Germany); Saft, Carsten; Kraus, Peter H.; Gold, Ralf [St. Josef Hospital, Ruhr University Bochum, Department of Neurology, Huntington Centre NRW, Bochum (Germany); Hartung, Hans-Peter [Heinrich Heine University Duesseldorf, Department of Neurology, Medical Faculty, Duesseldorf (Germany); Bauer, Andreas [Institute of Neuroscience and Medicine (INM-2), Juelich (Germany); Heinrich Heine University Duesseldorf, Department of Neurology, Medical Faculty, Duesseldorf (Germany)

    2014-06-15

    To study cerebral adenosine receptors (AR) in premanifest and manifest stages of Huntington's disease (HD). We quantified the cerebral binding potential (BP{sub ND}) of the A{sub 1}AR in carriers of the HD CAG trinucleotide repeat expansion using the radioligand [{sup 18} F]CPFPX and PET. Four groups were investigated: (i) premanifest individuals far (preHD-A; n = 7) or (ii) near (preHD-B; n = 6) to the predicted symptom onset, (iii) manifest HD patients (n = 8), and (iv) controls (n = 36). Cerebral A{sub 1}AR values of preHD-A subjects were generally higher than those of controls (by up to 31 %, p <.01, in the thalamus on average). Across stages a successive reduction of A{sub 1}AR BP{sub ND} was observed to the levels of controls in preHD-B and undercutting controls in manifest HD by down to 25 %, p <.01, in the caudatus and amygdala. There was a strong correlation between A{sub 1}AR BP{sub ND} and years to onset. Before onset of HD, the assumed annual rates of change of A{sub 1}AR density were -1.2 % in the caudatus, -1.7 % in the thalamus and -3.4 % in the amygdala, while the corresponding volume losses amounted to 0.6 %, 0.1 % and 0.2 %, respectively. Adenosine receptors switch from supra to subnormal levels during phenoconversion of HD. This differential regulation may play a role in the pathophysiology of altered energy metabolism. (orig.)

  7. Exploration of dopamine transporter and D2 receptors in morphine dependent rats through 125I-β-CTT, 125I-IBZM cerebral autoradiography and the biodistribution study

    International Nuclear Information System (INIS)

    Objective: To explore the variation of cerebral dopamine (DA) transmitting system in morphine dependent (MD) rats using dopamine transporter (DAT) and D2 receptors imaging agent. Methods: MD model rats were established by using a two-compartment (C1 and C2-morphine conditioned compartment) apparatus for assessing morphine conditioned place preferences in rats. 125I-2β-carbomethoxy-3β-(4-iodophenyl) tropane (125I-β-CIT) and 125I-3-iodo-2-hydroxy-6-methoxy-N[(1-ethyl-2-pyrrolidinyl) methyl] benzamide (125I-IBZM) cerebral DAT and D2 receptor autoradiography and biodistribution study were used to evaluate the variation of DAT and D2 receptors in morphine dependent rats. Results: The mean time of MD rats entering from C1 to C2 was (0.84 +- 0.50) min after 6 days' conditioned place preference training, shorter than that of the control group [(2.40 +- 1.10) min, P 125I-β-CIT uptake ratio of striatum (ST)/cerebellum (CB) and nucleus acumens (NAC)/CB in MD group were 4.76 +- 0.92 and 2.72 +- 0.96, significantly lower than that of control group (5.92 +- 0.67 and 4.16 +- 0.56, P 125I-IBZM uptake ratio in MD group were 4.11 +- 0.56 and 2.64 +- 0.25, lower than that in control group (5.43 +- 0.74 and 3.49 +- 0.65, P 125I-β-CIT, 125I-IBZM biodistribution study also showed that the DAT and D2 binding sites were reduced in ST of MD group by (21.68 +- 11.11)% and (18.69 +- 9.97)% comparing to the controls, respectively. Conclusions: The DAT and D2 receptors in both ST and NAC were all involved and reduced to some extent in morphine dependent model rats, the DAT and D2 receptor imaging agent could reflect the variation of DAT and D2receptors, this would afford the theoretical basis for D2 receptors and DAT imaging in study on preventing drug addiction and on its abstinence

  8. Histamine may contribute to vortioxetine's procognitive effects; possibly through an orexigenic mechanism.

    Science.gov (United States)

    Smagin, Gennady N; Song, Dekun; Budac, David P; Waller, Jessica A; Li, Yan; Pehrson, Alan L; Sánchez, Connie

    2016-07-01

    Vortioxetine is a novel multimodal antidepressant that acts as a serotonin (5-HT)3, 5-HT7, and 5-HT1D receptor antagonist; 5-HT1B receptor partial agonist; 5-HT1A receptor agonist; and 5-HT transporter inhibitor in vitro. In preclinical and clinical studies vortioxetine demonstrates positive effects on cognitive dysfunction. Vortioxetine's effect on cognitive function likely involves the modulation of several neurotransmitter systems. Acute and chronic administration of vortioxetine resulted in changes in histamine concentrations in microdialysates collected from the rat prefrontal cortex and ventral hippocampus. Based on these results and a literature review of the current understanding of the interaction between the histaminergic and serotonergic systems and the role of histamine on cognitive function, we hypothesize that vortioxetine through an activation of the orexinergic system stimulates the tuberomammilary nucleus and enhances histaminergic neurotransmission, which contributes to vortioxetine's positive effects on cognitive function. PMID:26945513

  9. Biochemical and ultrastructural studies suggest that the effects of thapsigargin on human platelets are mediated by changes in intracellular calcium but not by intracellular histamine

    DEFF Research Database (Denmark)

    Saxena, S P; McNicol, A; Becker, A B;

    1992-01-01

    observed at 1 microM Tg. Preincubation of platelets with inhibitors of histamine metabolizing enzymes had little effect on intracellular histamine levels in platelets stimulated by 0.5 microM Tg. In addition, the inhibitors of histidine decarboxylase (HDC), alpha-methyl histidine (alpha-MH) and alpha......-fluoromethyl histidine (alpha-FMH) failed to inhibit Tg-induced aggregation. The intracellular histamine receptor antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine. HCl (DPPE), inhibited Tg-induced aggregation but with IC50 values dependent on the concentration of agonist used. The inhibitory effects of...

  10. Sigma-1 Receptor Imaging in the Brain: Cerebral sigma-1 receptors and cognition: Small-animal PET studies using 11C-SA4503

    OpenAIRE

    Kuzhuppilly Ramakrishnan, Nisha

    2014-01-01

    The sigma-1 receptor is a unique orphan receptor, strongly expressed in neurons and glia. Sigma-1 receptors are involved in several central nervous system (CNS) disorders like depression, anxiety, psychosis, schizophrenia, Parkinson’s disease, Alzheimer’s disease, addiction and neuropathic pain. Several CNS drugs like haloperidol, donepezil, rimcazole, fluvoxamine, sertraline and clorgyline have moderate to high sigma-1 receptor affinity. Pharmaceutical companies currently involved in R&D and...

  11. Sigma-1 Receptor Imaging in the Brain : Cerebral sigma-1 receptors and cognition: Small-animal PET studies using 11C-SA4503

    NARCIS (Netherlands)

    Kuzhuppilly Ramakrishnan, Nisha

    2014-01-01

    The sigma-1 receptor is a unique orphan receptor, strongly expressed in neurons and glia. Sigma-1 receptors are involved in several central nervous system (CNS) disorders like depression, anxiety, psychosis, schizophrenia, Parkinson’s disease, Alzheimer’s disease, addiction and neuropathic pain. Sev

  12. Cerebral Hypoxia

    Science.gov (United States)

    ... Enhancing Diversity Find People About NINDS NINDS Cerebral Hypoxia Information Page Synonym(s): Hypoxia, Anoxia Table of Contents ( ... Trials Organizations Publicaciones en Español What is Cerebral Hypoxia? Cerebral hypoxia refers to a condition in which ...

  13. Microglia and macrophages express tumor necrosis factor receptor p75 following middle cerebral artery occlusion in mice

    DEFF Research Database (Denmark)

    Lambertsen, Kate Lykke; Clausen, Bettina Hjelm; Fenger, Claus;

    2007-01-01

    The proinflammatory and potential neurotoxic cytokine tumor necrosis factor (TNF) is produced by activated CNS resident microglia and infiltrating blood-borne macrophages in infarct and peri-infarct areas following induction of focal cerebral ischemia. Here, we investigated the expression of the ...

  14. Ethanol activation of protein kinase A regulates GABA-A receptor subunit expression in the cerebral cortex and contributes to ethanol-induced hypnosis

    Directory of Open Access Journals (Sweden)

    A LeslieMorrow

    2012-04-01

    Full Text Available Protein kinases are implicated in neuronal cell functions such as modulation of ion channel function, trafficking and synaptic excitability. Both protein kinase C (PKC and A (PKA are involved in regulation of γ-aminobutyric acid type A (GABA-A receptors through phosphorylation. However, the role of PKA in regulating GABA-A receptors following acute ethanol exposure is not known. The present study investigated the role of PKA in ethanol effects on GABA-A receptor α1 subunit expression in the P2 synaptosomal fraction of the rat cerebral cortex. Additionally, GABA-related behaviors were also examined. Rats were administered ethanol (2.0 – 3.5 g/kg or saline and PKC, PKA and GABA-A receptor α1 subunit levels were measured by Western blot analysis. Ethanol (3.5 g/kg transiently increased GABA-A receptor α1 subunit expression and PKA RIIβ subunit expression at similar time points whereas PKA RIIα was increased at later time points. In contrast, PKC isoform expression remained unchanged. Notably, the moderate ethanol dose (2.0g/kg had no effect on GABA-A α1 subunit levels although PKA RIIα and RIIβ were increased at 10 and 60 minutes, when PKC isozymes are also known to be elevated. To determine if PKA activation was responsible for the ethanol-induced elevation of GABA-A α1 subunits, the PKA antagonist H89 was administered to rats prior to ethanol exposure. H89 administration prevented ethanol-induced increases in GABA-A receptor α1 subunit expression. Moreover, increasing PKA activity intracerebroventricularly with Sp-cAMP prior to a hypnotic dose of ethanol increased ethanol-induced loss of righting reflex duration. This effect appears to be mediated in part by GABA-A receptors as increasing PKA activity also increased the duration of muscimol-induced loss of righting reflex. Overall these data suggest that PKA mediates ethanol-induced GABA-A receptor expression and contributes to ethanol behavioral effects involving GABA-A receptors.

  15. Glycopyrrolate abolishes the exercise-induced increase in cerebral perfusion in humans

    DEFF Research Database (Denmark)

    Seifert, Thomas; Fisher, James P; Young, Colin N;

    2010-01-01

    Brain blood vessels contain muscarinic receptors that are important for cerebral blood flow (CBF) regulation, but whether a cholinergic receptor mechanism is involved in the exercise-induced increase in cerebral perfusion or affects cerebral metabolism remains unknown. We evaluated CBF and cerebr...... abolished by glycopyrrolate (P <0.05). Thus, during both cycling and static handgrip, a cholinergic receptor mechanism is important for the exercise-induced increase in cerebral perfusion without affecting the cerebral metabolic rate for oxygen....

  16. Histamine (Scombroid) Fish Poisoning: a Comprehensive Review.

    Science.gov (United States)

    Feng, Charles; Teuber, Suzanne; Gershwin, M Eric

    2016-02-01

    Histamine fish poisoning, also known as scombroid poisoning, is the most common cause of ichythyotoxicosis worldwide and results from the ingestion of histamine-contaminated fish in the Scombroidae and Scomberesocidae families, including mackerel, bonito, albacore, and skipjack. This disease was first described in 1799 in Britain and re-emerged in the medical literature in the 1950s when outbreaks were reported in Japan. The symptoms associated with histamine fish poisoning are similar to that of an allergic reaction. In fact, such histamine-induced reactions are often misdiagnosed as IgE-mediated fish allergy. Indeed, histamine fish poisoning is still an underrecognized disease. In this review, we discuss the epidemiology, pathophysiology, evaluation, and treatment of scombroid disease. Because more than 80% of fish consumed in the USA is now imported from other countries, the disease is intimately linked with the global fish trade (National Marine Fisheries Service, 2012). Preventing future scombroid outbreaks will require that fishermen, public health officials, restaurant workers, and medical professionals work together to devise international safety standards and increase awareness of the disease. The implications of scombroid poisoning go far beyond that of fish and have broader implications for the important issues of food safety. PMID:25876709

  17. DETERMINATION HISTAMINE IN SALTED ANCHOVY (ENGRAULIS ENCRASICHOLUS) BY ELISA

    OpenAIRE

    TERZİ, Göknur; GÜCÜKOĞLU, Ali

    2012-01-01

    ABSTRACT Histamine is an organic compound with low molecule weight which is formed by the decarboxylation of amino acids as a result of microbiological activity or by animation of aldehydes and ketones. Histamin is present in normally compound of various foods such as fish and fish products, meat and fermented meat products, chicken, cheese, wine and beer. Histamine is formed as a result of the enzymatic decarboxylation of histidine. Histamine causes food poisoning when intake high levels in ...

  18. Gastrointestinal histamine after thoracic irradiation in the mouse.

    OpenAIRE

    Man, W K; Michalowski, A.; Li, S. K.; Barr, J.; Burgin, J.; Baron, J. H.; Spencer, J

    1986-01-01

    Thoracic irradiation induced duodenal lesions in mice as an indirect effect. We studied the influence of partial thoracic irradiation on endogenous histamine stores in the alimentary canal. Mice subjected to lower mediastinal irradiation had significantly higher (+19%) median gastric histamine, but lower (-44%) distal duodenal histamine than controls. They also had significantly lower proximal (-39%) and distal (-44%) duodenal histamine than mice who received upper mediastinal irradiation. Tw...

  19. Effects of 5-HT1B/1D receptor agonist rizatriptan on cerebral blood flow and blood volume in normal circulation.

    Science.gov (United States)

    Okazawa, Hidehiko; Tsuchida, Tatsuro; Pagani, Marco; Mori, Tetsuya; Kobayashi, Masato; Tanaka, Fumiko; Yonekura, Yoshiharu

    2006-01-01

    To investigate the vasoconstrictor effect of 5-hydroxytryptamine (5-HT1B/1D) receptor agonists for migraine treatment, changes in cerebral blood flow (CBF) and blood volume induced by rizatriptan were assessed by positron emission tomography (PET). Eleven healthy volunteers underwent PET studies before and after rizatriptan administration. Dynamic PET data were acquired after bolus injection of H2(15)O to analyze CBF and arterial-to-capillary blood volume (V0) images using the three-weighted integral method. After a baseline scan, three further acquisitions were performed at 40 to 50, 60 and 70 to 80 mins after drug administration. Global and regional differences in CBF and V0 between conditions were compared using absolute values in the whole brain and cortical regions, as well as statistical parametric mapping (SPM) analysis. The global and regional values for CBF and V0 decreased significantly after rizatriptan administration compared with the baseline condition. However, both values recovered to baseline within 80 mins after treatment. The maximal reduction in global CBF and V0 was approximately 13% of baseline value. The greatest decrease in CBF was observed approximately 60 mins after drug administration, whereas the maximal reduction in V0 was observed approximately 5 mins earlier. Statistical parametric mapping did not highlight any regional differences between conditions. Thus, in brain circulation, rizatriptan caused significant CBF and V0 decreases, which are consistent with the vasoconstrictor effect of triptans on the large cerebral arteries. The gradual recovery in the late phase from the maximal CBF and V0 decrease suggests that rizatriptan does not affect the cerebral autoregulatory response in small arteries induced by CBF reduction. PMID:15944648

  20. Expression of ET(A) and ET(B) receptor mRNA in human cerebral arteries

    DEFF Research Database (Denmark)

    Hansen-Schwartz, J; Szok, D; Edvinsson, L

    2002-01-01

    The vascular effects of endothelins (ET) are in mammals mediated via two receptor subtypes, endothelin A (ET(A), mainly constrictive) and endothelin B (ET(B), mainly dilating) receptors. We have examined the presence of ET(A) and ET(B) receptor mRNA using the reverse transcription polymerase chai...... pathophysiological significance of this difference is at present speculative, but does point to a vascular involvement of thisreceptor in cerebrovascular disease....

  1. The Effect of Treadmill Training Pre-Exercise on Glutamate Receptor Expression in Rats after Cerebral Ischemia

    OpenAIRE

    Yang Wang; Yi Wu; Feng Zhang; Jie Jia; Yongshan Hu

    2010-01-01

    Physical exercise has been demonstrated to be neuroprotective in both clinical and laboratory settings. However, the exact mechanism underlying this effect is unclear. Our study aimed to investigate whether pre-ischemic treadmill training could serve as a form of ischemic preconditioning in a rat model undergoing middle cerebral artery occlusion (MCAO). Thirty-six rats were divided into three groups: a sham control group, a non-exercise with operation group and an exercise with operation grou...

  2. Acute social defeat does not alter cerebral 5-HT2A receptor binding in male Wistar rats

    NARCIS (Netherlands)

    Visser, Anniek K. D.; Meerlo, Peter; Ettrup, Anders; Knudsen, Gitte M.; Bosker, Fokko J.; den Boer, Johan A.; Dierckx, Rudi A. J. O.; van Waarde, Aren

    2014-01-01

    It has been hypothesized that effects of uncontrollable stress on serotonin receptor expression contribute to the etiology of stress-related disorders like depression. While the serotonin-2A receptors (5-HT2AR) are thought to be important in this context, only few studies examined effects of stress

  3. Assessment of cerebral benzodiazepine receptor distribution in anxiety disorders by 123I-iomazenil-SPECT. Comparison to cerebral perfusion scintigraphy by 123I-IMP

    International Nuclear Information System (INIS)

    123I-Iomazenil (123I-IMZ) and 123I-IMP imaging were performed in 5 patients with anxiety disorder (PAD) and 6 normal volunteers (NV). On 123I-IMZ delayed imaging, the 2 PAD showed abnormally decreased findings. In anxiety disorder, decreased accumulation on 123I-IMZ delayed images was seen in left hippocampus and parahippocampal gyrus in one patient, in right frontal and temporal lobe and left occipital pole in the other. Compared with NV, PAD had lower 123I-IMZ uptake on delayed image in right upper and left lower frontal cortices, indicating the involvement of the benzodiazepine receptor complex in anxiety disorder. Compared with grading for anxiety disorder with Hamilton anxiety scale (HAS) and delayed to early count ratios of 123I-IMZ, negative correlation (R123I-IMP image, positive correlation (R>0.7) was recognized in the hippocampus, the parahippocampal gyrus, the lower outer temporal cortex and the lower frontal cortex. (author)

  4. In vivo localization and quantification of cerebral dopamine receptors. In vivo localisatie en kwantificatie van cerebrale dopamine receptoren; Studies gericht op toepassing van positron emissie tomografie

    Energy Technology Data Exchange (ETDEWEB)

    Werf, J.F. van der.

    1989-02-15

    This thesis is based on a number of studies directed upon the development of methods for in vivo determination of Dopamine (DA) receptors with positron-emitting compounds. A synthesis has been developed for the radioactive labelling of N-alkylated derivatives of the Da agonist ADTN with {sup 11}C. This investigation and the results of distribution studies with these compounds in the rate are described. Another DA agonist, N-n-propylnorapomorfine (NPA) has been tested for suitability for in vivo detection of cerebral DA receptors, making use of a tritiated compound. Firstly the regional localization of {sup 3}H-NPA in the brain of the rat, after in vivo administration of this compound, has been determined and the specificity of this localization has been defined pharmacologically. Also in this study the effects of the occupation of DA receptors with NPA upon the concentrations of DA, HVA and DOPAC in a number of brain regions have been investigated, and an estimation has been made of the maximal saturable striatal NPA compounds in vivo. Next the effects of specific injuries upon the in vivo accumulation after a tracer dose, also effects upon the total saturable in vivo compound have been quantified from saturation studies. These studies have been performed with the DA agonist {sup 3}H-NPA as well as with the antagonist {sup 3}H-spiperon. In the last study the in vivo tracer binding and the maximally saturable binding of {sup 3}H-NPA and {sup 3}H-spiperon in various regions of the rat brain have been compared in view of the application of PET for in vivo DA receptor detection with these compounds. (author). 511 refs.; 20 figs.; 14 tabs.

  5. Tuberculoma cerebral Cerebral tuberculoma

    OpenAIRE

    ELIZABETH CLARA BARROSO; TÂNIA REGINA BRÍGIDO DE OLIVEIRA; ANA MARIA DANTAS DO AMARAL; VALÉRIA GÓES FERREIRA PINHEIRO; ANA LÚCIA DE OLIVEIRA SOUSA

    2002-01-01

    Relata-se o caso de paciente com crises convulsivas de início recente. A tomografia computadorizada cerebral evidenciou imagem sugestiva de lesão expansiva metastática frontoparietal direita. A investigação de tumor primário ou outra doença foi negativa e o exame histopatológico do tecido cerebral diagnosticou tuberculoma. As convulsões foram controladas com a associação de hidantoína 300mg/dia ao esquema específico, utilizado por 18 meses. A tuberculose do sistema nervoso central representa ...

  6. Klebsiella pneumoniae Produces No Histamine: Raoultella planticola and Raoultella ornithinolytica Strains Are Histamine Producers

    OpenAIRE

    Kanki, Masashi; Yoda, Tomoko; Tsukamoto, Teizo; Shibata, Tadayoshi

    2002-01-01

    Histamine fish poisoning is caused by histamine-producing bacteria (HPB). Klebsiella pneumoniae and Klebsiella oxytoca are the best-known HPB in fish. However, 22 strains of HPB from fish first identified as K. pneumoniae or K. oxytoca by commercialized systems were later correctly identified as Raoultella planticola (formerly Klebsiella planticola) by additional tests. Similarly, five strains of Raoultella ornithinolytica (formerly Klebsiella ornithinolytica) were isolated from fish as new H...

  7. Homogeneous time resolved fluorescence assay to measure histamine release.

    Science.gov (United States)

    Claret, Emmanuel J; Ouled-Diaf, Josy; Seguin, Patrick

    2003-12-01

    Histamine is a biogenic amine synthesized by the enzymatic decarboxylation of histidine. Implication of histamine in allergy is well described but histamine is also found in some specific neurones, functions as a neurotransmitter and regulates sleep/wake cycles, hormonal secretion, cardiovascular control and thermo-regulation. We have developed a TR-FRET histamine assay, based on the competition between sample histamine and allophycocyanine (XL665) labelled histamine for binding to a Europium cryptate (EuK) labelled antibody. As histamine is a small monoamine molecule, high affinity antibodies have been raised against carrier protein conjugated histamine. Therefore, sample histamine needs to be derivatized in the same way as the conjugated histamine, so that the antibody will have a similar affinity for both molecules. This acylation step is performed directly in wells and does not need to be done in separate vials, making handling easier for large numbers of samples. The incubation takes place at room temperature for 3 hours. The assay covers a measurement range of 1.56 to 400 nM and shows an analytical sensitivity of 1.3nM. We have shown that miniaturization of sample and reagents volumes down to 20 micro l does not alter these performances. This histamine release assay provides a particularly well adapted procedure for HTS and secondary screening compared to current heterogeneous methods. PMID:14683484

  8. Perspectives in Drug Development and Clinical Pharmacology: The Discovery of Histamine H1 and H2 Antagonists.

    Science.gov (United States)

    Jones, Alan Wayne

    2016-01-01

    Knowledge about the history and development of therapeutic agents holds a central position in the education and training of pharmacists and pharmacologists. Students enjoy learning about the discovery of drugs, including details about the pioneer workers involved (apothecaries, organic chemists, pharmacologists, and physiologists) and the role played by serendipity. The treatment of people suffering from allergies and the development of drugs that block the actions of histamine at H1 and H2 receptors are the subject of this review. Pharmaceutical products that block H1 receptors are widely used as prophylactic treatment for seasonal allergies that plague millions of people worldwide. The development of H2 receptor antagonists revolutionized treatment of gastric hyperacidity, the principal cause of peptic ulcers. Antihistamine research has changed focus toward the development of drugs that block the action of histamine at H3 and H4 receptors and the therapeutic potential is gradually being appreciated. PMID:27119574

  9. Alteration in contractile G-protein coupled receptor expression by moist snuff and nicotine in rat cerebral arteries

    DEFF Research Database (Denmark)

    Sandhu, Hardip; Xu, Cang-Bao; Edvinsson, Lars

    2011-01-01

    The cardiovascular risk for users of use of Swedish snus/American snuff (moist tobacco) has been debated for a long time. The present study was designed to examine the effects of water- or lipid-soluble (DMSO-soluble) snus and nicotine, the most important substance in tobacco, on the expression of...... kinases (MAPK). However, the effects of moist tobacco on the expression of GPCR are less studied. Rat middle cerebral arteries were isolated and organ cultured in serum-free medium for 24h in the presence of water-soluble snus (WSS), DMSO-soluble snus (DSS), or nicotine. The dose of snus and nicotine was...

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

    Science.gov (United States)

    Yeung, Michelle; Treit, Dallas; Dickson, Clayton T

    2016-07-01

    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'. PMID:26400409

  11. Analgesic Effects of 1st Generation Anti-histamines in Mice.

    Science.gov (United States)

    Takahashi, Mebae; Shima, Kazuhiro; Tsuchiya, Masahiro; Hagiwara, Yoshihiro; Mizoguchi, Hirokazu; Sakurada, Shinobu; Sugawara, Shunji; Fujita, Takuo; Tadano, Takeshi; Watanabe, Makoto; Fukumoto, Satoshi; Endo, Yasuo

    2016-01-01

    Pain is sensed, transmitted, and modified by a variety of mediators and receptors. Histamine is a well-known mediator of pain. In addition to their anti-histaminic effects, the classical, or 1st generation, anti-histamines (1st AHs) possess, to various degrees, anti-muscarinic, anti-serotonergic, anti-adrenergic, and other pharmacologic effects. Although there have been attempts to use 1st AHs as analgesics and/or analgesic adjuvants, the advent of non-steroidal anti-inflammatory drugs (NSAIDs) discouraged such trials. We previously reported that in patients with temporomandibular disorders, osteoporosis, and/or osteoarthritis, the analgesic effects of certain 1st AHs (chlorpheniramine and diphenhydramine) are superior to those of the NSAIDs flurbiprofen and indomethacin. Here, we compared analgesic effects among 1st AHs and NSAIDs against responses shown by mice to intraperitoneally injected 0.7% acetic acid. Since 1st AHs are water soluble, we selected water-soluble NSAIDs. For direct comparison, drugs were intravenously injected 30 min before the above tests. Histamine-H1-receptor-deficient (H1R-KO) mice were used for evaluating H1-receptor-independent effects. The tested 1st AHs (especially cyproheptadine) displayed or tended to display analgesic effects comparable to those of NSAIDs in normal and H1R-KO mice. Our data suggest that the anti-serotonergic and/or anti-adrenergic effects of 1st AHs make important contributions to their analgesic effects. Moreover, combination of a 1st AH with an NSAID (cyclooxygenase-1 inhibitor) produced remarkably potent analgesic effects. We propose that a 1st AH, by itself or in combination with a cyclooxygenase-1 inhibitor, should undergo testing to evaluate its usefulness in analgesia. PMID:27040636

  12. Compound 48/80, a histamine-depleting agent, blocks the protective effect of morphine against electroconvulsive shock in mice

    Directory of Open Access Journals (Sweden)

    Karadag C.H.

    2000-01-01

    Full Text Available We have shown that morphine has an anticonvulsive effect against maximal electroconvulsive shock (MES in mice, and this effect is antagonized by histamine H1-receptor antagonists. Brain histamine is localized both in neurons and in mast cells, and morphine is known to enhance the turnover of neuronal histamine and to release histamine from mast cells. In the present experiments, compound 48/80 was injected chronically (0.5 mg/kg on day 1, 1 mg/kg on day 2, 2 mg/kg on day 3, 3 mg/kg on day 4, and 4 mg/kg on day 5, twice daily, ip to deplete mast cell contents. Morphine (0.001-10 mg/kg, ip; N = 20 produced a dose-dependent anticonvulsive effect against MES seizure in mice with non-depleted mast cells, whereas it did not exert any anticonvulsive effect in mice with depleted mast cells. These results indicate that morphine produces its anticonvulsive effect against maximal electroconvulsive shock in mice by liberating histamine from mast cells.

  13. An investigation into the receptor-regulating effects of the acute administration of opioid agonists and an antagonist on beta adrenergic receptors in the rat cerebral cortex

    International Nuclear Information System (INIS)

    Past and current research indicated that biochemical deviations which might be involved in the etiology and pathophysiology of depression, included abnormalities or imbalances in the noradrenergic, serotonergic, hormonal and possibly in the endogenous opioid, dopaminergic, histaminergic, cholinergic and trace amine systems. In order to investigate a possible link between the noradrenergic system and opioids, it was decided to test the acute effects of opioid administration on cortical beta adrenoceptor numbers and affinity. As these receptors have been most consistently downregulated by antidepressant treatment, they may be involved in the mechanism of antidepressant action of these agents. It was decided to investigate beta adrenoceptor-regulatory effects of opioid treatment. Naloxone was tested alone, with a view to suppressing any possible endogenous opioid influences upon beta receptor status and revealing an effect which would possibly be the opposite of that brought about by the administration of opioid agonists. Naloxone was administered together with morphine to demonstrate that any beta receptor up- or downregulation which might be measured, had indeed been opioid-receptor mediated. It was found that the acute administration of four different mu opioid agonists, naloxone and naloxone plus morphine, did not cause any statistically significant alterations in cortical beta adrenergic receptor numbers or affinity in the rat. A radioactive ligand, the beta adrenoceptor-labelling compound referred to as DHA (L-dihydroalprenolol HCI) was used in this study

  14. Hyperammonemia inhibits the natriuretic peptide receptor 2 (NPR-2)-mediated cyclic GMP synthesis in the astrocytic compartment of rat cerebral cortex slices.

    Science.gov (United States)

    Zielińska, Magdalena; Fresko, Inez; Konopacka, Agnieszka; Felipo, Vicente; Albrecht, Jan

    2007-11-01

    The decrease of cyclic GMP (cGMP) level in the brain, contributing to cognitive and memory deficit in hyperammonemia (HA), has been attributed to the interference of ammonia with the NMDA/nitric oxide/soluble guanylate cyclase (GC)/cGMP pathway in neurons. The present study tested the hypotheses that (a) HA also affects cGMP synthesis elicited by stimulation of the natriuretic peptide receptor 2 (NPR-2) with its natural ligand, C-type natriuretic peptide (CNP) and (b) the latter effect may involve astrocytes, the ammonia-sensitive cells. In the cerebral cortical slices of control rats, CNP stimulated cGMP synthesis in a degree comparable to the NO donor, S-nitroso-N-acetylpenicillamine (SNAP) used at an optimal concentration. Fluoroacetate (FA), a metabolic inhibitor specifically affecting astrocytic mitochondria, inhibited the CNP-dependent cGMP synthesis by about 50%. Ammonium acetate-induced HA decreased by 68% the CNP-dependent cGMP generation in slices incubated in the absence of FA. In slices incubated in the presence of FA, cGMP synthesis in slices derived from HA rats did not differ from that in control slices. The results indicate that HA inhibits CNP-dependent cGMP synthesis in the FA-vulnerable, astrocytic compartment, but not in the FA-resistant compartment(s) of the brain. HA did not affect the expression of NPR-2 mRNA in the cerebral cortex tissue as tested using real-time PCR, indicating that the effect of ammonia involves as yet unidentified events occurring posttranscriptionally. Deregulation of NPR-2 function in astrocytes by ammonia may contribute to neurophysiological symptoms of HA. PMID:17629948

  15. Cerebral Palsy

    Science.gov (United States)

    Cerebral palsy is a group of disorders that affect a person's ability to move and to maintain balance ... do not get worse over time. People with cerebral palsy may have difficulty walking. They may also have ...

  16. Distribution of mRNA for VIP and PACAP receptors in human cerebral arteries and cranial ganglia

    DEFF Research Database (Denmark)

    Knutsson, Mikael; Edvinsson, Lars

    2002-01-01

    arteries and in trigeminal, otic, sphenopalatine and superior cervical ganglia. RT-PCR products of the expected sizes were detected in the arteries, in both the presence and absence of endothelium. In the majority (80%) of the trigeminal, otic and superior cervical ganglia, mRNA for all three receptors...

  17. Endogenous plasma estradiol in healthy men is positively correlated with cerebral cortical serotonin 2A receptor binding

    DEFF Research Database (Denmark)

    Frokjaer, Vibe G.; Erritzoe, David; Juul, Anders; Nielsen, Finn Årup; Holst, Klaus; Svarer, Claus; Madsen, Jacob; Paulson, Olaf B.; Knudsen, Gitte Moos

    2010-01-01

    = 0.0001), whereas no independent effects of testosterone could be demonstrated. Correction for other factors of importance for 5-HT2A receptor binding did not change the result. A voxel-based analysis suggested that there were no regional differences in the estradiol effect on cortical 5-HT2A...

  18. Cerebral Atrophy

    Science.gov (United States)

    ... Alzheimer’s disease, Pick’s disease, and fronto-temporal dementia cerebral palsy , in which lesions (damaged areas) may impair motor ... lead to cerebral atrophy. NIH Patient Recruitment for Cerebral Atrophy Clinical Trials ... by: Office of Communications and Public Liaison National Institute of Neurological Disorders ...

  19. Late cerebral ischaemia after subarachnoid haemorrhage

    DEFF Research Database (Denmark)

    Edvinsson, L; Povlsen, G K

    2011-01-01

    Late cerebral ischaemia after subarachnoid haemorrhage (SAH) carries high morbidity and mortality because of reduced cerebral blood flow (CBF) and subsequent cerebral ischaemia. This is associated with upregulation of contractile receptors in cerebral artery smooth muscles via the activation of...... intracellular signalling. In addition, delayed cerebral ischaemia after SAH is associated with inflammation and disruption of the blood-brain barrier (BBB). This article reviews recent evidence concerning the roles of vasoconstrictor receptor upregulation, inflammation and BBB breakdown in delayed cerebral...... ischaemia after SAH. In addition, recent studies investigating the role of various intracellular signalling pathways in these processes and the possibilities of targeting signalling components in SAH treatment are discussed. Studies using a rat SAH model have demonstrated that cerebral arteries increase...

  20. Reflex effects of aerosolized histamine on phrenic nerve activity.

    OpenAIRE

    Pack, A I; Hertz, B C; Ledlie, J F; Fishman, A. P.

    1982-01-01

    Studies were conducted in anesthetized, paralyzed dogs on the effect of aerosolized histamine on phrenic nerve activity. The paralyzed dogs were ventilated in phase with their recorded phrenic nerve activity at a constant inspiratory flow-rate, using a cycle-triggered ventilator. Phrenic nerve activity was measured before and during administration of aerosolized histamine while the inspiratory flow-rate and arterial blood gases were kept constant. In addition, before and after histamine, phre...

  1. Histamine bronchial challenge: effect on regional ventilation and aerosol deposition.

    OpenAIRE

    Clague, H.; Ahmad, D.; Chamberlain, M. J.; Morgan, W K; Vinitski, S

    1983-01-01

    We studied regional changes in ventilation and aerosol deposition after histamine challenge in six patients with asthma and two with rhinitis and a history of wheezing. All were known to have bronchial hyperreactivity and all showed an increased response to histamine. Ventilation and aerosol deposition studies, using xenon-133 and an aerosol of sulphur colloid tagged with technetium 99m, were performed while they were sitting. Before administration of histamine radioaerosol scintiscans were a...

  2. Methodology for histamine and biogenic amines analysis. Seafoodplus Traceability

    OpenAIRE

    Etienne, Monique

    2006-01-01

    Histamine, putrescine, cadaverine, tyramine and agmatine are produced from the decarboxylation of histidine, ornithine, lysine tyrosine and arginine respectively. Histamine is associated of scombroid poisoning in conjonction with the ingestion of some fish species such as tuna, mackerel, sardine, herring,anchovy. The formation of histamine in fish products is directly correlated with the concentration of histidine in the tissue and the level of microorganisms present in the product, due to ...

  3. Mechanism of histamine-induced excitation of the cat pylorus.

    OpenAIRE

    Biancani, P.; CiCalzi, L K; McCallum, R. W.

    1981-01-01

    Intravenous histamine causes high amplitude repetitive phasic contractions of the in vivo cat pylorus but has little effect on the antrum and duodenum. The genesis of this phasic response was studied using a pinned perfused catheter with openings at the pylorus, antrum, and duodenum. 2-Pyridylethylamine, an H1 agonist, produced phasic contractions similar to histamine whereas dimaprit, an H2 agonist, did not. Conversely, histamine-induced excitation is competitively antagonized by the H1 inhi...

  4. Positive inotropic effects of histamine in anaesthetized dogs.

    OpenAIRE

    Einstein, R.; Mihailidou, A. S.; Richardson, D. P.

    1987-01-01

    1 The cardiovascular effects of histamine were examined in dogs anaesthetized with pentobarbitone 2 The effect of histamine on heart rate, blood pressure, left ventricular pressure, dP/dtmax and dP/dt: IIT (integrated isometric tension) was compared in the presence and absence of autonomic reflexes and blood pressure control. 3 In innervated animals with no attempt to control blood pressure, histamine produced dose-dependent decreases in blood pressure and heart rate and either positive or ne...

  5. Histamine N-methyltransferase Modulates Human Bronchial Smooth Muscle Contraction

    OpenAIRE

    Tamaoki, J.; Chiyotani, A.; Tagaya, E; Isono, K; Konno, K

    1994-01-01

    To elucidate the modulatory role of histamine-degrading enzymes in airway constrictor responses, human bronchial strips were studied under isometric conditions in vitro. Pretreatment of tissues with the histamine N-methyltransferase (HMT) inhibitor SKF 91488 specifically potentiated the contractile responses to histamine, causing a leftward displacement of the concentration response curves, whereas the diamine oxidase inhibitor aminoguanidine had no effect. This potentiation was attenuated by...

  6. Acute social defeat does not alter cerebral 5-HT2A receptor binding in male Wistar rats

    DEFF Research Database (Denmark)

    Visser, Anniek K D; Meerlo, Peter; Ettrup, Anders;

    2014-01-01

    stress on this receptor subtype. In this study, we therefore assessed acute and long-term changes in 5HT2A R binding after social defeat stress in rats. Male Wistar rats were subjected to social defeat by placing them in the home cage of an aggressive, dominant Long Evans rat. Acute social defeat...... suppressed growth, but did not affect anxiety-like behavior in an open field test. A positron emission tomography scan with the 5-HT2A R tracer [11C]MDL 100907 1 day and 3 weeks after defeat did not show significant changes in receptor binding. To verify these results, [3H]MDL 100907 binding assays were...

  7. 5HT2 receptors in cerebral cortex of migraineurs studied using PET and 18F-fluorosetoperoene

    International Nuclear Information System (INIS)

    Since the brain 5HT2 might be implicated in migraine pathogenesis, the authors have used positron emission tomography and 18F-fluorosetoperone, a 5HT2 specific radioligand, to investigate in vivo the cortical 5HT2 receptors in migraine subjects. Nine migraineurs who had either migraine with and without aura or only migraine without aura were studied between attacks. 12 unmedicated healthy subjects of similar mean age were used as controls. Brain radioactivity was measured after 18F-setoperone IV injection for 90 min. A decrease of the regional specific distribution volumes (SDV) of the ligand was observed both in migraineurs and in controls. The age adjusted group means of SDV did not differ between patients and controls for the whole and for the right or left frontal, temporal, parietal and occipital cortex. These results suggest that cortical 5HT2 receptors may be unaltered between attacks in migraine sufferers. 30 refs., 4 figs., 2 tabs

  8. The Effect of Treadmill Training Pre-Exercise on Glutamate Receptor Expression in Rats after Cerebral Ischemia

    Directory of Open Access Journals (Sweden)

    Yang Wang

    2010-07-01

    Full Text Available Physical exercise has been demonstrated to be neuroprotective in both clinical and laboratory settings. However, the exact mechanism underlying this effect is unclear. Our study aimed to investigate whether pre-ischemic treadmill training could serve as a form of ischemic preconditioning in a rat model undergoing middle cerebral artery occlusion (MCAO. Thirty-six rats were divided into three groups: a sham control group, a non-exercise with operation group and an exercise with operation group. After treadmill training, ischemia was induced by occluding the MCA for 2 h, followed by reperfusion. Half of the rats in each group were sacrificed for mRNA detection of mGluR5 and NR2B 80 min after occlusion. The remaining animals were evaluated for neurological deficits by behavioral scoring and then decapitated to assess the infarct volume. The mRNA expression of mGluR5 and NR2B was detected by real-time PCR. The results suggest that pre-ischemic treadmill training may induce brain ischemic tolerance by reducing the mRNA levels of mGluR5 and NR2B, and thus, the results indicate that physical exercise might be an effective method to establish ischemic preconditioning.

  9. Effect of pentagastrin on histamine output from the stomach in patients with duodenal ulcer.

    OpenAIRE

    Man, W K; Saunders, J H; Ingoldby, C; Spencer, J

    1981-01-01

    The role of histamine in acid secretion is controversial. Improvements in the techniques of histamine assay allow a better assessment of the relationship of histamine to acid secretion. Patients with duodenal ulcers were studied to determine the mucosal histamine responses to pentagastrin stimulation to relate the appearance of histamine in the gastric juice to acid production during stimulation, and to detect changes in the plasma histamine concentration during pentagastrin stimulation. Ther...

  10. 犬冠状动脉和脑动脉多巴胺受体亚型对比研究%Comparative studies on the characteristics of dopamine receptors in canines' coronary and cerebral arteries

    Institute of Scientific and Technical Information of China (English)

    王毅; 朱琳; 郑丽丽; 赵荣瑞

    2001-01-01

    Aim:To study the (DA) receptor subtypes and functional significance in canine coronary and cerebral arteries.Methods:Vascular ring technique was used for determining vasorelaxing response to fenoldopam and PBDA in canine coronary and cerebral arteries.Results:①DA1 receptors were distributed in the coronary and cerebral arteries,however,a great variation in their functional potency existed;②DA2 receptors were only present in the cerebral artery. Conclusion:To clarify the heterogeneity in subtype and responsiveness of DA receptors in the coronary and cerebral arteries may help to evaluate the physiological signifiance of DA receptors.%目的:对比分析犬冠状动脉和脑动脉多巴胺(DA)受体亚型类别与反应特性。方法:利用离体血管微量生物反应检测技术,测定多巴胺1(DA1)受体激动剂非诺多泮(Fenoldopam,FODA)和多巴胺2(DA2)受体激动剂propylbutyl-dopamine(PBDA)对冠状动脉和脑动脉血管环的舒张反应。结果:①冠状动脉和脑动脉均有DA1受体分布,但其分布密度存在明显差别;②脑动脉内既有DA1受体又有DA2受体分布;③用6-羟多巴胺(6-OHDA)处理后的实验进一步证实脑动脉存在有DA2受体。结论:冠状动脉和脑动脉DA受体亚型存在明显的异质性,阐明这种异质性将有助于了解多巴胺受体对冠脉循环和脑循环的不同生理反应。

  11. Metallothionein-I plus II and receptor megalin are altered in relation to oxidative stress in cerebral lymphomas

    DEFF Research Database (Denmark)

    Pedersen, M.O.; Hansen, P.B.; Nielsen, Signe Ledou;

    2010-01-01

    Primary central nervous system lymphoma (PCNSL) in immunocompetent patients is highly malignant and has a poor prognosis. The PCNSL molecular features are reminiscent to some degree of diffuse large B-cell lymphoma (DLBCL), yet PCNSL shows unique molecular profiles and a distinct clinical behavior....... This article characterizes the histopathology and expression profiles of metallothionein-I + II (MT-I + II) and their receptor megalin along with proliferation, oxidative stress, and apoptosis in PCNSL and in central nervous system (CNS) lymphomas due to relapse from DLBCL (collectively referred to as...

  12. 5HT{sub 2} receptors in cerebral cortex of migraineurs studied using PET and {sup 18}F-fluorosetoperoene

    Energy Technology Data Exchange (ETDEWEB)

    Chabriat, H.; Tehindrazanarivelo, A.; Vera, P.; Samson, Y.; Pappata, S.; Boullais, N.; Bousser, M.G. [Hospital Saint Antoine, Paris (France)

    1995-04-01

    Since the brain 5HT{sub 2} might be implicated in migraine pathogenesis, the authors have used positron emission tomography and {sup 18}F-fluorosetoperone, a 5HT{sub 2} specific radioligand, to investigate in vivo the cortical 5HT{sub 2} receptors in migraine subjects. Nine migraineurs who had either migraine with and without aura or only migraine without aura were studied between attacks. 12 unmedicated healthy subjects of similar mean age were used as controls. Brain radioactivity was measured after {sup 18}F-setoperone IV injection for 90 min. A decrease of the regional specific distribution volumes (SDV) of the ligand was observed both in migraineurs and in controls. The age adjusted group means of SDV did not differ between patients and controls for the whole and for the right or left frontal, temporal, parietal and occipital cortex. These results suggest that cortical 5HT{sub 2} receptors may be unaltered between attacks in migraine sufferers. 30 refs., 4 figs., 2 tabs.

  13. Preparation of an imaging agent for cerebral muscarinic acetylcholine receptor, (R,S)131I-QNB

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    The method to synthesize a high affinity muscarinic receptor antagonist (R,S)I-QNB[(R)-(-)-1-azabicyclo [2,2,2]oct-3-yl-(S)-(+)-α-hydroxy-α-(4-[127I]iodophenyl)-α-phenyl acetate] from 4-nitrobenzophenone with improvement compared to literatures was reported in this article. IR, MS and 1HNMR characterized the final product. (R,S)131I-QNB was prepared using Cu(I) assisted iodine exchange labeling, and showed by TLC that the radiolabeling yield(RLY) was over 80%, and radiochemical purity(RCP) was over 95%. Stability of the labeled compound was also determined. It was found that (R,S)131I-QNB dried by nitrogen blowing can stay at 4-10℃ for a week without change of RCP.

  14. Tuberculoma cerebral Cerebral tuberculoma

    Directory of Open Access Journals (Sweden)

    ELIZABETH CLARA BARROSO

    2002-01-01

    Full Text Available Relata-se o caso de paciente com crises convulsivas de início recente. A tomografia computadorizada cerebral evidenciou imagem sugestiva de lesão expansiva metastática frontoparietal direita. A investigação de tumor primário ou outra doença foi negativa e o exame histopatológico do tecido cerebral diagnosticou tuberculoma. As convulsões foram controladas com a associação de hidantoína 300mg/dia ao esquema específico, utilizado por 18 meses. A tuberculose do sistema nervoso central representa 5-15% das formas extrapulmonares e é reconhecida como de alta letalidade. Apresentação tumoral como a relatada é rara, particularmente em imunocompetentes. Quando tratada, pode ter bom prognóstico e deve entrar sempre no diagnóstico diferencial de massas cerebrais.It is reported a case of a previously healthy man with seizures of sudden onset. A contrast head computerized tomogram (CT showed a right frontoparietal expanding lesion suggesting to be metastatic. No prior disease was found on investigation. The histologic exam of the brain revealed tuberculoma. The seizures were controlled with Hidantoin 300 mg/day and antituberculosis chemotherapy for 18 months. Central nervous system tuberculosis (5-15% of the extrapulmonary forms is highly lethal. The case reported herein is specially rare in immunocompetent patients. It may have good prognosis and should be considered in the differential diagnosis of brain tumours.

  15. [Histamine intolerance - are the criteria of an adverse reaction met?].

    Science.gov (United States)

    Reese, Imke

    2016-06-01

    Searching the internet for an explaination of recurring symptoms, many people come across the so-called histamine intolerance disorder. Also many practitioners like to diagnose this disorder without making sure that reproducibility, a prerequisite for an adverse reaction, is present. Consequently, presumably affected persons are often advised to follow a low-histamine diet. Depending on the source of information, these diets often avoid a huge variety of foods containing more or less histamine, which has a considerable impact on patient quality of life. While most persons benefit from such a diet in the beginning - this might be due to the change in dietary habits or the expectation of symptom improvement by dieting - in the long run the expected loss of symptoms will not happen. Underlying a diminished capacity for histamine degradation, the lack of partial or complete symptom improvement might be due to the fact that endogenous histamine release is responsible for reactions. The role of ingested histamine is discussed controversially. However, it is more than obvious that the histamine content of a certain food alone is not enough to predict its tolerance.If histamine intolerance is suspected, an individual diagnostic and therapeutic procedure is mandatory in order to minimize avoidance and to preserve a high quality of life. Ideally this is done in a close cooperation between allergologists and nutritionists/dieticians. PMID:27177895

  16. The effect of histamine on changes in mental energy and fatigue after a single bout of exercise.

    Science.gov (United States)

    Loy, Bryan D; O'Connor, Patrick J

    2016-01-01

    The purpose of this research was to determine if histamine, acting on brain H1 receptors, influences changes in feelings of energy and fatigue or cognitive test performance after acute exercise. Women (n=20) with low vigor and high fatigue were administered the H1 antagonist drug doxepin hydrocholoride (6 mg) in tomato juice and tomato juice alone (placebo) in a randomized, double-blinded, cross-over experiment before performing 30 min of light intensity cycling exercise and completing energy, fatigue, sleepiness, and motivation scales, and cognitive tasks. After exercise, mental fatigue increased for the doxepin condition (p=0.014) but not placebo (p=0.700), while mental energy decreased for both PLA and DOX (pcognitive task performance was unaffected. It is inferred that histamine binding to H1 receptors in the brain has a role in exercise-induced reductions in mental fatigue, but not increases in energy. PMID:26482543

  17. Opioid-receptor (OR) signaling cascades in rat cerebral cortex and model cell lines: the role of plasma membrane structure.

    Science.gov (United States)

    Ujčíková, H; Brejchová, J; Vošahlíková, M; Kagan, D; Dlouhá, K; Sýkora, J; Merta, L; Drastichová, Z; Novotný, J; Ostašov, P; Roubalová, L; Parenti, M; Hof, M; Svoboda, P

    2014-01-01

    Large number of extracellular signals is received by plasma membrane receptors which, upon activation, transduce information into the target cell interior via trimeric G-proteins (GPCRs) and induce activation or inhibition of adenylyl cyclase enzyme activity (AC). Receptors for opioid drugs such as morphine (micro-OR, delta-OR and kappa-OR) belong to rhodopsin family of GPCRs. Our recent results indicated a specific up-regulation of AC I (8-fold) and AC II (2.5-fold) in plasma membranes (PM) isolated from rat brain cortex exposed to increasing doses of morphine (10-50 mg/kg) for 10 days. Increase of ACI and ACII represented the specific effect as the amount of ACIII-ACIX, prototypical PM marker Na, K-ATPase and trimeric G-protein alpha and beta subunits was unchanged. The up-regulation of ACI and ACII faded away after 20 days since the last dose of morphine. Proteomic analysis of these PM indicated that the brain cortex of morphine-treated animals cannot be regarded as being adapted to this drug because significant up-regulation of proteins functionally related to oxidative stress and alteration of brain energy metabolism occurred. The number of delta-OR was increased 2-fold and their sensitivity to monovalent cations was altered. Characterization of delta-OR-G-protein coupling in model HEK293 cell line indicated high ability of lithium to support affinity of delta-OR response to agonist stimulation. Our studies of PM structure and function in context with desensitization of GPCRs action were extended by data indicating participation of cholesterol-enriched membrane domains in agonist-specific internalization of delta-OR. In HEK293 cells stably expressing delta-OR-G(i)1alpha fusion protein, depletion of PM cholesterol was associated with the decrease in affinity of G-protein response to agonist stimulation, whereas maximum response was unchanged. Hydrophobic interior of isolated PM became more "fluid", chaotically organized and accessible to water molecules

  18. Histamine release from cord blood basophils

    DEFF Research Database (Denmark)

    Nielsen, Bent Windelborg; Damsgaard, Tine Engberg; Herlin, Troels;

    1990-01-01

    The histamine release (HR) after challenge with anti-IgE, concanavalin A, N-formyl-met-leu-phe and the calcium ionophore A23187 from 97 cord blood samples was determined by a microfiber-based assay. Maximum HR with anti-IgE showed great inter-individual variation (median: 20.5; range: 1-104 ng...... stimulated by the calcium ionophore A 23187 was found to be highly dependent on the storage time of the EDTA-anticoagulated blood samples, which should be carefully controlled....

  19. Experimental study on alteration of adrenergic receptors activity in neuronal membranes protein of cerebral cortex following brain trauma in rats

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xin-wei; XU Ru-xiang; QI Yi-long; CHEN Chang-cai

    2001-01-01

    Objective: To define the course of changes taken by α1 and β adrenergic receptors (AR) activity after traumatic brain injury (TBI) and explore the approach for secondary brain injury (SBI) management. Methods: The neuronal membrane protein of cortex were extracted from the rats subject to traumatic brain injury, and the changes of α1- and β-AR activities in the neuronal membranes were examined by radio ligand binding assay (RLBA). Results: α1- and β-AR activities underwent obvious changes, reaching their peak values at 24 h after TBI. α1-AR binding density (Bmax) reduced by 22.6%while the ligand affinity increased by 66.7%, and for β-AR, however, Bmax increased by 116.9% and the ligand affinity reduced by 50.7%. Their antagonists could counteract the changes ofα1- and β-AR activity. Conclusion: The patterns of changes varies between α1- and β-AR activity after TBI, suggesting their different roles in the neuronal membranes after brain trauma, and timely administration of AR antagonists is potentially beneficial in TBI management.

  20. Association between cerebral cannabinoid 1 receptor availability and body mass index in patients with food intake disorders and healthy subjects: a [(18)F]MK-9470 PET study.

    Science.gov (United States)

    Ceccarini, J; Weltens, N; Ly, H G; Tack, J; Van Oudenhove, L; Van Laere, K

    2016-01-01

    Although of great public health relevance, the mechanisms underlying disordered eating behavior and body weight regulation remain insufficiently understood. Compelling preclinical evidence corroborates a critical role of the endocannabinoid system (ECS) in the central regulation of appetite and food intake. However, in vivo human evidence on ECS functioning in brain circuits involved in food intake regulation as well as its relationship with body weight is lacking, both in health and disease. Here, we measured cannabinoid 1 receptor (CB1R) availability using positron emission tomography (PET) with [(18)F]MK-9470 in 54 patients with food intake disorders (FID) covering a wide body mass index (BMI) range (anorexia nervosa, bulimia nervosa, functional dyspepsia with weight loss and obesity; BMI range=12.5-40.6 kg/m(2)) and 26 age-, gender- and average BMI-matched healthy subjects (BMI range=18.5-26.6 kg/m(2)). The association between regional CB1R availability and BMI was assessed within predefined homeostatic and reward-related regions of interest using voxel-based linear regression analyses. CB1R availability was inversely associated with BMI in homeostatic brain regions such as the hypothalamus and brainstem areas in both patients with FID and healthy subjects. However, in FID patients, CB1R availability was also negatively correlated with BMI throughout the mesolimbic reward system (midbrain, striatum, insula, amygdala and orbitofrontal cortex), which constitutes the key circuit implicated in processing appetitive motivation and hedonic value of perceived food rewards. Our results indicate that the cerebral homeostatic CB1R system is inextricably linked to BMI, with additional involvement of reward areas under conditions of disordered body weight. PMID:27404285

  1. The histamine degradative uptake pathway in human vascular endothelial cells and skin fibroblasts is dependent on extracellular Na+ and Cl-

    International Nuclear Information System (INIS)

    We have previously reported that human vascular endothelial cells and skin fibroblasts carry out degradation of [3H]histamine by a mechanism involving two successive enzymatic steps: imidazole ring tele-methylation by the cells' endogenous methyltransferase and subsequent amine oxidation by an exogenous diamine oxidase. Both histamine and the exogenous second enzyme in the pathway associate with the cells via separate binding sites or receptors. The enzymatic degradation process results in cellular accumulation of the proximal and distal metabolites tele-methylhistamine and 1-methyl-4-imidazoleacetic acid (MIAA). We have now demonstrated that this two-stage histamine degradative pathway is dependent on Na+ and Cl- in the extracellular environment. Accumulation of [3H] histamine-derived products is partially inhibited under conditions of Na+ deprivation and more substantially when Cl- is also withdrawn. The individual tele-methylation and amine oxidation enzymatic reactions themselves are unaffected or actually facilitated under these conditions. This indicates that it is the cellular mechanism for uptake coupled to the degradative pathway which reflects the cation and anion dependency. Restoration of degradative uptake displays a biphasic Na+ concentration curve, suggesting that the uptake process may be driven by multiple components. These findings indicate a role for both inward Na+ and Cl- ion movement in this cellular degradative uptake mechanism

  2. The effects of thermal stimuli on intracellular calcium change and histamine releases in rat basophilic leukemia mast cells

    Science.gov (United States)

    Wu, Zu-Hui; Zhu, Dan; Chen, Ji-Yao; Zhou, Lu-Wei

    2012-05-01

    The effects of thermal stimuli on rat basophilic leukemia mast cells were studied. The cells in calcium-contained or calcium-free buffers were thermally stimulated in the temperature range of 25-60 °C. The corresponding calcium ion concentration in cells [Ca2+]i as well as the released histamine from cells was measured with fluorescence staining methods. The ruthenium red (RR), a block of membrane calcium channels (transient receptor potential family V (TRPV)), was used in experiments. Under the stimulus of 25-50 °C, no significant difference on [Ca2+]i was found between these three groups of the cells in calcium-contained buffer without or with RR and cells in calcium-free saline, indicating that the increased calcium in cytosol did not result from the extracellular buffer but came from the intracellular calcium stores. The [Ca2+]i continuously increased under the temperature of 50-60 °C, but the RR and calcium-free saline can obviously diminish the [Ca2+]i increase at these high temperatures, reflecting that the opening of the TRPV2 channels leads to a calcium influx resulting in the [Ca2+]i increment. The histamine release also became significant in these cases. Since the released histamine is a well-known mediator for the microcirculation promotion, the histamine release from mast cells could be one of the mechanisms of thermal therapy.

  3. Cerebral Palsy

    Science.gov (United States)

    ... 1 • 2 • 3 For Teens For Kids For Parents MORE ON THIS TOPIC Cerebral Palsy: Keith's Story Physical Therapy I Have Cerebral Palsy. Can I Babysit? Body Image and Self-Esteem Contact Us Print Resources Send to a friend ...

  4. Quantitative estimation of I-123-Iomazenil receptor binding in temporal lobe epilepsies using two SPECT acquisitions - comparison with the regional cerebral blood flow and a compartment model

    Energy Technology Data Exchange (ETDEWEB)

    Venz, S.; Hierholzer, J.; Cordes, M.; Keske, U.; Eichstaedt, H.; Felix, R. [Humboldt-Universitaet, Berlin (Germany). Strahlenklinik und Poliklinik; Straub, H.B.; Meencke, H.J. [Humboldt Univ., Berlin (Germany). Neurologische Klinik und Poliklinik

    1998-03-01

    28 patients were studied. 13/28 patients had a drug-resistant unilateral temporal lobe epilepsy with a successful focus localisation performed by an extensive video/EEG monitoring. 15 other patients with clinically suspected focal epilepsy and a normal MRI and IMZ SPECT scanning were used as controls. SPECT scanning was performed in all patients 15 and 100 min after intravenous injection of 111 MBq IMZ and 10 min after application of 740 MBq Tc-99m-HMPAO. Quantification of the regional uptake was performed using ROI-technique and the specific and non-specific binding of IMZ was calculated. The receptor index was calculated by the difference of the specific binding from 15 to 100 min p.i. divided by the time interval. The receptor index showed a linear correlation with recently published fractional rate constants k{sub 3} (r=0.69 and 0.67; p=0.15) and a moderate correlation with the k{sub 4} constant (-0.53 and -0.43; p=0.28) by the means of C-11-Flumazenil PET and I-123-Iomazenil SPECT studies, respectively. However, statistical significance was not reached due to the few data points available from the published reports. Furthermore, the IMZ receptor index was lower in the epileptogenic area of patients with unilateral temporal lobe epilepsies compared with their contralateral side. The IMZ receptor index showed a weak correlation with the regional cerebral blood flow independent of the evaluated region (r<0.4; p<0.05). (orig./MG) [Deutsch] 28 Patienten wurden in die Studie eingeschlossen. 13/28 Patienten litten unter pharmakoresistenten unilateralen Temporallappenepilepsien mit erfolgreicher Fokuslokalisation durch ein Video/EEG-Monitoring. 15 weitere Patienten mit klinisch vermuteten fokalen Epilepsien und unauffaelligem MRT, HMPAO und IMZ SPECT Untersuchungen dienten als Kontrollgruppe. Die SPECT wurde 15 und 100 Minuten nach Applikation von 111 MBq I-123-Iomazenil und 10 Minuten nach Applikation von 740 MBq Tc-99m-HMPAO durchgefuehrt. Die Quantifizierung der

  5. Differential binding of 3H-imipramine and 3H-mianserin in rat cerebral cortex

    International Nuclear Information System (INIS)

    Drug competition profiles, effect of raphe lesion, and sodium dependency of the binding of two antidepressant drugs 3H-imipramine and 3H-mianserin to rat cerebral cortex homogenate were compared to examine whether the drugs bound to a common ''antidepressant receptor.'' Of the neurotransmitters tested, only serotonin displaced binding of both 3H-imipramine and 3H-mianserin. 3H-Mianserin binding was potently displaced by serotonin S2 antagonists and exhibited a profile similar to that of 3H-spiperone binding. In the presence of the serotonin S2 antagonist spiperone, antihistamines (H1) potently displaced 3H-mianserin binding. 3H-Imipramine binding was displaced potently by serotonin uptake inhibitors. The order of potency of serotonergic drugs in displacing 3H-imipramine binding was not similar to their order in displacing 3H-spiperone or -3H-serotonin binding. Prior midbrain raphe lesions greatly decreased the binding of 3H-imipramine but did not alter binding of 3H-mianserin. Binding of 3H-imipramine but not 3H-mianserin was sodium dependent. These results show that 3H-imipramine and 3H-mianserin bind to different receptors. 3H-Imipramine binds to a presynaptic serotonin receptor which is probably related to a serotonin uptake recognition site, the binding of which is sodium dependent. 3H-Mianserin binds to postsynaptic receptors, possibly both serotonin S2 and histamine H1 receptors, the binding of which is sodium independent

  6. The histamine system in human brain. Changes in neurological and psychiatric disorders

    International Nuclear Information System (INIS)

    Autoradiographical examination of the distribution of H1- and H3- histamine receptor subtypes, using [3H]-mepyramine and [3H]-R-(α) methylhistamine respectively, found high H1-receptor binding densities in neocortex, dentate gyrus and basolateral amygdala, with low binding in all subdivisions of the thalamus and other subcortical areas. H3-receptor binding was enriched within the nucleus accumbens, globus pallidus and substantia nigra, whilst was low in the hippocampus, subthalamic nucleus, temporal cortex, motor and somatosensory thalamic areas and basolateral amygdala. In situ hybridisation found H2-receptor mRNA located in the striatum, thalamus, hippocampal pyramidal cell layer and dentate gyrus, and specific laminae of neocortex. Comparison of autoradiographically determined H1-, H2- and H3-receptor binding densities between normal and pathological cases found significantly decreased (p 3-receptor binding in Huntington's disease (HD), with unaltered binding in the insular cortex. A significant correlation (p 1-receptor was increased (p 2- (measured using [125I]-iodoaminopotentidine) and H3-receptor binding densities were normal in all areas examined. H1-receptor binding was also increased in the hippocampus of Lewy-body dementia (DLB) cases (p 2-receptor binding densities were decreased in DLB, together with Alzheimer's disease (AD) (p 3-receptor binding was increased in the insular cortex and decreased in the temporal cortex of DLB, but not AD, cases (p 1-receptor binding to tissue from patients with schizophrenia was significantly reduced in all cortical (p 2-receptor binding was unaltered in all areas, however H3-receptor binding was increased in the posterior putamen (p < 0.05), and highly significantly decreased (p < 0.005, Students two-tailed T-Test) in the external globus pallidus in schizophrenia. (author)

  7. Histamine modifies malignant biological behaviour in irradiated breast cancer cells

    International Nuclear Information System (INIS)

    MDA MB 231, a metastatic breast cancer cell line, expresses the four known types of histamine receptors (HAR), which differentially regulate cell proliferation. HA also exerts a radiosensitizing effect when is added to MDA MB 231 cells before irradiation in a way related to the elevation of H2O2 levels. However, ionizing radiation (IR) has also been demonstrated to affect malignant biological behaviour depending upon cell type and irradiation characteristics. The present study was conducted to investigate the action of HA and IR on two events involved in metastatic capacity such as the expression and activity of matrix metalloproteinases (MMPs) and cell motility. HA decreased MMP2 and MMP9 expression assessed by RT-PCR and cytochemistry as well enzymatic activity determined by zimography. This effect was mimicked by H2 agonists, while an opposite action was mainly observed when H4 agonists were employed. Cell motility, evaluated by wound healing assay, was also distinctly modulated through HAR. It was significantly augmented via H4R and to a lesser extent via H1R and H3R, though diminished through H2R. 2 Gy irradiated cells showed an enhanced MMP2 and MMP9 activity and cell motility compared to control cells. However, this effect was counteracted by HA. Results suggest that HA treatment could improve radiotherapy efficacy regarding the potential development of metastases. (authors)

  8. Fibroblasts induce epithelial to mesenchymal transition in breast tumor cells which is prevented by fibroblasts treatment with histamine in high concentration.

    Science.gov (United States)

    Porretti, Juliana C; Mohamad, Nora A; Martín, Gabriela A; Cricco, Graciela P

    2014-06-01

    Epithelial to mesenchymal transition (EMT) of cancer cells is an essential process in cancer progression. Cancer cells that undergone EMT loose cell-cell contacts, acquire mesenchymal properties and develop migratory and invasive abilities. In previous studies we have demonstrated that histamine may modify the invasive phenotype of pancreatic and mammary tumor cells. In this work we proposed to investigate whether histamine may also influence the interaction between tumor cells and normal fibroblasts. The potential activation of normal CCD-1059Sk fibroblasts by histamine and EMT phenotypic changes induced in MCF-7 and MDA-MB-231 breast tumor cells by the conditioned media (CM) derived from fibroblasts were evaluated. Initially, we determined the presence of H1, H2 and H4 histamine receptors and matrix metalloproteinase 2 (MMP2) mRNA in CCD-1059Sk fibroblasts. MMP2 gelatinolytic activity, cell migration and alpha-smooth muscle actin expression were increased in fibroblasts by low doses (histamine. MCF-7 cells cultured with CM from fibroblasts exhibited spindle-shaped morphology, cell spreading and cytoplasmic expression of β-catenin but there was no change in MMP2 activity and cell migration. MDA-MB-231 cells cultured with CM from fibroblasts showed a more elongated phenotype, cell spreading, cytoplasmic β-catenin, increased MMP2 activity and endogenous TGF-β1 expression, and enhanced cell migration and invasion. Notably, all these features were reversed when mammary tumor cells were cultured with CM from fibroblasts treated with 20μM histamine. In conclusion, high doses of histamine may prevent the activation of fibroblasts and also avert the EMT related changes induced in epithelial tumor cells by fibroblasts CM. PMID:24685678

  9. Cervical squamous carcinoma cells are resistant to the combined action of tumor necrosis factor-α and histamine whereas normal keratinocytes undergo cytolysis

    International Nuclear Information System (INIS)

    Previous reports showed that mast cells can typically be found in the peritumoral stroma of cervix carcinomas as well as in many other cancers. Both histamine and TNF-α are potent preformed mast cell mediators and they can act simultaneously after release from mast cells. Thus, the effect of TNF-α and histamine on cervical carcinoma cell lines was studied. TNF-α alone induced slight growth inhibition and cell cycle arrest at G0/G1 phase in SiHa cells, but increased their migration. Histamine alone had no effect on cells. In addition, TNF-α and histamine in combination showed no additional effect over that by TNF-α alone, although SiHa cells were even pretreated with a protein synthesis inhibitor. Furthermore, TNF-α-sensitive ME-180 carcinoma cells were also resistant to the combination effect of TNF-α and histamine. In comparison, TNF-α or histamine alone induced growth inhibition in a non-cytolytic manner in normal keratinocytes, an effect that was further enhanced to cell cytolysis when both mediators acted in combination. Keratinocytes displayed strong TNF receptor (TNFR) I and II immunoreactivity, whereas SiHa and ME-180 cells did not. Furthermore, cervix carcinoma specimens revealed TNF-α immunoreactivity in peritumoral cells and carcinoma cells. However, the immunoreactivity of both TNFRs was less intense in carcinoma cells than that in epithelial cells in cervical specimens with non-specific inflammatory changes. SiHa and ME-180 cells are resistant to the cytolytic effect of TNF-α and histamine whereas normal keratinocytes undergo cytolysis, possibly due to the smaller amount of TNFRs in SiHa and ME-180 cells. In the cervix carcinoma, the malignant cells may resist this endogenous cytolytic action and TNF-α could even enhance carcinoma cell migration

  10. Cerebral palsy.

    Science.gov (United States)

    Graham, H Kerr; Rosenbaum, Peter; Paneth, Nigel; Dan, Bernard; Lin, Jean-Pierre; Damiano, Diane L; Becher, Jules G; Gaebler-Spira, Deborah; Colver, Allan; Reddihough, Dinah S; Crompton, Kylie E; Lieber, Richard L

    2016-01-01

    Cerebral palsy is the most common cause of childhood-onset, lifelong physical disability in most countries, affecting about 1 in 500 neonates with an estimated prevalence of 17 million people worldwide. Cerebral palsy is not a disease entity in the traditional sense but a clinical description of children who share features of a non-progressive brain injury or lesion acquired during the antenatal, perinatal or early postnatal period. The clinical manifestations of cerebral palsy vary greatly in the type of movement disorder, the degree of functional ability and limitation and the affected parts of the body. There is currently no cure, but progress is being made in both the prevention and the amelioration of the brain injury. For example, administration of magnesium sulfate during premature labour and cooling of high-risk infants can reduce the rate and severity of cerebral palsy. Although the disorder affects individuals throughout their lifetime, most cerebral palsy research efforts and management strategies currently focus on the needs of children. Clinical management of children with cerebral palsy is directed towards maximizing function and participation in activities and minimizing the effects of the factors that can make the condition worse, such as epilepsy, feeding challenges, hip dislocation and scoliosis. These management strategies include enhancing neurological function during early development; managing medical co-morbidities, weakness and hypertonia; using rehabilitation technologies to enhance motor function; and preventing secondary musculoskeletal problems. Meeting the needs of people with cerebral palsy in resource-poor settings is particularly challenging. PMID:27188686

  11. Mast cells and histamine play an important role in edema and leukocyte recruitment induced by Potamotrygon motoro stingray venom in mice.

    Science.gov (United States)

    Kimura, Louise F; Prezotto-Neto, José Pedro; Távora, Bianca C L F; Faquim-Mauro, Eliana L; Pereira, Nicole A; Antoniazzi, Marta M; Jared, Simone G S; Teixeira, Catarina F P; Santoro, Marcelo L; Barbaro, Katia C

    2015-09-01

    This work aimed to investigate mechanisms underlying the inflammatory response caused by Potamotrygon motoro stingray venom (PmV) in mouse paws. Pre-treatment of animals with a mast cell degranulation inhibitor (cromolyn) diminished edema (62% of inhibition) and leukocyte influx into the site of PmV injection. Promethazine (histamine type 1 receptor antagonist) or thioperamide (histamine type 3 and 4 receptor antagonist) also decreased edema (up to 30%) and leukocyte numbers, mainly neutrophils (40-50 %). Cimetidine (histamine type 2 receptor antagonist) had no effect on PmV-induced inflammation. In the RBL-2H3 lineage of mast cells, PmV caused proper cell activation, in a dose-dependent manner, with release of PGD2 and PGE2. In addition, the role of COXs products on PmV inflammatory response was evaluated. Indomethacin (COX-1/COX-2 inhibitor) or etoricoxib (COX-2 inhibitor) partially diminished edema (around 20%) in PmV-injected mice. Indomethacin, but not etoricoxib, modulated neutrophil influx into the site of venom injection. In conclusion, mast cell degranulation and histamine, besides COXs products, play an important role in PmV-induced reaction. Since PmV mechanism of action remains unknown, hindering accurate treatment, clinical studies can be performed to validate the prescription of antihistaminic drugs, besides NSAIDs, to patients injured by freshwater stingrays. PMID:26100666

  12. OCCURANCE OF HISTAMINE IN FISH PRODUCTS ON MARKET

    Directory of Open Access Journals (Sweden)

    R. Mancusi

    2012-08-01

    Full Text Available Histamine fish poisoning is quite common and occur in consequence of microbial decarboxylase whose activity begin early in the post-mortem but are triggered in consequence of abuse in the shelf life of fish products. In this study forty-eight samples of tuna, mackerel, anchovies, sardines, fresh or processed were sampled from fish shops and supermarkets in the City of Bologna in the period from January to July 2010. Concentration of histamine was assessed using ELISA quantitative test and presence of psicrotrophic histamine forming bacteria was searched using a modified Niven agar medium which allow detection of suspect colonies that were confirmed by PCR for detecting the presence of the histidine decarboxylase genes in their DNA. The positive colonies were then identified on the basis of their morphology, Gram reaction and biochemical characteristics with API20E. The differential capability of the Niven agar was found to be low and approximately one fifth of the suspect colonies were confirmed by the PCR test, which however included both strong and weak histamine producing strains. The presence of Morganella morganii was associated with concentration of histamine 460 mg∙kg-1 above the allowed limit in a sample of tuna sampled from a fish shop. The same bacterium was found in samples of Atlantic horse mackerel (Trachurus trachurus. High histamine concentration (between 258 and > 300 mg∙kg-1 were observed in salted European pilchard and European anchovy (228 mg∙kg-1 sold loose in supermarkets. Because temperature abuse could occur when Tuna (fresh/defrozen are hold on chopping board to sell fresh cuts and during shelf life of salted pilchard and pickled anchovies held in opened cans in chilled display cabinets for extended period, which might results in very high histamine concentration, controls on time and temperature at the retail, in addition to those done during the harvest and processing are needed. The studies aiming at

  13. Cerebral hypoxia

    Science.gov (United States)

    ... the veins ( deep vein thrombosis ) Lung infections (pneumonia) Malnutrition When to Contact a Medical Professional Cerebral hypoxia ... References Bernat JL. Coma, vegetative state, and brain death. In: Goldman L, Schafer AI, eds. Goldman's Cecil ...

  14. Modulation of neutrophil oxidative burst via histamine receptors

    Czech Academy of Sciences Publication Activity Database

    Číž, Milan; Lojek, Antonín

    2013-01-01

    Roč. 170, č. 1 (2013), s. 17-22. ISSN 0007-1188 R&D Projects: GA MŠk(CZ) LD11010 Institutional support: RVO:68081707 Keywords : neutrophil * oxidative burst * reactive oxygen species Subject RIV: BO - Biophysics Impact factor: 4.990, year: 2013

  15. Expression of histamine receptors in the human endolymphatic sac

    DEFF Research Database (Denmark)

    Møller, M Nue; Kirkeby, S; Vikeså, J.;

    2016-01-01

    The human endolymphatic sac (ES) is situated in a duplicature of the dura in the posterior cranial fossa and constitutes a part of the inner ear. The sac possesses immunological capacities and is responsible for a major part of the trans-epithelial ion transport occurring within the inner ear, via...

  16. In Vivo Histamine Optical Nanosensors

    Directory of Open Access Journals (Sweden)

    Heather A. Clark

    2012-08-01

    Full Text Available In this communication we discuss the development of ionophore based nanosensors for the detection and monitoring of histamine levels in vivo. This approach is based on the use of an amine-reactive, broad spectrum ionophore which is capable of recognizing and binding to histamine. We pair this ionophore with our already established nanosensor platform, and demonstrate in vitro and in vivo monitoring of histamine levels. This approach enables capturing rapid kinetics of histamine after injection, which are more difficult to measure with standard approaches such as blood sampling, especially on small research models. The coupling together of in vivo nanosensors with ionophores such as nonactin provide a way to generate nanosensors for novel targets without the difficult process of designing and synthesizing novel ionophores.

  17. Quality assurance of histamine analysis in fresh and canned fish.

    Science.gov (United States)

    Evangelista, Warlley P; Silva, Tarliane M; Guidi, Letícia R; Tette, Patrícia A S; Byrro, Ricardo M D; Santiago-Silva, Paula; Fernandes, Christian; Gloria, Maria Beatriz A

    2016-11-15

    Histamine determination is relevant for fish safety, quality and trade. Recently a study by the European Union (EU) compared the Codex and the EU mandated methods for the analysis of histamine and observed that they underestimated and overestimated the results, respectively. To solve this problem, a simple and efficient procedure for the extraction and quantification of histamine by ion-pair HPLC method with post-column derivatization and fluorimetric detection is proposed. It was optimized and validated for the analysis of histamine in fish. The method attended the performance criteria established by Commission Decision 2002/657/CE. The method was also submitted to proficiency testing; uncertainty was calculated; and the stability of solutions and standards was investigated. There was no matrix effect. The LOD, LOQ, CCα and CCβ were fit for the purpose. The method was successfully used in the analyses of freshwater fish and fresh and canned tuna. PMID:27283612

  18. Mechanisms of histamine stimulated secretion in rabbit ileal mucosa.

    OpenAIRE

    Linaker, B D; McKay, J S; Higgs, N B; Turnberg, L A

    1981-01-01

    Histamine is present in high concentrations in the intestine and we investigated the possibility that it might have a role here in intestinal transport. When added to the basal side of rabbit ileal mucosa in vitro histamine (10(-4)M) induced a short-lived increase in electrical potential difference and short circuit current. It inhibited net chloride absorption but did not influence sodium transport. Alkali secretion, measured by a pH stat technique, was inhibited, suggesting that bicarbonate...

  19. Effect of cysteamine on gastroduodenal mucosal histamine in rat.

    OpenAIRE

    Boesby, S; Man, W K; Mendez-Diaz, R; Spencer, J

    1983-01-01

    Cysteamine administration to rats is followed by a high incidence of peptic ulceration. The aim of the present study was to investigate the effect of cysteamine on gastric and duodenal mucosal histamine and gastric mucosal histamine formation capacity. After a four hour fast, cysteamine in doses of 50, 100, 200, 300, 400, and 500 mg/kg bodyweight was injected subcutaneously to male Wistar rats; saline injection was used as control. After 24 hours the animals were killed; the stomach and duode...

  20. Cerebral Palsy (For Parents)

    Science.gov (United States)

    ... Story" 5 Things to Know About Zika & Pregnancy Cerebral Palsy KidsHealth > For Parents > Cerebral Palsy Print A A ... kids who are living with the condition. About Cerebral Palsy Cerebral palsy is one of the most common ...