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2.
Psychopharmacology (Berl) ; 238(6): 1495-1511, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33550481

RESUMO

RATIONALE: Samelisant (SUVN-G3031) is a potent and selective histamine H3 receptor (H3R) inverse agonist with good brain penetration and oral bioavailability. OBJECTIVES: Pharmacological and neurochemical characterisation to support the utility of Samelisant (SUVN-G3031) in the treatment of sleep-related disorders like narcolepsy. METHODS: Samelisant (SUVN-G3031) was tested in rat brain microdialysis studies for evaluation of modulation in histamine, dopamine and norepinephrine. Sleep EEG studies were carried out in orexin knockout mice to study the effects of Samelisant (SUVN-G3031) on the sleep-wake cycle and cataplexy. RESULTS: Samelisant (SUVN-G3031) has a similar binding affinity towards human (hH3R; Ki = 8.7 nM) and rat (rH3R; Ki = 9.8 nM) H3R indicating no inter-species differences. Samelisant (SUVN-G3031) displays inverse agonist activity and it exhibits very high selectivity towards H3R. Samelisant (SUVN-G3031) treatment in mice produced a dose-dependent increase in tele-methylhistamine levels indicating the activation of histaminergic neurotransmission. Apart from increasing the levels of histamine, Samelisant (SUVN-G3031) also modulates dopamine and norepinephrine levels in the cerebral cortex while it has no effects on dopamine levels in the striatum or nucleus accumbens. Treatment with Samelisant (SUVN-G3031; 10 and 30 mg/kg, p.o.) produced a significant increase in wakefulness with a concomitant decrease in NREM sleep in orexin knockout mice subjected to sleep EEG. Samelisant (SUVN-G3031) also produced a significant decrease in Direct REM sleep onset (DREM) episodes, demonstrating its anticataplectic effects in an animal model relevant to narcolepsy. Modulation in cortical levels of histamine, norepinephrine and dopamine provides the neurochemical basis for wake-promoting and anticataplectic effects observed in orexin knockout mice. CONCLUSIONS: Pre-clinical studies of Samelisant (SUVN-G3031) provide a strong support for utility in the treatment of sleep-related disorders related to EDS and is currently being evaluated in a phase 2 proof of concept study in the USA for the treatment of narcolepsy with and without cataplexy.


Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Morfolinas/farmacologia , Narcolepsia/tratamento farmacológico , Piperidinas/farmacologia , Animais , Eletroencefalografia , Histamina/metabolismo , Humanos , Masculino , Metilistaminas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Orexinas/genética , Ratos , Ratos Wistar , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos
3.
Comp Med ; 69(2): 130-134, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30803469

RESUMO

Chronic lymphocytic enteritis (CLE) is a frequent disease in common marmosets. However, no diagnostic test for early detection of CLE is available. Mast cells have an important role in gastrointestinal disease. The purpose of this study was to measure fecal concentrations of N-methylhistamine (NMH), a breakdown product of histamine metabolism, in common marmosets. A previously established NMH gas chromatography-mass spectrometry assay for canine feces and urine was used, and partial validation was performed. The reference intervals (n = 30) established for fecal NMH concentrations in common marmoset were 118.2 ng/g or less for a single fecal sample, 121.7 ng/g or less for the 3-d mean, and less than or equal to 167.5 ng/g for the 3-d maximum. Considerable day-to-day variation was observed in fecal NMH concentrations; the mean %CV was 42.2% (minimum, 7.1%; maximum, 141.4%). Fecal NMH concentrations were measured in 14 marmosets for which necropsy reports were available; 7 of the 8 marmosets with CLE and the 1 animal with lymphoma and ulcerative enteritis had increased fecal NMH concentrations. Increased fecal NMH concentrations may serve as a potential marker for CLE; however, further studies exploring the role of mast cells in marmosets with CLE are needed.


Assuntos
Enterite/veterinária , Doenças dos Macacos/metabolismo , Animais , Biomarcadores/metabolismo , Callithrix , Enterite/metabolismo , Fezes , Feminino , Masculino , Metilistaminas/metabolismo
4.
Clin Cancer Res ; 24(20): 5085-5097, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30084838

RESUMO

Purpose: Kaposi sarcoma (KS) is a vascular tumor initiated by infection of endothelial cells (ECs) with KS-associated herpesvirus (KSHV). KS is dependent on sustained proinflammatory signals provided by intralesional leukocytes and continued infection of new ECs. However, the sources of these cytokines and infectious virus within lesions are not fully understood. Here, mast cells (MCs) are identified as proinflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV.Experimental Design: Three validated MC lines were used to assess permissivity of MCs to infection with KSHV and to evaluate MCs activation following infection. Biopsies from 31 AIDS-KS cases and 11 AIDS controls were evaluated by IHC for the presence of MCs in KS lesions and assessment of MC activation state and infection with KSHV. Plasma samples from 26 AIDS-KS, 13 classic KS, and 13 healthy adults were evaluated for levels of MC granule contents tryptase and histamine.Results: In culture, MCs supported latent and lytic KSHV infection, and infection-induced MC degranulation. Within KS lesions, MCs were closely associated with spindle cells. Furthermore, MC activation was extensive within patients with KS, reflected by elevated circulating levels of tryptase and a histamine metabolite. One patient with clinical signs of extensive MC activation was treated with antagonists of MC proinflammatory mediators, which resulted in a rapid and durable regression of AIDS-KS lesions.Conclusions: Using complimentary in vitro and in vivo studies we identify MCs as a potential long-lived reservoir for KSHV and a source of proinflammatory mediators within the KS lesional microenvironment. In addition, we identify MC antagonists as a promising novel therapeutic approach for KS. Clin Cancer Res; 24(20); 5085-97. ©2018 AACR.


Assuntos
Infecções por Herpesviridae/complicações , Infecções por Herpesviridae/virologia , Herpesvirus Humano 8 , Mastócitos/imunologia , Sarcoma de Kaposi/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Citocinas/metabolismo , Suscetibilidade a Doenças , Feminino , Humanos , Imuno-Histoquímica , Masculino , Mastócitos/metabolismo , Metilistaminas/metabolismo , Pessoa de Meia-Idade , Modelos Biológicos , Sarcoma de Kaposi/metabolismo , Sarcoma de Kaposi/patologia , Pele/metabolismo , Pele/patologia , Triptases/metabolismo
5.
Biochim Biophys Acta Mol Basis Dis ; 1864(9 Pt B): 3050-3059, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29953926

RESUMO

Monoamine oxidase (MAO), a mitochondrial enzyme that oxidizes biogenic amines generating hydrogen peroxide, is a major source of oxidative stress in cardiac injury. However, the molecular mechanisms underlying its overactivation in pathological conditions are still poorly characterized. Here, we investigated whether the enhanced MAO-dependent hydrogen peroxide production can be due to increased substrate availability using a metabolomic profiling method. We identified N1-methylhistamine -the main catabolite of histamine- as an important substrate fueling MAO in Langendorff mouse hearts, directly perfused with a buffer containing hydrogen peroxide or subjected to ischemia/reperfusion protocol. Indeed, when these hearts were pretreated with the MAO inhibitor pargyline we observed N1-methylhistamine accumulation along with reduced oxidative stress. Next, we showed that synaptic terminals are the major source of N1-methylhistamine. Indeed, in vivo sympathectomy caused a decrease of N1-methylhistamine levels, which was associated with a marked protection in post-ischemic reperfused hearts. As far as the mechanism is concerned, we demonstrate that exogenous histamine is transported into isolated cardiomyocytes and triggers a rise in the levels of reactive oxygen species (ROS). Once again, pargyline pretreatment induced intracellular accumulation of N1-methylhistamine along with decrease in ROS levels. These findings uncover a receptor-independent mechanism for histamine in cardiomyocytes. In summary, our study reveals a novel and important pathophysiological causative link between MAO activation and histamine availability during pathophysiological conditions such as oxidative stress/cardiac injury.


Assuntos
Ventrículos do Coração/patologia , Histamina/metabolismo , Monoaminoxidase/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Animais , Modelos Animais de Doenças , Ventrículos do Coração/citologia , Humanos , Preparação de Coração Isolado , Masculino , Metabolômica , Metilistaminas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Traumatismo por Reperfusão Miocárdica/etiologia , Miocárdio/citologia , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Oxirredução , Estresse Oxidativo , Pargilina/farmacologia , Espécies Reativas de Oxigênio/metabolismo
6.
Sci Rep ; 7(1): 4829, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28684785

RESUMO

Virtual screening offers an efficient alternative to high-throughput screening in the identification of pharmacological tools and lead compounds. Virtual screening is typically based on the matching of target structures or ligand pharmacophores to commercial or in-house compound catalogues. This study provides the first proof-of-concept for our recently reported method where pharmacophores are instead constructed based on the inference of residue-ligand fragments from crystal structures. We demonstrate its unique utility for G protein-coupled receptors, which represent the largest families of human membrane proteins and drug targets. We identified five neutral antagonists and one inverse agonist for the histamine H3 receptor with potencies of 0.7-8.5 µM in a recombinant receptor cell-based inositol phosphate accumulation assay and validated their activity using a radioligand competition binding assay. H3 receptor antagonism is of large therapeutic value and our ligands could serve as starting points for further lead optimisation. The six ligands exhibit four chemical scaffolds, whereof three have high novelty in comparison to the known H3 receptor ligands in the ChEMBL database. The complete pharmacophore fragment library is freely available through the GPCR database, GPCRdb, allowing the successful application herein to be repeated for most of the 285 class A GPCR targets. The method could also easily be adapted to other protein families.


Assuntos
Agonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/química , Fosfatos de Inositol/química , Metilistaminas/química , Receptores Histamínicos H3/química , Sequência de Aminoácidos , Sítios de Ligação , Ligação Competitiva , Cristalografia por Raios X , Bases de Dados de Produtos Farmacêuticos , Expressão Gênica , Células HEK293 , Ensaios de Triagem em Larga Escala , Agonistas dos Receptores Histamínicos/metabolismo , Antagonistas dos Receptores Histamínicos/metabolismo , Humanos , Fosfatos de Inositol/metabolismo , Cinética , Ligantes , Metilistaminas/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica em alfa-Hélice , Domínios e Motivos de Interação entre Proteínas , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Termodinâmica , Interface Usuário-Computador
7.
ACS Chem Neurosci ; 8(9): 1839-1846, 2017 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-28617575

RESUMO

Histamine has been shown to modulate visual system and photic behavior in arthropods. However, few methods are available for the direct quantification of histamine and its precursor and metabolites in arthropod brain. In this work, a method for the separation of histamine, its precursor histidine, and its metabolite N-methyl-histamine from brain extracts of a freshwater crustacean has been developed using capillary electrophoresis with laser-induced fluorescence detection. Molecules were tagged on their primary amine function with naphthalene-2,3-dicarboxaldehyde, but derivatized histamine and N-methyl-histamine exhibited poor stability in contrast to derivatized histidine. To overcome this limitation, an automated derivatization performed within the capillary electrophoresis instrument was optimized and quantitatively validated. The limits of detection were 50, 30, and 60 nmol/L for histidine, histamine, and N-methyl-histamine, respectively. This study reports, for the first time, the amounts of histamine and its related compounds in brain extracts from populations of the freshwater amphipod Gammarus fossarum, and shows that these amounts vary mainly according to population and season, but are not affected by an experimental electrical shock.


Assuntos
Anfípodes/metabolismo , Automação Laboratorial , Eletroforese Capilar , Histamina/metabolismo , Histidina/metabolismo , Metilistaminas/metabolismo , Animais , Automação Laboratorial/métodos , Encéfalo/metabolismo , Calibragem , Eletroforese Capilar/métodos , Reprodutibilidade dos Testes , Rios , Estações do Ano
8.
J Biochem ; 161(2): 155-158, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28069864

RESUMO

Hypertensive disorders of pregnancy globally affect 6-8% of gestation and remain a major cause of both foetal and maternal morbidity and mortality. However, the antihypertensive medications for the patients of this disease are strictly limited due to the teratogenic potentials. Here, we found that tele-methylhistamine (tMH) increased in response to the administration of hydralazine (Hdz), a vasodilative agent, in the pregnancy-associated hypertensive (PAH) mice. Hdz abrogated the degradation of tMH catalyzed by monoamine oxidase B (MAO-B) in vitro. These results suggested that Hdz inhibited the MAO-B activity and consequently tMH increased in the maternal circulation of PAH mice.


Assuntos
Hidralazina/farmacologia , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Metilistaminas/metabolismo , Monoaminoxidase/metabolismo , Aminas/sangue , Animais , Anti-Hipertensivos/farmacologia , Biocatálise/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Humanos , Hipertensão Induzida pela Gravidez/enzimologia , Hipertensão Induzida pela Gravidez/metabolismo , Metilistaminas/sangue , Camundongos , Gravidez , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Especificidade por Substrato
9.
Chemistry ; 23(12): 2915-2925, 2017 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-28052533

RESUMO

Monoamine oxidase (MAO) enzymes catalyze the degradation of a very broad range of biogenic and dietary amines including many neurotransmitters in the brain, whose imbalance is extensively linked with the biochemical pathology of various neurological disorders. Although sharing around 70 % sequence identity, both MAO A and B isoforms differ in substrate affinities and inhibitor sensitivities. Inhibitors that act on MAO A are used to treat depression, due to their ability to raise serotonin concentrations, whereas MAO B inhibitors decrease dopamine degradation and improve motor control in patients with Parkinson disease. Despite this functional importance, the factors affecting MAO selectivity are poorly understood. Here, we used a combination of molecular dynamics (MD) simulations, molecular mechanics with Poisson-Boltzmann and surface area solvation (MM-PBSA) binding free energy evaluations, and quantum mechanical (QM) cluster calculations to address the unexpected, yet challenging MAO B selectivity for N-methylhistamine (NMH) over histamine (HIS), differing only in a single methyl group distant from the reactive ethylamino center. This study shows that a dominant selectivity contribution is offered by a lower activation free energy for NMH by 2.6 kcal mol-1 , in excellent agreement with the experimental ΔΔG≠EXP =1.4 kcal mol-1 , together with a more favorable reaction exergonicity and active-site binding. This study also confirms the hydrophobic nature of the MAO B active site and underlines the important role of Ile199, Leu171, and Leu328 in properly orienting substrates for the reaction.


Assuntos
Histamina/metabolismo , Metilistaminas/metabolismo , Monoaminoxidase/metabolismo , Sítios de Ligação , Biocatálise , Domínio Catalítico , Histamina/química , Humanos , Metilistaminas/química , Simulação de Dinâmica Molecular , Monoaminoxidase/química , Teoria Quântica , Termodinâmica
10.
Neurosci Lett ; 609: 74-80, 2015 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-26453761

RESUMO

Lesch-Nyhan syndrome (LNS) is an X-chromosomal disorder with congenital deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) as underlying defect. We determined the concentrations of dopamine, histamine and their metabolites in brains of HPRT knockout mice, which serve as an animal model for LNS, and compared the results to those obtained from wild-type controls. Analyses were performed by high performance liquid chromatography (HPLC)-coupled tandem mass spectrometry (MS/MS). Besides a decrease of dopamine and 3-methoxytyramine (3-MT) concentrations in the cerebral hemisphere, HPRT-deficient mice also exhibited significantly reduced 1-methylhistamine (1-MH) and 1-methylimidazole-4-acetic acid (1-MI4AA) concentrations in the brain hemisphere and medulla. Moreover, the amount of 1-MI4AA was significantly decreased in the cerebellum. Our findings show that neuronal perturbations caused by HPRT deficiency are not restricted to the dopamine system but also affect histaminergic neurotransmission. These new insights into the brain metabolism of an LNS mouse model may help to find new therapeutic strategies to improve the quality of life of LNS patients.


Assuntos
Histamina/metabolismo , Hipoxantina Fosforribosiltransferase/genética , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Encéfalo/metabolismo , Dopamina/análogos & derivados , Dopamina/metabolismo , Ácido Homovanílico/metabolismo , Imidazóis/metabolismo , Síndrome de Lesch-Nyhan/genética , Metilistaminas/metabolismo , Camundongos Knockout , Transmissão Sináptica
11.
Acta Vet Scand ; 56: 90, 2014 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-25528646

RESUMO

BACKGROUND: This study sought to correlate faecal and urinary N-methylhistamine (NMH) concentrations with resting versus degranulated duodenal mast cell numbers in dogs with chronic enteropathies (CE), and investigate correlations between intestinal mast cell activation and clinical severity of disease as assessed by canine chronic enteropathy clinical activity index (CCECAI), and between urinary and faecal NMH concentrations, mast cell numbers, and histopathological scores. Twenty-eight dogs with CE were included. Duodenal biopsies were stained with haematoxylin and eosin (H&E), toluidine blue, and by immunohistochemical labelling for tryptase. Duodenal biopsies were assigned a histopathological severity score, and duodenal mast cell numbers were counted in five high-power fields after metachromatic and immunohistochemical staining. Faecal and urinary NMH concentrations were measured by gas chromatography-mass spectrometry. RESULTS: There was no correlation between the CCECAI and faecal or urinary NMH concentrations, mast cell numbers, or histopathological score - or between faecal or urinary NMH concentration and mast cell numbers. Post hoc analysis revealed a statistically significant difference in toluidine blue positive mast cells between two treatment groups (exclusion diet with/without metronidazole versus immunosuppression (IS)), with higher numbers among dogs not requiring IS. CONCLUSION: Faecal and urinary NMH concentrations and duodenal mast cell numbers were not useful indicators of severity of disease as assessed by the CCECAI or histological evaluation. The number of duodenal mast cells was higher in dogs that did not need IS, i.e. in dogs responding to an exclusion diet (with/without metronidazole), than in dogs requiring IS. Further studies comparing the role of mast cells in dogs with different forms of CE are needed.


Assuntos
Degranulação Celular , Doenças do Cão/patologia , Doenças do Cão/fisiopatologia , Enteropatias/veterinária , Mastócitos/fisiologia , Metilistaminas/metabolismo , Animais , Biomarcadores/análise , Doença Crônica , Cães , Feminino , Enteropatias/patologia , Enteropatias/fisiopatologia , Masculino , Metilistaminas/urina
12.
Vet J ; 201(3): 289-94, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24907867

RESUMO

Due to their ability to release inflammatory mediators, such as histamine, mast cells are potentially important in gastrointestinal disease. The purpose of this study was to measure N-methylhistamine (NMH), a histamine metabolite, in fecal and urine samples from dogs with chronic gastrointestinal disease. Fecal and urinary NMH concentrations were compared between dogs with chronic gastrointestinal disease and control dogs, and/or to control ranges. Correlation between fecal and urinary NMH concentrations, serum C-reactive protein (CRP) concentration, the clinical disease activity index (CCECAI), and gastrointestinal mucosal mast cell numbers (where available) in dogs with gastrointestinal disease was evaluated. Seven of 16 dogs with gastrointestinal disease had increased urinary or fecal NMH concentrations, but there was no correlation between NMH concentrations and the CCECAI or mucosal mast cells numbers. Urinary NMH concentrations were positively associated with histological grading and serum CRP concentrations. The lack of correlation between NMH concentrations and the CCECAI suggests that NMH may not be a good marker for clinical disease activity in dogs as determined by the CCECAI. Based on their association with severity of intestinal mucosal inflammation, urinary NMH concentrations may potentially have clinical utility as a marker of intestinal inflammation in certain groups of dogs with chronic gastrointestinal disease, but future studies in a larger number of dogs are necessary to further characterize the role of mast cell-mediated inflammation in dogs with chronic gastrointestinal disease.


Assuntos
Doenças do Cão/diagnóstico , Gastroenteropatias/veterinária , Inflamação/veterinária , Metilistaminas/metabolismo , Animais , Biomarcadores/metabolismo , Biomarcadores/urina , Doença Crônica , Doenças do Cão/imunologia , Cães , Fezes/química , Gastroenteropatias/diagnóstico , Gastroenteropatias/imunologia , Inflamação/diagnóstico , Inflamação/imunologia , Mucosa Intestinal/metabolismo , Mastócitos/metabolismo , Metilistaminas/urina
13.
Mol Immunol ; 62(1): 19-28, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24934979

RESUMO

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-ß1, TNF-α, TNF-ß, 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-1ß (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.


Assuntos
Mastócitos/imunologia , Receptores Acoplados a Proteínas G/fisiologia , Receptores Histamínicos/fisiologia , Células Cultivadas , Citocinas/metabolismo , Expressão Gênica , Humanos , Sistema Imunitário/metabolismo , Recém-Nascido , Mediadores da Inflamação/metabolismo , Leucotrienos/metabolismo , Metilistaminas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Receptores Histamínicos H1/genética , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H4 , Células Th1/metabolismo , Células Th2/metabolismo
14.
Neuropharmacology ; 81: 188-94, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24530460

RESUMO

Histaminergic neurons are activated by histamine H(3) receptor (H(3)R) antagonists, increasing histamine and other neurotransmitters in the brain. The prototype H(3)R antagonist thioperamide increases locomotor activity and anxiety-like behaviours; however, the mechanisms underlying these effects have not been fully elucidated. This study aimed to determine the mechanism underlying H(3)R-mediated behavioural changes using a specific H(3)R antagonist, JNJ-10181457 (JNJ). First, we examined the effect of JNJ injection to mice on the concentrations of brain monoamines and their metabolites. JNJ exclusively increased N(τ)-methylhistamine, the metabolite of brain histamine used as an indicator of histamine release, suggesting that JNJ dominantly stimulates the release of histamine release but not of other monoamines. Next, we examined the mechanism underlying JNJ-induced behavioural changes using open-field tests and elevated zero maze tests. JNJ-induced increase in locomotor activity was inhibited by α-fluoromethyl histidine, an inhibitor of histamine synthesis, supporting that H(3)R exerted its effect through histamine neurotransmission. The JNJ-induced increase in locomotor activity in wild-type mice was preserved in H(1)R gene knockout mice but not in histamine H2 receptor (H(2)R) gene knockout mice. JNJ-induced anxiety-like behaviours were partially reduced by diphenhydramine, an H(1)R antagonist, and dominantly by zolantidine, an H(2)R antagonist. These results suggest that H(3)R blockade induces histamine release, activates H(2)R and elicits exploratory locomotor activity and anxiety-like behaviours.


Assuntos
Ansiedade/fisiopatologia , Comportamento Exploratório/fisiologia , Receptores Histamínicos H3/fisiologia , Animais , Ansiedade/induzido quimicamente , Ansiedade/genética , Monoaminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Metilistaminas/metabolismo , Metilistidinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfolinas/toxicidade , Piperidinas/toxicidade , Receptores Histamínicos H1/deficiência , Receptores Histamínicos H1/genética , Receptores Histamínicos H2/deficiência , Receptores Histamínicos H2/genética
15.
Eur J Neurosci ; 39(2): 218-28, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24438489

RESUMO

Brain histamine is involved in the regulation of the sleep-wake cycle and alertness. Despite the widespread use of the mouse as an experimental model, the periodic properties of major markers of the mouse histaminergic system have not been comprehensively characterized. We analysed the daily levels of histamine and its first metabolite, 1-methylhistamine, in different brain structures of C57BL/6J and CBA/J mouse strains, and the mRNA level and activity of histidine decarboxylase and histamine-N-methyltransferase in C57BL/6J mice. In the C57BL/6J strain, histamine release, assessed by in vivo microdialysis, underwent prominent periodic changes. The main period was 24 h peaking during the activity period. Additional 8 h periods were also observed. The release was highly positively correlated with active wakefulness, as shown by electroencephalography. In both mouse strains, tissue histamine levels remained steady for 24 h in all structures except for the hypothalamus of CBA/J mice, where 24-h periodicity was observed. Brain tissue 1-methylhistamine levels in both strains reached their maxima in the periods of activity. The mRNA level of histidine decarboxylase in the tuberomamillary nucleus and the activities of histidine decarboxylase and histamine-N-methyltransferase in the striatum and cortex did not show a 24-h rhythm, whereas in the hypothalamus the activities of both enzymes had a 12-h periodicity. These results show that the activities of histamine-metabolizing enzymes are not under simple direct circadian regulation. The complex and non-uniform temporal patterns of the histaminergic system of the mouse brain suggest that histamine is strongly involved in the maintenance of active wakefulness.


Assuntos
Encéfalo/fisiologia , Histamina/metabolismo , Vigília/fisiologia , Animais , Eletroencefalografia , Eletromiografia , Histamina N-Metiltransferase/metabolismo , Histidina Descarboxilase/metabolismo , Hibridização In Situ , Masculino , Metilistaminas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , RNA Mensageiro/metabolismo , Fatores de Tempo
16.
Int Arch Allergy Immunol ; 163(2): 130-4, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24335343

RESUMO

Recurrent, pulseless-electrical-activity (PEA) cardiac arrests were the novel presentation of untreated systemic mastocytosis in an 85-year-old woman who lacked cutaneous findings of mastocytosis. Despite prior implantation of a dual-chamber cardiac pacemaker 3 weeks previously for similar spells, she experienced a PEA arrest accompanied by flushing, increased urinary N-methylhistamine excretion and serum tryptase values on the day of presentation to our clinic. Bone marrow biopsy findings conducted to rule out breast cancer metastases showed 30% mast cell infiltration, aberrant expression of CD25 and a positive c-kit Asp816Val mutation. Treatment with a combination of H1 and H2 receptor blockers reduced flushing and eliminated hypotension. Maintenance medication included aspirin, cetirizine, ranitidine, montelukast, oral cromolyn sodium and an epinephrine autoinjector (as needed). At 6-month follow-up, the patient remained free of PEA arrests, flushing, or any clinical signs of mastocytosis or mast cell degranulation. PEA cardiac arrests may therefore be a presenting sign of untreated systemic mastocytosis.


Assuntos
Morte Súbita Cardíaca/etiologia , Quimioterapia Combinada/métodos , Histamina/metabolismo , Mastócitos/patologia , Mastocitose Sistêmica/diagnóstico , Acetatos/administração & dosagem , Idoso de 80 Anos ou mais , Aspirina/administração & dosagem , Cromolina Sódica/administração & dosagem , Ciclopropanos , Morte Súbita Cardíaca/prevenção & controle , Eletrocardiografia , Feminino , Frequência Cardíaca , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Mastocitose Sistêmica/complicações , Mastocitose Sistêmica/terapia , Metilistaminas/metabolismo , Mutação/genética , Marca-Passo Artificial/estatística & dados numéricos , Quinolinas/administração & dosagem , Recidiva , Fator de Células-Tronco/genética , Sulfetos , Triptases/sangue
17.
Zh Evol Biokhim Fiziol ; 49(1): 39-43, 2013.
Artigo em Russo | MEDLINE | ID: mdl-23662480

RESUMO

Based on data of substrate-inhibitory analysis with use of specific inhibitors--deprenyl, chlorgi-lin--and specific substrates--serotonin, noradrenalin, benzylamine, beta-phenylethylamine, and N-methylhistamine--a suggestion is put forward about the possible existence of one molecular form of monoamine oxidase (MAO) in liver of mature individuals of the European lamprey Lampetra fluviatilis. There are determined kinetic parameters of monoamine oxidase deamination of eight substrates, which indicates the large spectrum of substrate specificity of the lamprey liver MAO. The studied enzyme does not deaminate histamine and putrescine and is not sensitive to 10(-2) M semicarbaside. Results of study of the substrate-inhibitor specificity allow us to suggest some resemblance of catalytic properties of the lamprey liver MAO and the mammalian form A MAO. The revealed low activity of the enzyme at deamination of all used substrates seems to be connected with low detoxational functional of the lamprey liver.


Assuntos
Lampreias , Mitocôndrias Hepáticas , Monoaminoxidase/metabolismo , Especificidade por Substrato , Animais , Benzilaminas/farmacologia , Clorgilina/metabolismo , Humanos , Cinética , Lampreias/sangue , Lampreias/metabolismo , Metilistaminas/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/enzimologia , Mitocôndrias Hepáticas/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Fenetilaminas/metabolismo , Selegilina/metabolismo , Serotonina/metabolismo
18.
Anal Chim Acta ; 774: 1-10, 2013 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-23567111

RESUMO

Histamine, a neurotransmitter crucially involved in a number of basic physiological functions, undergoes changes in neuropsychiatric disorders. Detection of histamine in biological samples such as cerebrospinal fluid (CSF) is thus of clinical importance. The most commonly used method for measuring histamine levels is high performance liquid chromatography (HPLC). However, factors such as very low levels of histamine, the even lower CSF-histamine and CSF-histamine metabolite levels, especially in certain neuropsychiatric diseases, rapid formation of histamine metabolites, and other confounding elements during sample collection, make analysis of CSF-histamine and CSF-histamine metabolites a challenging task. Nonetheless, this challenge can be met, not only with respect to HPLC separation column, derivative reagent, and detector, but also in terms of optimizing the CSF sample collection. This review aims to provide a general insight into the quantitative analyses of histamine in biological samples, with an emphasis on HPLC instruments, methods, and hyphenated techniques, with the aim of promoting the development of an optimal and practical protocol for the determination of CSF-histamine and/or CSF-histamine metabolites.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Histamina/líquido cefalorraquidiano , Histamina/metabolismo , Animais , Cromatografia Líquida de Alta Pressão/instrumentação , Humanos , Imidazóis/líquido cefalorraquidiano , Imidazóis/metabolismo , Metilistaminas/líquido cefalorraquidiano , Metilistaminas/metabolismo
20.
Burns ; 38(7): 1005-9, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22652469

RESUMO

BACKGROUND: The increased vascular permeability seen after burn contribute to morbidity and mortality as it interferes with organ function and the healing process. Large efforts have been made to explore underlying pathophysiological mechanisms that generate increased vascular permeability after burns. Many different substances have been proposed as mediators of which histamine, serotonin and oxygen radicals are claimed most important. However, no specific blocker has convincingly been shown to be clinically effective. Early work has claimed increased histamine plasma-concentrations in humans after burn and data from animal models pointed at histamine as an important mediator. Modern human clinical studies investigating the role of histamine as a mediator of the generalized post burn increase in vascular permeability are lacking. METHOD: We examined histamine turnover by measuring the urinary excretion of histamine and methyl histamine for 48 h after burns in 8 patients (mean total burn surface area 24%). RESULTS: Over time, in this time frame and compared to healthy controls we found a small increase in the excretion of histamine, but no increase of its metabolite methylhistamine. CONCLUSION: Our findings do not support that histamine is an important mediator of the increased systemic vascular permeability seen after burn.


Assuntos
Queimaduras/metabolismo , Permeabilidade Capilar , Histamina/metabolismo , Metilistaminas/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Feminino , Histamina/urina , Humanos , Inflamação/metabolismo , Masculino , Metilistaminas/urina , Pessoa de Meia-Idade , Fatores de Tempo
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