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1.
Yakugaku Zasshi ; 141(1): 93-110, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33390452

RESUMO

There has been little information about the role of histamine on the central nervous system (CNS), different from dopamine and serotonin. In the present study, therefore, the effects of histamine and related compounds on the CNS were studied using rats. Intracerebroventricular (i.c.v.) injection of histamine and 2-methylhistamine ameliorated memory deficit after long interrution of learning in active avoidance response. First generation H1-antagonists inhibited active avoidance response, whereas newly develpoed H1-antagonists showed little effect. α-Fluoromethylhistidine, an histidine decarboxylase inhibitor, also inhibited active avoidance response. In radial maze performance, almost the same findings were obtained. I.c.v. injection of histamine and H1-agonists inhibited amygdaloid kindled seizures. First generation H1-antagonists attenuated histamine-induced inhibition of amygdaloid kindled seizures. Both i.c.v. and intraperitoneal injections of H3-antagonist, thioperamide, resulted in a dose-related inhibition of amygdaloid kindled seizures. The effect of thioperamide was inhibited by an H3-agonists and H1-antagonists. Similar to nitrazepam, diphenhydramine and chlorpheniramine caused a shortening of sleep latency. On the other hand, no significant effects were observed with second generation H1-antagonists. These findings suggest that histamine plays an important role in learning and memory via H1-receptors, an inhibition of amygdaloid kindled seizures induced by histamine occurred through not only H1-receptors but also H3-receptors, and that classic H1-antagonists can be useful as a effective hypnotic for difficulty in falling asleep.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Histamina/farmacologia , Metilistaminas/farmacologia , Metilistidinas/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Histamina/administração & dosagem , Histamina/metabolismo , Histamina/fisiologia , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Hipnóticos e Sedativos , Injeções Intraventriculares , Excitação Neurológica/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Metilistaminas/administração & dosagem , Metilistidinas/administração & dosagem , Camundongos , Ratos , Receptores Histamínicos H3/metabolismo , Receptores Histamínicos H3/fisiologia , Convulsões/tratamento farmacológico , Sono/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico
2.
Cell Mol Neurobiol ; 41(1): 185-190, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32211996

RESUMO

Motoneuron activity is modulated by histamine receptors. While H1 and H2 receptors have been widely explored, H3 histamine receptors (H3Rs) have not been sufficiently characterized. This paper targets the effects of the selective activation of H3Rs and their expression on the membranes of large ventral horn cells. The application of selective pharmacological agents to spinal cords isolated from neonatal rats was used to identify the presence of functional H3Rs on the membrane of physiologically identified lumbar motoneurons. Intra and extracellular recordings revealed that H3R agonist, α-methylhistamine, depolarized both single motoneurons and ventral roots, even in the presence of tetrodotoxin, an effect prevented by H3R antagonist, thioperamide. Finally, immunohistochemistry located the expression of H3Rs on a subpopulation of large cells in lamina IX. This study identifies H3Rs as a new exploitable pharmacological target against motor disturbances.


Assuntos
Neurônios Motores/metabolismo , Receptores Histamínicos/metabolismo , Corno Ventral da Medula Espinal/metabolismo , Animais , Metilistaminas/farmacologia , Neurônios Motores/efeitos dos fármacos , Ratos , Corno Ventral da Medula Espinal/efeitos dos fármacos
3.
J Neuroinflammation ; 17(1): 217, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32698899

RESUMO

BACKGROUND: Microglia, the principal sentinel immune cells of the central nervous system (CNS), play an extensively vital role in neuroinflammation and perioperative neurocognitive disorders (PND). Histamine, a potent mediator of inflammation, can both promote and prevent microglia-related neuroinflammation by activating different histamine receptors. Rat microglia express four histamine receptors (H1R, H2R, H3R, and H4R), among which the histamine 1 and 4 receptors can promote microglia activation, whereas the role and cellular mechanism of the histamine 2 and 3 receptors have not been elucidated. Therefore, we evaluated the effects and potential cellular mechanisms of histamine 2/3 receptors in microglia-mediated inflammation and PND. METHODS: This study investigated the role of histamine 2/3 receptors in microglia-induced inflammation and PND both in vivo and in vitro. In the in vivo experiments, rats were injected with histamine 2/3 receptor agonists in the right lateral ventricle and were then subjected to exploratory laparotomy. In the in vitro experiments, primary microglia were pretreated with histamine 2/3 receptor agonists before stimulation with lipopolysaccharide (LPS). Cognitive function, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotypes, cell migration, and Toll-like receptor-4 (TLR4) expression were assessed. RESULTS: In our study, the histamine 2/3 receptor agonists inhibited exploratory laparotomy- or LPS-induced cognitive decline, microglia activation, proinflammatory cytokine production, NF-κb expression, M1/M2 phenotype transformation, cell migration, and TLR4 expression through the PI3K/AKT/FoxO1 pathway. CONCLUSION: Based on our findings, we conclude that histamine 2/3 receptors ameliorate PND by inhibiting microglia activation through the PI3K/AKT/FoxO1 pathway. Our results highlight histamine 2/3 receptors as potential therapeutic targets to treat neurological conditions associated with PND.


Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Microglia/efeitos dos fármacos , Complicações Cognitivas Pós-Operatórias/imunologia , Complicações Cognitivas Pós-Operatórias/metabolismo , Envelhecimento , Animais , Método Duplo-Cego , Proteína Forkhead Box O1/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Metilistaminas/farmacologia , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos , Transdução de Sinais/efeitos dos fármacos , Tiazóis/farmacologia
4.
Am J Physiol Endocrinol Metab ; 317(6): E1158-E1171, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31550180

RESUMO

Although many studies have shown that histamine and its signaling regulate energy homeostasis through the central nervous system, their roles in adipose tissues remain poorly understood. Here, we identified that the histamine H4 receptor (HrH4) was highly expressed in adipocytes at a level higher than that of the other three receptors (i.e., HrH1, HrH2, and HrH3). The HrH4 expression in adipocytes responded to cold through thermogenesis and lipolysis, supported by results from both mouse and cell models. When HrH4 expression was knocked down in the subcutaneous white adipose tissue (scWAT), browning and lipolysis effects triggered by cold were ablated, and the oxygen consumption was also lowered both at the normal and cold conditions. Moreover, mice exhibited browned scWAT, accelerated metabolic rates, and tolerance to hypothermia when 4-methylhistamine (4MH), a selective HrH4 agonist, was adjacently injected to the scWAT. Consistent with these findings, 4MH also triggered the browning and lipolytic effects in cultured C3H10T1/2 adipocytes. Mechanically, we demonstrated that p38/MAPK and ERK/MAPK pathways were involved in these processes. In conclusion, our findings have uncovered an effective role of HrH4 in adipose tissue browning.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Temperatura Baixa , Consumo de Oxigênio/genética , Receptores Histamínicos H4/genética , Gordura Subcutânea/metabolismo , Termogênese/genética , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Metabolismo Basal/efeitos dos fármacos , Metabolismo Basal/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Técnicas de Silenciamento de Genes , Agonistas dos Receptores Histamínicos/farmacologia , Lipólise/efeitos dos fármacos , Lipólise/genética , Sistema de Sinalização das MAP Quinases , Metilistaminas/farmacologia , Camundongos , Consumo de Oxigênio/efeitos dos fármacos , Receptores Histamínicos H4/agonistas , Receptores Histamínicos H4/metabolismo , Gordura Subcutânea/efeitos dos fármacos , Termogênese/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
J Recept Signal Transduct Res ; 38(3): 204-212, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29863427

RESUMO

CONTEXT: Mast cell (MC) activation through H4R releases various inflammatory mediators which are associated with allergic asthma. OBJECTIVES: To investigate the siRNA-mediated gene silencing effect of H4R on human mast cells (HMCs) functions and the activation of stress-activated protein kinases (SAPK)/jun amino-terminal kinases (JNK) signaling pathways for the release of ineterleukin-1ß (IL-1ß) in HMCs. MATERIALS AND METHODS: H4R expression was analyzed by RT-PCR and western blotting in human mast cell line-1 (HMC-1) cells and H4RsiRNA transfected cells. The effect of H4RsiRNA and H4R-antagonist on H4R mediated MC functions such as intracellular Ca2+ release, degranulation, IL-6 and IL-1ß release, and the activation SAPK/JNK signaling pathways were studied. HMC-1 cells were stimulated with 10 µM of histamine (His) and 4-methylhistamine (4-MH) and pretreated individually with H4R-antagonist JNJ7777120 (JNJ), histamine H1 receptor (H1R)-antagonist mepyramine, and signaling molecule inhibitors SP600125 (SP) and Bay117082. RESULTS: We found that the HMC-1 cells expressed H4R and H4RsiRNA treatment down regulated the H4R expression in HMC-1 cells. Both His and 4-MH induced the intracellular Ca2+ release and degranulation whereas; H4R siRNA and JNJ inhibited the effect. Furthermore, the activation of H4R caused the phosphorylation of SAPK/JNK pathways. H4R gene silencing and pretreatment with SP and JNJ decreased His and 4-MH induced phosphorylation of SAPK/JNK. We found that the activation of H4R caused the release of IL-1ß (124.22 pg/ml) and IL-6 (122.50 pg/ml) on HMC-1 cells. Whereas, SAPK/JNK inhibitor (68.36 pg/ml) inhibited the H4R mediated IL-1ß release. CONCLUSIONS: Taken together, the silencing of H4R inhibited the H4R mediated MC functions and SAPK/JNK phosphorylation. Furthermore, the H4R activation utilized SAPK/JNK signaling pathway for IL-1ß release in HMC-1 cells.


Assuntos
Interleucina-1beta/genética , MAP Quinase Quinase 4/genética , Mastócitos/metabolismo , Receptores Histamínicos H4/genética , Cálcio/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Histamina/farmacologia , Humanos , Indóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Metilistaminas/farmacologia , Piperazinas/farmacologia , Pirilamina/farmacologia , RNA Interferente Pequeno/genética , Receptores Histamínicos H4/antagonistas & inibidores
6.
Drug Des Devel Ther ; 12: 179-194, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29403264

RESUMO

The imidazole-based H3R antagonist 2-18 with high in vitro H3R antagonist affinity, excellent in vitro selectivity profile, and high in vivo H3R antagonist potency was tested for its anticonvulsant effect in maximal electroshock (MES)-induced convulsions in mice having valproic acid (VPA) as a reference antiepileptic drug (AED). Additionally, H3R antagonist 2-18 was evaluated for its reproductive toxicity in the same animal species. The results show that acute systemic administration (intraperitoneal; i.p.) of H3R antagonist 2-18 (7.5, 15, 30, and 60 mg/kg, i.p.) significantly and dose dependently protected male as well as female mice against MES-induced convulsion. The protective action observed for H3R antagonist 2-18 in both mice sexes was comparable to that of VPA and was reversed when mice were pretreated with the selective H3R agonist (R)-alpha-methylhistamine (RAMH, 10 mg/kg, i.p.). Moreover, the results show that acute systemic administration of single (7.5, 15, 30, or 60 mg/kg, i.p.) or multiple doses (15×3 mg/kg, i.p.) of H3R antagonist 2-18 on gestation day (GD) 8 or 13 did not affect the maternal body weight of mice when compared with the control group. Furthermore, no significant differences were observed in the average number of implantations and resorptions between the control and H3R antagonist 2-18-treated group at the early stages of gestation and the organogenesis period. However, oral treatment with H3R antagonist 2-18 (15 mg/kg) on GD 8 induced a reduced number of live embryos when compared with the i.p.-treated mice. In addition, no significant changes in the fetal body and placental weights were observed after injection of H3R antagonist 2-18 with all selected doses. However, three dose groups of i.p. and oral 15 mg/kg on GD 13 significantly affected the placental weight when compared with control group. Notably, the treatment of pregnant female with the H3R antagonist 2-18 did not produce significant malformation in the fetus in both groups. In conclusion, the novel H3R antagonist 2-18 proves to be a very safe compound and displays a low incidence of malformations, demonstrating that H3R antagonist 2-18 may have a potential future therapeutic value in epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Antagonistas dos Receptores Histamínicos H3/toxicidade , Imidazóis/farmacologia , Imidazóis/toxicidade , Teratógenos/toxicidade , Anormalidades Induzidas por Medicamentos/patologia , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Feto/efeitos dos fármacos , Masculino , Metilistaminas/farmacologia , Metilistaminas/toxicidade , Camundongos , Organogênese/efeitos dos fármacos , Placenta/efeitos dos fármacos , Gravidez , Ácido Valproico/farmacologia , Ácido Valproico/toxicidade
7.
Neuroscience ; 376: 188-203, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29374538

RESUMO

Histamine H3 receptors are widely distributed Gi-coupled receptors whose activation reduces neuronal activity and inhibits release of numerous neurotransmitters. Although these receptors are abundantly expressed in the striatum, their modulatory role on activity-dependent dopamine release is not well understood. Here, we observed that histamine H3 receptor activation indirectly diminishes dopamine overflow in the ventral striatum by reducing cholinergic interneuron activity. Acute brain slices from C57BL/6 or channelrhodopsin-2-transfected DAT-cre mice were obtained, and dopamine transients evoked either electrically or optogenetically were measured by fast-scan cyclic voltammetry. The H3 agonist α-methylhistamine significantly reduced electrically- evoked dopamine overflow, an effect blocked by the nicotinic acetylcholine receptor antagonist dihydro-ß-erythroidine, suggesting involvement of cholinergic interneurons. None of the drug treatments targeting H3 receptors affected optogenetically evoked dopamine overflow, indicating that direct H3-modulation of dopaminergic axons is unlikely. Next, we used qPCR and confirmed the expression of histamine H3 receptor mRNA in cholinergic interneurons, both in ventral and dorsal striatum. Activation of H3 receptors by α-methylhistamine reduced spontaneous firing of cholinergic interneurons in the ventral, but not in the dorsal striatum. Resting membrane potential and number of spontaneous action potentials in ventral-striatal cholinergic interneurons were significantly reduced by α-methylhistamine. Acetylcholine release from isolated striatal synaptosomes, however, was not altered by α-methylhistamine. Together, these results indicate that histamine H3 receptors are important modulators of dopamine release, specifically in the ventral striatum, and that they do so by decreasing the firing rate of cholinergic neurons and, consequently, reducing cholinergic tone on dopaminergic axons.


Assuntos
Acetilcolina/metabolismo , Dopamina/metabolismo , Interneurônios/metabolismo , Receptores Histamínicos H3/metabolismo , Estriado Ventral/metabolismo , Animais , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Feminino , Agonistas dos Receptores Histamínicos/farmacologia , Interneurônios/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Metilistaminas/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Optogenética , RNA Mensageiro/metabolismo , Sinaptossomos/metabolismo , Técnicas de Cultura de Tecidos , Estriado Ventral/efeitos dos fármacos
8.
Biochem Biophys Res Commun ; 490(4): 1314-1318, 2017 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-28688766

RESUMO

Recently we found that synthetic compounds containing amino group linked to hydrophobic or aromatic moiety are potent modulators of the proton-gated channels (ASICs). These structures have clear similarity with ligands of histamine receptors. We have also demonstrated that histamine potentiates homomeric ASIC1a by shifting its activation dependence to less acidic conditions. In the present work the action of a series of histamine receptors ligands on recombinant ASIC1a and ASIC2a was characterized. Two types of action were found for ASIC1a. 1-methylhistamine, N-alpha-methylhistamine, dimaprit and thioperamide caused significant potentiation, which was pH-dependent and voltage-independent. The H4R antagonist A943931 caused inhibition, which is likely due to voltage-dependent pore block. ASIC2a were virtually insensitive to the drugs tested. We conclude that ligands of histamine receptors should also be considered as ASIC modulators.


Assuntos
Canais Iônicos Sensíveis a Ácido/genética , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Histamina/farmacologia , Receptores Histamínicos/genética , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Células CHO , Cricetulus , Dimaprit/farmacologia , Regulação da Expressão Gênica , Humanos , Concentração de Íons de Hidrogênio , Ligantes , Metilistaminas/farmacologia , Técnicas de Patch-Clamp , Piperidinas/farmacologia , Receptores Histamínicos/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais
9.
Pharmacol Res ; 113(Pt A): 209-215, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27491560

RESUMO

The cytokine thymic stromal lymphopoietin (TSLP) is involved in the development and the progression of allergic diseases. It is mainly released by epithelial cells at barriers such as skin and gut in response to danger signals. Overexpression of TSLP in keratinocytes (KC) can provoke the development of a type 2 inflammatory response. Additionally, TSLP directly acts on sensory neurons and thereby triggers itch. Since histamine is also increased in lesions of inflammatory skin diseases, the aim of this study was to investigate possible effects of histamine as well as different histamine receptor subtype agonists and antagonists on TSLP production in KC. We therefore stimulated human KC with histamine in the presence or absence of the known TSLP-inductor poly I:C and measured TSLP production at protein as well as mRNA level. Histamine alone did not induce TSLP production in human KC, but pre-incubation with histamine prior to challenge with poly I:C resulted in a significant increase of TSLP production compared to stimulation with poly I:C alone. Experiments with different histamine receptor agonists (H1R: 2-pyridylethylamine; H2R: amthamine; H2R/H4R: 4-methylhistamine (4MH)) revealed a dominant role for the H4R receptor, as 4-MH in combination with poly I:C displayed a significant increase of TSLP secretion, while the other agonists did not show any effect. The increase in TSLP production by 4MH was blocked with the H4R antagonist JNJ7777120. This effect was reproducible also in the murine KC cell line MSC. Taken together, our study indicates a new role for the H4 receptor in the regulation of TSLP in keratinocytes. Therefore, blocking of the H4R receptor in allergic diseases might be promising to alleviate inflammation and pruritus via TSLP.


Assuntos
Citocinas/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Receptores Histamínicos/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , Linhagem Celular , Citocinas/metabolismo , Células HEK293 , Histamina/metabolismo , Humanos , Queratinócitos/metabolismo , Metilistaminas/farmacologia , Camundongos , Poli I-C/farmacologia , Piridinas/farmacologia , RNA Mensageiro/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo
10.
Toxicol Appl Pharmacol ; 306: 8-16, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27368152

RESUMO

Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100µM) and doxorubicin (0.2µM) decreased the cell survival rate, but olanzapine (1-100µM) did not. Under granulocytic differentiation for 5days, clozapine, even at a concentration of 25µM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H4 receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H4 receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H4 receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H4 receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation.


Assuntos
Antipsicóticos/toxicidade , Diferenciação Celular/efeitos dos fármacos , Clozapina/toxicidade , Granulócitos/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Apoptose/efeitos dos fármacos , Granulócitos/fisiologia , Células HL-60 , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Metilistaminas/farmacologia , Piperidinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Histamínicos H4 , Tretinoína/farmacologia
11.
J Basic Clin Physiol Pharmacol ; 27(5): 463-71, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27089413

RESUMO

BACKGROUND: Animal models based on N-methyl-d-aspartate receptor blockade have been extensively used for schizophrenia. Ketamine and MK-801 produce behaviors related to schizophrenia and exacerbated symptoms in patients with schizophrenia, which led to the use of PCP (phencyclidine)- and MK-801 (dizocilpine)-treated animals as models for schizophrenia. METHODS: The study investigated the effect of subchronic dosing (once daily, 7 days) of histamine H3 receptor (H3R) antagonists, ciproxifan (CPX) (3 mg/kg, i.p.), and clobenpropit (CBP) (15 mg/kg, i.p.) on MK-801 (0.2 mg/kg, i.p.)-induced locomotor activity and also measured dopamine and histamine levels in rat's brain homogenates. The study also included clozapine (CLZ) (3.0 mg/kg, i.p.) and chlorpromazine (CPZ) (3.0 mg/kg, i.p.), the atypical and typical antipsychotic, respectively. RESULTS: Atypical and typical antipsychotic was used to serve as clinically relevant reference agents to compare the effects of the H3R antagonists. MK-801 significantly increased horizontal locomotor activity, which was reduced with CPX and CBP. MK-801-induced locomotor hyperactivity attenuated by CPX and CBP was comparable to CLZ and CPZ. MK-801 raised striatal dopamine level, which was reduced in rats pretreated with CPX and CBP. CPZ also significantly lowered striatal dopamine levels, although the decrease was less robust compared to CLZ, CPX, and CBP. MK-801 increased histamine content although to a lesser degree. Subchronic treatment with CPX and CBP exhibited further increased histamine levels in the hypothalamus compared to MK-801 treatment alone. Histamine H3 receptor agonist, R-α methylhistamine (10 mg/kg, i.p.), counteracted the effect of CPX and CBP. CONCLUSIONS: The present study shows the positive effects of CPX and CBP on MK-801-induced schizophrenia-like behaviors in rodents.


Assuntos
Antipsicóticos/farmacologia , Maleato de Dizocilpina/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Esquizofrenia/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Histamina/metabolismo , Imidazóis/farmacologia , Metilistaminas/farmacologia , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Esquizofrenia/metabolismo , Tioureia/análogos & derivados , Tioureia/farmacologia
12.
Eur J Pharmacol ; 777: 49-59, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26939881

RESUMO

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.


Assuntos
Adesão Celular/efeitos dos fármacos , Endotélio/citologia , Endotélio/efeitos dos fármacos , Eosinófilos/citologia , Eosinófilos/efeitos dos fármacos , Histamina/metabolismo , Receptores Histamínicos/metabolismo , Comunicação Celular/efeitos dos fármacos , Linhagem Celular , Separação Celular , Sobrevivência Celular/efeitos dos fármacos , Agonismo Inverso de Drogas , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Indóis/farmacologia , Ligantes , Metilistaminas/farmacologia , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia
13.
Scand J Immunol ; 83(6): 409-17, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26900758

RESUMO

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.


Assuntos
Inflamação/tratamento farmacológico , Metilistaminas/uso terapêutico , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Aminoquinolinas/administração & dosagem , Animais , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imiquimode , Inflamação/induzido quimicamente , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Metilistaminas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Psoríase/induzido quimicamente , Receptores Acoplados a Proteínas G/agonistas , Receptores Histamínicos , Receptores Histamínicos H4 , Pele/imunologia , Pele/patologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia
14.
Neuropharmacology ; 106: 46-55, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26525191

RESUMO

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 performance through actions on different memory stages. Therefore, H3Rs may have implications for the treatment of degenerative disorders associated with impaired memory function and may represent a novel therapeutic pharmacological target to tackle cognitive problems associated with the chronic use of antiepileptic drugs. This article is part of the Special Issue entitled 'Histamine Receptors'.


Assuntos
Anticonvulsivantes/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Nootrópicos/farmacologia , Éteres Fenílicos/farmacologia , Piperidinas/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Benzotiazóis/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Epilepsia/tratamento farmacológico , Epilepsia/psicologia , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Metilistaminas/farmacologia , Fenoxipropanolaminas/farmacologia , Fenitoína/farmacologia , Distribuição Aleatória , Ratos Wistar , Receptores Histamínicos H3/metabolismo
15.
Neuropharmacology ; 106: 37-45, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26400408

RESUMO

CEP-32215 is a new, potent, selective, and orally bioavailable inverse agonist of the histamine H3 receptor (H3R) with drug-like properties. High affinity in human (hH3R Ki = 2.0 ± 0.2 nM) and rat (rH3R Ki = 3.6 ± 0.7 nM) H3R radioligand binding assays was demonstrated. Potent functional antagonism (Kb = 0.3 ± 0.1 nM) and inverse agonism (EC50 = 0.6 ± 0.2 nM) were demonstrated in [(35)S]guanosine 5(')-O-(γ-thio)-triphosphate binding assays. Oral bioavailability and dose-related exposure was consistent among rat, dog, and monkey. After oral dosing, occupancy of H3R by CEP-32215 was estimated by the inhibition of ex vivo binding in rat cortical slices (ED50 = 0.1 mg/kg p.o.). Functional antagonism in brain was demonstrated by the inhibition of R-α-methylhistamine-induced drinking in the rat dipsogenia model (ED50 = 0.92 mg/kg). CEP-32215 significantly increased wake duration in the rat EEG model at 3-30 mg/kg p.o. Increased motor activity, sleep rebound or undesirable events (such as spike wave or seizure activity) was not observed following doses up to 100 mg/kg p.o., indicating an acceptable therapeutic index. CEP-32215 may have potential utility in the treatment of a variety of sleep disorders. This article is part of the Special Issue entitled 'Histamine Receptors'.


Assuntos
Agonismo Inverso de Drogas , Antagonistas dos Receptores Histamínicos H3/farmacologia , Piperidinas/farmacologia , Pirazinas/farmacologia , Compostos de Espiro/farmacologia , Vigília/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cães , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Líquidos/fisiologia , Avaliação Pré-Clínica de Medicamentos , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Macaca fascicularis , Masculino , Metilistaminas/farmacologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Piperidinas/farmacocinética , Pirazinas/farmacocinética , Ratos Sprague-Dawley , Receptores Histamínicos H3/metabolismo , Sono/efeitos dos fármacos , Sono/fisiologia , Compostos de Espiro/farmacocinética , Vigília/fisiologia
16.
J Neuroimmunol ; 289: 30-42, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26616869

RESUMO

Recently, the expression of histamine 4 receptor (H4R) on neurons was reported, however its function in cells within the central nervous system (CNS) remains poorly understood. To this end, we used the H4R agonist, 4-methylhistamine (4-MeH), and the H4R antagonist, JNJ77777120 (JNJ), to investigate the function of H4R signaling in immune cells in a murine model of chronic stress. Treatment of stressed mice with 4-MeH resulted in an increase in the proportion of lymphocyte subsets (CD3(+), CD8(+), CD28(+), and CD4(+)CD28(+)) and cells expressing the co-stimulatory molecules CD80(+) (B7.1) and CD86(+) (B7.2) in heparinized blood as compared to normal control (NC) and stressed control (SC) groups. We also observed that as compared to NC and SC mice, 4-MeH-treated mice showed greater production of IL-2(+), IL-6(+), IL-9(+), IL-21(+), and IL-27(+) cytokines in the spleen and by splenic CD4(+) T cells. Furthermore, 4-MeH treatment of stressed mice led to an increase in the levels of serum Th1/Th17 cytokines and corticosterone, and a decrease in Th2 cytokines. Treatment of chronically-stressed mice with 4-MeH also augmented expression of IL-6, IL-21, NF-κB p65, and STAT3 mRNA. Moreover, Western blot analyses confirmed increased protein expression of NF-κB, iNOS, and STAT3 expression following 4-MeH treatment of chronically-stressed mice as compared to controls. These proteins provide a novel relevant targets for the manipulation of chronic stress induced immune regulation. In striking contrast, treatment of stressed mice with the H4R antagonist, JNJ, resulted in a substantial reduction in all of the aforementioned effects upon immune cell percentages and cytokine production.


Assuntos
Antígeno B7-1/metabolismo , Antígenos CD28/metabolismo , Citocinas/metabolismo , Receptores Histamínicos/metabolismo , Transdução de Sinais/imunologia , Estresse Psicológico/imunologia , Análise de Variância , Animais , Antígenos CD28/genética , Corticosterona/sangue , Citocinas/genética , Indóis/farmacologia , Masculino , Metilistaminas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Piperazinas/farmacologia , RNA Mensageiro/metabolismo , Restrição Física/psicologia , Transdução de Sinais/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Estresse Psicológico/sangue , Estresse Psicológico/etiologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
17.
Physiol Behav ; 151: 189-97, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26169446

RESUMO

It has become clear that histamine H3 receptors (H3R) have been implicated in modulating ethanol intake and preference in laboratory animals. The novel non-imidazole H3R antagonist DL77 with excellent selectivity profile shows high in-vivo potency as well as in-vitro antagonist affinity with ED50 of 2.1 ± 0.2 mg/kg and pKi=8.08, respectively. In the present study, and applying an unlimited access two-bottle choice procedure, the anti-alcohol effects of the H3R antagonist, DL77 (0, 3, 10 and 30 mg/kg; i.p.), were investigated in adult mice. In this C57BL/6 line, effects of DL77 on voluntary alcohol intake and preference, as well as on total fluid intake were evaluated. Results have shown that DL77, dose-dependently, reduced both ethanol intake and preference. These effects were very selective as both saccharin and quinine, used to control for taste sensitivity, and intakes were not affected following DL77 pre-application. More importantly, systemic administration of DL77 (10 mg/kg) during acquisition inhibited ethanol-induced conditioned-place preference (EtOH-CPP) as measured using an unbiased protocol. The anti-alcohol activity observed for DL77 was abrogated when mice were pretreated with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10 mg/kg), or with the CNS penetrant H1R antagonist pyrilamine (PYR) (10mg/kg). These results suggest that DL77 has a predominant role in two in vivo effects of ethanol. Therefore, signaling via H3R is essential for ethanol-related consumption and conditioned reward and may represent a novel therapeutic pharmacological target to tackle ethanol abuse and alcoholism.


Assuntos
Dissuasores de Álcool/farmacologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Antagonistas dos Receptores Histamínicos H3/farmacologia , Éteres Fenílicos/farmacologia , Piperidinas/farmacologia , Dissuasores de Álcool/química , Consumo de Bebidas Alcoólicas/fisiopatologia , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Etanol/administração & dosagem , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H3/química , Masculino , Metilistaminas/farmacologia , Camundongos Endogâmicos C57BL , Éteres Fenílicos/química , Piperidinas/química , Pirilamina/farmacologia , Comportamento Espacial/efeitos dos fármacos , Percepção Gustatória/efeitos dos fármacos , Volição
18.
Eur J Pharmacol ; 754: 173-8, 2015 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-25746421

RESUMO

Histamine is a neurotransmitter and chemical mediator in multiple physiological processes. Histamine H3 receptor is expressed in the nervous system, heart, and gastrointestinal tract; however, little is known about H3 receptor in skeletal muscle. The aim of this study was to investigate the role of H3 receptor in skeletal myotubes. The expression of H3 receptor and myosin heavy chain (MHC), a late myogenesis marker, was assessed by real-time PCR and immunostaining in C2C12 skeletal myogenesis and adult mid-urethral skeletal muscle tissues. H3 receptor mRNA showed a significant increase upon differentiation of C2C12 into myotubes: 1-, 26-, 91-, and 182-fold at days 0, 2, 4, and 6, respectively. H3 receptor immunostaining in differentiated C2C12 cells and adult skeletal muscles was positive and correlated with that of MHC. The functional role of H3receptor in differentiated myotubes was assessed using an H3 receptor agonist, (R)-a-methylhistamine ((R)-α-MeHA). Ca(2+) imaging, stimulated by electric pacing, was decreased by 55% after the treatment of mature C2C12 myotubes with 1µM (R)-α-MeHA for 10min and 20min, while treatment with 100nm (R)-α-MeHA for 5min caused 45% inhibition. These results suggested that H3 receptor may participate in the maintenance of the relaxed state and prevention of over-contraction in mature differentiated myotubes. The elucidation of the role of H3R in skeletal myogenesis and adult skeletal muscle may open a new direction in the treatment of skeletal muscle disorders, such as muscle weakness, atrophy, and myotonia in motion systems or peri-urethral skeletal muscle tissues.


Assuntos
Cálcio/metabolismo , Agonistas dos Receptores Histamínicos/farmacologia , Desenvolvimento Muscular/fisiologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/fisiologia , Receptores Histamínicos H3/fisiologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Estimulação Elétrica , Metilistaminas/farmacologia , Camundongos , Microscopia de Fluorescência , Desenvolvimento Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Receptores Histamínicos H3/biossíntese
19.
Immunobiology ; 220(7): 889-98, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25666529

RESUMO

Histamine 4 receptor (H4R) is a novel target for the pharmacological modulation of histamine-mediated immune signals during inflammatory diseases. The purpose of this study was to assess the effects of the H4R agonist 4-methylhistamine dihydrochloride (4-MeH) and antagonist JNJ7777120 (JNJ) in the inflamed rat knee. Animals were fasted for 18h before a single dose of 4-MeH or JNJ (30mg/kg) was administered intraperitoneally (i.p.), both followed by intra-articular (i.a.) injection of LPS 2h later. Blood and synovial fluid were collected after a short incubation period and TNF-α, NF-κB, and IkB-α levels were measured via flow cytometry. Additionally, we assessed the effects of H4R engagement on the expression of IL-1ß, TNF-α, and NF-κB mRNAs and the protein levels of TNF-α, NF-κB, JAK-1, and STAT-3 in the inflamed knee tissue. These results revealed increased TNF-α and NF-κB expression and decreased IkB-α levels in both the LPS alone and 4-MeH treated groups in whole blood and synovial fluid. Further, IL-1ß, TNF-α, and NF-κB mRNA levels were significantly increased and western blot analysis confirmed increased expression of TNF-α, NF-κB, JAK-1, and STAT-3 in both LPS and 4-MeH treatment groups. Furthermore, these increases were completely inhibited in the inflamed knee tissue of the JNJ-treated group. Thus, the inhibition of inflammatory mediators and signaling pathways by the H4R antagonist JNJ suggests the anti-arthritic importance of this molecule.


Assuntos
Inflamação/patologia , Articulação do Joelho/patologia , NF-kappa B/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Histamínicos/genética , Fator de Necrose Tumoral alfa/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Ativação Enzimática , Feminino , Regulação da Expressão Gênica , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Proteínas I-kappa B/sangue , Indóis/farmacologia , Inflamação/diagnóstico , Inflamação/imunologia , Interleucina-1beta/genética , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Articulação do Joelho/imunologia , Lipopolissacarídeos , Metilistaminas/farmacologia , Inibidor de NF-kappaB alfa , NF-kappa B/sangue , NF-kappa B/genética , Piperazinas/farmacologia , RNA Mensageiro/biossíntese , Ratos , Ratos Wistar , Receptores Histamínicos H4 , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética
20.
Immunobiology ; 220(3): 341-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25457414

RESUMO

Alterations to the immune system caused by stress have been considered to markedly increase the risk for immune-related diseases such as cancer and autoimmune disorders. We investigated the potential anti-stress effects of the histamine 4 receptor (H4R) agonist, 4-methylhistamine (4-MeH), in a murine stress model. Mice were placed in 50ml conical centrifuge tubes for 12h followed by a 12h rest. The effects of treatment with 4-MeH (30mg/kg, i.p., twice daily) for 2 days were assessed. At 2 days after physical restraint, mice were sacrificed and tissues harvested. We evaluated the effects of 4-MeH treatment on CD4(+) T cell production, and intracellular IFN-γ and IL-4 expression in these cells. We also assessed IL-1ß, IFN-γ, TNF-α, and IL-4 mRNA expression as well as IFN-γ, TNF-α, GITR, Ox40 and IL-4 protein expression in the spleen. The results showed that 4-MeH treatment of stressed mice results in a substantial increase in the CD4(+) T cells as well as in IFN-γ production by these cells. Compared to both untreated and stressed controls. In contrast, IL-4 expression decreased significantly following 4-MeH treatment of mice. Moreover, stimulation of the H4R resulted in up-regulated expression of IL-1ß, IFN-γ and TNF-α mRNAs and decreased the expression of IL-4. Western blot analysis confirmed decreased protein expression of IFN-γ, TNF-α, GITR, Ox40 and increased IL-4 in the SC group and treatment of mice with 4-MeH reversed these effects. Our results confirm the significant impact of chronic stress on T cell function and production of Th1/Th2 mediators H4R.


Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Metilistaminas/farmacologia , Receptores Histamínicos/imunologia , Estresse Fisiológico/imunologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Animais , Gliceraldeído 3-Fosfato Desidrogenase (NADP+)/genética , Interferon gama/sangue , Interferon gama/genética , Interleucina-1beta/genética , Interleucina-4/sangue , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/biossíntese , Restrição Física , Baço/imunologia , Células Th1/imunologia , Células Th2/imunologia , Fator de Necrose Tumoral alfa/genética , Regulação para Cima
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