RESUMO
Histidine decarboxylase (HDC), a histamine synthase, is expressed in various hematopoietic cells and is induced by hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF). We previously showed that nitrogen-containing bisphosphonate (NBP)-treatment induces extramedullary hematopoiesis via G-CSF stimulation. However, the function of HDC in NBP-induced medullary and extramedullary hematopoiesis remains unclear. Here, we investigated changes in hematopoiesis in wild-type and HDC-deficient (HDC-KO) mice. NBP treatment did not induce anemia in wild-type or HDC-KO mice, but did produce a gradual increase in serum G-CSF levels in wild-type mice. NBP treatment also enhanced Hdc mRNA expression and erythropoiesis in the spleen and reduced erythropoiesis in bone marrow and the number of vascular adhesion molecule 1 (VCAM-1)-positive macrophages in wild-type mice, as well as increased the levels of hematopoietic progenitor cells and proliferating cells in the spleen and enhanced expression of bone morphogenetic protein 4 (Bmp4), CXC chemokine ligand 12 (Cxcl12), and hypoxia inducible factor 1 (Hif1) in the spleen. However, such changes were not observed in HDC-KO mice. These results suggest that histamine may affect hematopoietic microenvironments of the bone marrow and spleen by changing hematopoiesis-related factors in NBP-induced extramedullary hematopoiesis.
Assuntos
Alendronato/antagonistas & inibidores , Medula Óssea/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Hematopoese Extramedular/efeitos dos fármacos , Histidina Descarboxilase/deficiência , Baço/efeitos dos fármacos , Alendronato/farmacologia , Alendronato/toxicidade , Anemia/induzido quimicamente , Animais , Medula Óssea/metabolismo , Proteína Morfogenética Óssea 4/biossíntese , Proteína Morfogenética Óssea 4/genética , Quimiocina CXCL12/biossíntese , Quimiocina CXCL12/genética , Indução Enzimática/efeitos dos fármacos , Células Eritroides/patologia , Citometria de Fluxo , Fator Estimulador de Colônias de Granulócitos/sangue , Histamina/biossíntese , Histidina Descarboxilase/biossíntese , Histidina Descarboxilase/genética , Histidina Descarboxilase/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Baço/metabolismoRESUMO
Antihistamine medications have been suggested to elicit clinical features of restless legs syndrome. The available data are limited, particularly concerning periodic leg movements during sleep, which are common in restless legs syndrome and involve bursts of tibialis anterior electromyogram. Here, we tested whether the occurrence of tibialis anterior electromyogram bursts during non-rapid eye movement sleep is altered in histidine decarboxylase knockout mice with congenital histamine deficiency compared with that in wild-type control mice. We implanted six histidine decarboxylase knockout and nine wild-type mice to record neck muscle electromyogram, bilateral tibialis anterior electromyogram, and electroencephalogram during the rest (light) period. The histidine decarboxylase knockout and wild-type mice did not differ significantly in terms of sleep architecture. In both histidine decarboxylase knockout and wild-type mice, the distribution of intervals between tibialis anterior electromyogram bursts had a single peak for intervals <â 10 s. The total occurrence rate of tibialis anterior electromyogram bursts during non-rapid eye movement sleep and the occurrence rate of the tibialis anterior electromyogram bursts separated by intervals <â 10 s were significantly lower in histidine decarboxylase knockout than in wild-type mice. These data do not support the hypothesis that preventing brain histamine signalling may promote restless legs syndrome. Rather, the data suggest that limb movements during sleep, including those separated by short intervals, are a manifestation of subcortical arousal requiring the integrity of brain histamine signalling.
Assuntos
Eletromiografia , Extremidades/fisiologia , Histamina/deficiência , Síndrome das Pernas Inquietas/fisiopatologia , Sono/fisiologia , Animais , Nível de Alerta , Feminino , Histamina/metabolismo , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de SinaisRESUMO
Neutrophil-platelet interactions are responsible for thrombosis as well as inflammatory responses following acute myocardial infarction (AMI). While histamine has been shown to play a crucial role in many physiological and pathological processes, its effects on neutrophil-platelet interactions in thromboinflammatory complications of AMI remain elusive. In this study, we show a previously unknown mechanism by which neutrophil-derived histamine protects the infarcted heart from excessive neutrophil-platelet interactions and redundant arterial thrombosis. Using histamine-deficient (histidine decarboxylase knockout, HDC-/- ) and wild-type murine AMI models, we demonstrate that histamine deficiency increases the number of microthrombosis after AMI, in accordance with depressed cardiac function. Histamine-producing myeloid cells, mainly Ly6G+ neutrophils, directly participate in arteriole thrombosis. Histamine deficiency elevates platelet activation and aggregation by enhancing Akt phosphorylation and leads to dysfunctional characteristics in neutrophils which was confirmed by high levels of reactive oxygen species production and CD11b expression. Furthermore, HDC-/- platelets were shown to elicit neutrophil extracellular nucleosomes release, provoke neutrophil-platelet interactions and promote HDC-expressing neutrophils recruitment in arteriole thrombosis in vivo. In conclusion, we provide evidence that histamine deficiency promotes coronary microthrombosis and deteriorates cardiac function post-AMI, which is associated with the enhanced platelets/neutrophils function and neutrophil-platelet interactions.
Assuntos
Plaquetas/patologia , Comunicação Celular , Vasos Coronários/patologia , Histamina/deficiência , Infarto do Miocárdio/complicações , Neutrófilos/patologia , Trombose/etiologia , Animais , Plaquetas/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Histamina/farmacologia , Histidina Descarboxilase/deficiência , Camundongos , Modelos Biológicos , Infarto do Miocárdio/patologia , Miocárdio/patologia , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Histamínicos/metabolismo , Trombopoese/efeitos dos fármacos , Trombose/patologiaRESUMO
Histidine decarboxylase (HDC) catalyses the formation of histamine from L-histidine. Histamine is a biogenic amine involved in many physiological and pathological processes, but its role in the regeneration of skeletal muscles has not been thoroughly clarified. Here, using a murine model of hindlimb ischaemia, we show that histamine deficiency in Hdc knockout (Hdc-/- ) mice significantly reduces blood perfusion and impairs muscle regeneration. Using Hdc-EGFP transgenic mice, we demonstrate that HDC is expressed predominately in CD11b+ Gr-1+ myeloid cells but not in skeletal muscles and endothelial cells. Large amounts of HDC-expressing CD11b+ myeloid cells are rapidly recruited to injured and inflamed muscles. Hdc-/- enhances inflammatory responses and inhibits macrophage differentiation. Mechanically, we demonstrate that histamine deficiency decreases IGF-1 (insulin-like growth factor 1) levels and diminishes myoblast proliferation via H3R/PI3K/AKT-dependent signalling. These results indicate a novel role for HDC-expressing CD11b+ myeloid cells and histamine in myoblast proliferation and skeletal muscle regeneration.
Assuntos
Proliferação de Células/fisiologia , Histamina/deficiência , Inflamação/fisiopatologia , Músculo Esquelético/fisiopatologia , Mioblastos/metabolismo , Regeneração/fisiologia , Animais , Linhagem Celular , Proliferação de Células/genética , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/genética , Inflamação/genética , Inflamação/metabolismo , Isquemia/fisiopatologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Mioblastos/citologia , Regeneração/genética , Transdução de Sinais/fisiologiaRESUMO
Hypothalamic histaminergic neurons regulate a variety of homeostatic, metabolic and cognitive functions. Recent data have suggested a modulatory role of histamine and histamine receptors in shaping striatal activity and connected the histaminergic system to neuropsychiatric disorders. We characterized exploratory behavior and striatal neurotransmission in mice lacking the histamine producing enzyme histidine decarboxylase (Hdc). The mutant mice showed a distinct behavioral pattern during exploration of novel environment, specifically, increased frequency of rearing seated against the wall, jumping and head/body shakes. This behavioral phenotype was associated with decreased levels of striatal dopamine and serotonin and increased level of dopamine metabolite DOPAC. Gene expression levels of dynorphin and enkephalin, opioids released by medium spiny neurons of striatal direct and indirect pathways respectively, were lower in Hdc mutant mice than in control animals. A low dose of amphetamine led to similar behavioral and biochemical outcomes in both genotypes. Increased striatal dopamine turnover was observed in Hdc KO mice after treatment with dopamine precursor l-Dopa. Overall, our study suggests a role for striatal dopamine and opioid peptides in formation of distinct behavioral phenotype of Hdc KO mice.
Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Histamina/metabolismo , Histidina Descarboxilase/genética , Movimento , Peptídeos Opioides/genética , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Corpo Estriado/fisiopatologia , Histamina/deficiência , Histidina Descarboxilase/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos Opioides/metabolismo , Serotonina/metabolismoRESUMO
BACKGROUND: Histamine is an important immunomodulator influencing both the innate and adaptive immune system. Certain host cells express the histidine decarboxylase enzyme (HDC), which is responsible for catalysing the decarboxylation of histidine to histamine. We and others have shown that bacterial strains can also express HDC and secrete histamine; however, the influence of bacterial-derived histamine on the host immune responses distant to the gut is unclear. METHODS: The Escherichia coli BL21 (E coli BL21) strain was genetically modified to express the Morganella morganii (M morganii)-derived HDC gene (E coli BL21_HTW). E coli BL21 and E coli BL21_HTW were gavaged to ovalbumin (OVA) sensitized and challenged mice to investigate the effect of bacterial-derived histamine on lung inflammatory responses. RESULTS: Oral administration of E coli BL21_HTW, which is able to secrete histamine, to wild-type mice reduced lung eosinophilia and suppressed ex vivo OVA-stimulated cytokine secretion from lung cells in the OVA respiratory inflammation mouse model. In histamine receptor 2 (H2R)-deficient mice, administration of histamine-secreting bacteria also reduced inflammatory cell numbers in bronchoalveolar lavage (BAL). However, the suppressive effect of bacterial-derived histamine on BAL inflammation was lost in HDC-deficient mice. This loss of activity was associated with increased expression of histamine degrading enzymes and reduced histamine receptor expression. CONCLUSION: Histamine secretion from bacteria within the gut can have immunological consequences at distant mucosal sites, such as within the lung. These effects are influenced by host histamine receptor expression and the expression of histamine degrading enzymes.
Assuntos
Bactérias/metabolismo , Fenômenos Fisiológicos Bacterianos , Microbioma Gastrointestinal , Histamina/biossíntese , Imunidade , Pulmão/imunologia , Pulmão/metabolismo , Animais , Modelos Animais de Doenças , Escherichia coli/fisiologia , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Camundongos , Receptores Histamínicos H2/genética , Receptores Histamínicos H2/metabolismoRESUMO
It has been suggested that the bioactive lipid mediator oleoylethanolamide (OEA), a potent agonist of the peroxisome proliferator-activated receptor-alpha (PPAR-α) possesses anti-depressant-like effects in several preclinical models. We recently demonstrated that several of OEA's behavioural actions require the integrity of the brain histaminergic system, and that an intact histaminergic neurotransmission is specifically required for selective serotonin re-uptake inhibitors to exert their anti-depressant-like effect. The purpose of our study was to test if OEA requires the integrity of the histaminergic neurotransmission to exert its antidepressant-like effects. Immobility time in the tail suspension test was measured to assess OEA's potential (10â¯mg/kg i.p.) as an antidepressant drug in histidine decarboxylase null (HDC-/-) mice and HDC+/+ littermates, as well as in PPAR-α+/+ and PPAR-α-/- mice. CREB phosphorylation was evaluated using Western blot analysis in hippocampal and cortical homogenates, as pCREB is considered partially responsible for the efficacy of antidepressants. Serotonin release from ventral hippocampi of HDC+/+ and HDC-/- mice was measured with in-vivo microdialysis, following OEA administration. OEA decreased immobility time and increased brain pCREB levels in HDC+/+ mice, whereas it was ineffective in HDC-/- mice. Comparable results were obtained in PPAR-α+/+ and PPAR-α-/- mice. Microdialysis revealed a dysregulation of serotonin release induced by OEA in HDC-/- mice. Our observations corroborate our hypothesis that brain histamine and signals transmitted by OEA interact to elaborate appropriate behaviours and may be the basis for the efficacy of OEA as an antidepressant-like compound.
Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Endocanabinoides/farmacologia , Histamina/deficiência , Ácidos Oleicos/farmacologia , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/genética , Imipramina/farmacologia , Masculino , Camundongos Knockout , PPAR alfa/deficiência , PPAR alfa/genética , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Distribuição Aleatória , Serotonina/metabolismoRESUMO
A premature termination codon in the human histidine decarboxylase (Hdc) gene has been identified in a family suffering from Guilles de la Tourette syndrome (GTS). In the current study we investigated if mice lacking the histamine producing enzyme HDC share the morphological and cytological phenotype with GTS patients by using magnetic resonance (MRI) and diffusion tensor imaging (DTI), unbiased stereology and immunohistochemistry. Behavior of Hdc knock-out (Hdc KO) mice was assessed in an open field test. The results of stereological, volumetric and DTI analysis measurements showed no significant differences between control and Hdc KO mice. The numbers and distribution of GABAergic parvalbumin or nitric oxide-expressing and cholinergic interneurons were normal in Hdc KO mice. Cortical morphology and layering in adult Hdc KO mice were also preserved. In open field test Hdc KO mice showed impaired exploratory activity and habituation when introduced to novel environment. Our results indicate that Hdc deficiency in mice does not disturb the development of striatal and cortical interneurons and does not lead to the morphological and cytological phenotypes characterized by humans with GTS. Nevertheless, histamine deficiency leads to behavioral alterations probably due to neurotransmitter dysbalance on the level of the striatum.
Assuntos
Encéfalo/patologia , Comportamento Exploratório/fisiologia , Histidina Descarboxilase/deficiência , Síndrome de Tourette , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Contagem de Células , Colina O-Acetiltransferase/metabolismo , Imagem de Tensor de Difusão , Modelos Animais de Doenças , Habituação Psicofisiológica/genética , Histidina Descarboxilase/genética , Proteínas de Homeodomínio/metabolismo , Processamento de Imagem Assistida por Computador , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibras Nervosas/patologia , Proteínas Nucleares/metabolismo , Parvalbuminas/metabolismo , Proteínas Repressoras/metabolismo , Síndrome de Tourette/diagnóstico por imagem , Síndrome de Tourette/genética , Síndrome de Tourette/patologia , Síndrome de Tourette/fisiopatologia , Proteína Vesicular 2 de Transporte de Glutamato/metabolismoRESUMO
Pharmacological studies in mammals and zebrafish suggest that histamine plays an important role in promoting arousal. However, genetic studies using rodents with disrupted histamine synthesis or signaling have revealed only subtle or no sleep/wake phenotypes. Studies of histamine function in mammalian arousal are complicated by its production in cells of the immune system and its roles in humoral and cellular immunity, which can have profound effects on sleep/wake states. To avoid this potential confound, we used genetics to explore the role of histamine in regulating sleep in zebrafish, a diurnal vertebrate in which histamine production is restricted to neurons in the brain. Similar to rodent genetic studies, we found that zebrafish that lack histamine due to mutation of histidine decarboxylase (hdc) exhibit largely normal sleep/wake behaviors. Zebrafish containing predicted null mutations in several histamine receptors also lack robust sleep/wake phenotypes, although we are unable to verify that these mutants are completely nonfunctional. Consistent with some rodent studies, we found that arousal induced by overexpression of the neuropeptide hypocretin (Hcrt) or by stimulation of hcrt-expressing neurons is not blocked in hdc or hrh1 mutants. We also found that the number of hcrt-expressing or histaminergic neurons is unaffected in animals that lack histamine or Hcrt signaling, respectively. Thus, while acute pharmacological manipulation of histamine signaling has been shown to have profound effects on zebrafish and mammalian sleep, our results suggest that chronic loss of histamine signaling due to genetic mutations has only subtle effects on sleep in zebrafish, similar to rodents.
Assuntos
Histamina/genética , Histamina/metabolismo , Receptores Histamínicos H1/genética , Receptores Histamínicos H1/metabolismo , Sono/genética , Sono/fisiologia , Animais , Animais Geneticamente Modificados , Ensaio de Imunoadsorção Enzimática , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/genética , Imuno-Histoquímica , Larva , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Optogenética , Orexinas/genética , Orexinas/metabolismo , Estimulação Física , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Vigília/fisiologia , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Histamine has pleiotropic pathophysiological effects, but its role in myocardial infarction (MI)-induced cardiac remodeling remains unclear. Histidine decarboxylase (HDC) is the main enzyme involved in histamine production. Here, we clarified the roles of HDC-expressing cells and histamine in heart failure post-MI using HDC-EGFP transgenic mice and HDC-knockout (HDC-/-) mice. HDC+CD11b+ myeloid cell numbers markedly increased in the injured hearts, and histamine levels were up-regulated in the circulation post-MI. HDC-/- mice exhibited more adverse cardiac remodeling, poorer left ventricular function and higher mortality by increasing cardiac fibrogenesis post-MI. In vitro assays further confirmed that histamine inhibited heart fibroblast proliferation. Furthermore, histamine enhanced the signal transducer and activator of transcription (STAT)-6 phosphorylation level in murine heart fibroblasts, and the inhibitive effects of histamine on fibroblast proliferation could be blocked by JAK3/STAT6 signaling selective antagonist. STAT6-knockout (STAT6-/-) mice had a phenotype similar to that of HDC-/- mice post-MI; however, in contrast to HDC-/- mice, the beneficial effects of exogenous histamine injections were abrogated in STAT6-/- mice. These data suggest that histamine exerts protective effects by modulating cardiac fibrosis and remodeling post-MI, in part through the STAT6-dependent signaling pathway.
Assuntos
Insuficiência Cardíaca/patologia , Histamina/metabolismo , Infarto do Miocárdio/patologia , Remodelação Ventricular/fisiologia , Animais , Citocinas/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Histamina/sangue , Histamina/farmacologia , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/genética , Humanos , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Mieloides/citologia , Células Mieloides/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/veterinária , Miocárdio/citologia , Miocárdio/patologia , Fosforilação , Receptores Histamínicos/metabolismo , Fator de Transcrição STAT6/antagonistas & inibidores , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: It is known that histamine participates in pain modulation. However, the effect of central histamine on neuropathic pain is not fully understood. Here, we report a critical time window for the analgesic effect of central histamine in the partial sciatic nerve ligation model of neuropathic pain. METHODS: Neuropathic pain was induced by partial sciatic nerve ligation (PSL) in rats, wild-type (C57BL/6J) mice and HDC(-/-) (histidine decarboxylase gene knockout) and IL-1R(-/-) (interleukin-1 receptor gene knockout) mice. Histidine, a precursor of histamine that can increase the central histamine levels, was administered intraperitoneally (i.p.). Histidine decarboxylase (HDC) enzyme inhibitor α-fluoromethylhistidine was administered intracerebroventricularly (i.c.v.). Histamine H1 receptor antagonist mepyramine and H2 receptor antagonist cimetidine were given intrathecally (i.t.) and intracisternally (i.c.). Withdrawal thresholds to tactile and heat stimuli were measured with a set of von Frey hairs and infrared laser, respectively. Immunohistochemistry and Western blot were carried out to evaluate the morphology of microglia and IL-1ß production, respectively. RESULTS: Histidine (100 mg/kg, i.p.) administered throughout days 0-3, 0-7, or 0-14 postoperatively (PO) alleviated mechanical allodynia and thermal hyperalgesia in the hindpaw following PSL in rats. Intrathecal histamine reversed PSL-induced thermal hyperalgesia in a dose-dependent manner and intracisternal histamine alleviated both mechanical allodynia and thermal hyperalgesia. Moreover, α-fluoromethylhistidine (i.c.v.) abrogated the analgesic effect of histidine. However, histidine treatment initiated later than the first postoperative day (treatment periods included days 2-3, 4-7, and 8-14 PO) did not show an analgesic effect. In addition, histidine treatment initiated immediately, but not 3 days after PSL, inhibited microglial activation and IL-1ß upregulation in the lumbar spinal cord, in parallel with its effects on behavioral hypersensitivity. Moreover, the inhibitory effects on pain hypersensitivity and spinal microglial activation were absent in HDC(-/-) mice and IL-1R(-/-) mice. H1 receptor antagonist mepyramine (200 ng/rat i.t. or i.c.), but not H2 receptor antagonist cimetidine (200, 500 ng/rat i.t. or 500 ng/rat i.c.), blocked the effects of histidine on pain behavior and spinal microglia. CONCLUSIONS: These results demonstrate that central histamine is analgesic within a critical time window in the PSL model of neuropathic pain via histamine H1 receptors. This effect may partly relate to the inhibition of microglial activation and IL-1ß production in the spinal cord following nerve injury.
Assuntos
Analgésicos/uso terapêutico , Sistema Nervoso Central/metabolismo , Histidina/uso terapêutico , Neuropatia Ciática , Analgésicos/farmacologia , Animais , Sistema Nervoso Central/efeitos dos fármacos , Cimetidina/farmacologia , Modelos Animais de Doenças , Vias de Administração de Medicamentos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Histidina/farmacologia , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/genética , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Limiar da Dor/efeitos dos fármacos , Pirilamina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Interleucina-1/deficiência , Receptores de Interleucina-1/genética , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologiaRESUMO
Histaminergic H3 receptors (H3R) antagonists enhance cognition in preclinical models and modulate neurotransmission, in particular acetylcholine (ACh) release in the cortex and hippocampus, two brain areas involved in memory processing. The cognitive deficits seen in aging and Alzheimer's disease have been associated with brain cholinergic deficits. Donepezil is one of the acetylcholinesterase (AChE) inhibitor approved for use across the full spectrum of these cognitive disorders. We addressed the question if H3R antagonists and donepezil require an intact histamine neuronal system to exert their procognitive effects. The effect of the H3R antagonist ABT-239 and donepezil were evaluated in the object recognition test (ORT), and on the level of glycogen synthase kinase 3 beta (GSK-3ß) phosphorylation in normal and histamine-depleted mice. Systemic administration of ABT-239 or donepezil ameliorated the cognitive performance in the ORT. However, these compounds were ineffective in either genetically (histidine decarboxylase knock-out, HDC-KO) or pharmacologically, by means of intracerebroventricular (i.c.v.) injections of the HDC irreversible inhibitor a-fluoromethylhistidine (a-FMHis), histamine-deficient mice. Western blot analysis revealed that ABT-239 or donepezil systemic treatments increased GSK-3ß phosphorylation in cortical and hippocampal homogenates of normal, but not of histamine-depleted mice. Furthermore, administration of the PI3K inhibitor LY294002 that blocks GSK-3ß phosphorylation, prevented the procognitive effects of both drugs in normal mice. Our results indicate that both donepezil and ABT-239 require the integrity of the brain histaminergic system to exert their procognitive effects and strongly suggest that impairments of PI3K/AKT/GSK-3ß intracellular pathway activation is responsible for the inefficacy of both drugs in histamine-deficient animals.
Assuntos
Benzofuranos/farmacologia , Encéfalo/metabolismo , Inibidores da Colinesterase/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Histamina/deficiência , Indanos/farmacologia , Nootrópicos/farmacologia , Piperidinas/farmacologia , Pirrolidinas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Cognição/fisiologia , Donepezila , Agonismo Inverso de Drogas , Histidina Descarboxilase/antagonistas & inibidores , Histidina Descarboxilase/deficiência , Masculino , Camundongos , Camundongos Knockout , Receptores Histamínicos H3/metabolismoRESUMO
Histamine and orexins are wake promoters released by hypothalamic neurons. The activity of histamine neurons is increased by orexin neurons. Recently, it has been shown that orexin deficiency entails high-amplitude theta wave bursts during rapid eye movement sleep and cataplexy in narcoleptic mice. The primary aim of this study was to assess whether histamine system is involved in high-amplitude theta wave burst generation during rapid eye movement sleep. The secondary aim was to assess the effects of combined histamine and orexin deficiency on high-amplitude theta wave bursts during rapid eye movement sleep in mice. Twelve histidine-decarboxylase knockout mice with congenital histamine deficiency, seven double mutant mice with combined deficiency of orexin neurons and histamine, and 11 wild-type control mice were studied with electrodes for sleep recordings and a telemetric blood pressure transducer. High-amplitude theta wave bursts during rapid eye movement sleep were detected in each of the histidine-decarboxylase knockout and double mutant mice, whereas only one burst was found in a wild-type control mouse. High-amplitude theta wave bursts occurred significantly more often and were significantly longer in double mutant than in histidine-decarboxylase knockout mice. In conclusion, it was demonstrated that, similarly to orexin, the chronic impairment of histamine entailed high-amplitude theta wave bursts during rapid eye movement sleep. The current data also suggested a synergistic role of orexin and histamine signalling on high-amplitude theta wave bursts during rapid eye movement sleep in mice.
Assuntos
Cataplexia/fisiopatologia , Histamina/deficiência , Sono REM , Ritmo Teta , Animais , Pressão Sanguínea , Cataplexia/genética , Histamina/metabolismo , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Mutação , Neurônios/metabolismo , Orexinas/deficiência , Orexinas/genética , Orexinas/metabolismoRESUMO
Narcolepsy type 1 is associated with loss of orexin neurons, sleep-wake derangements, cataplexy, and a wide spectrum of alterations in other physiological functions, including energy balance, cardiovascular, and respiratory control. It is unclear which narcolepsy signs are directly related to the lack of orexin neurons or are instead modulated by dysfunction of other neurotransmitter systems physiologically controlled by orexin neurons, such as the histamine system. To address this question, we tested whether some of narcolepsy signs would be detected in mice lacking histamine signaling (HDC-KO). Moreover, we studied double-mutant mice lacking both histamine signaling and orexin neurons (DM) to evaluate whether the absence of histamine signaling would modulate narcolepsy symptoms produced by orexin deficiency. Mice were instrumented with electrodes for recording the electroencephalogram and electromyogram and a telemetric arterial pressure transducer. Sleep attacks fragmenting wakefulness, cataplexy, excess rapid-eye-movement sleep (R) during the activity period, and enhanced increase of arterial pressure during R, which are hallmarks of narcolepsy in mice, did not occur in HDC-KO, whereas they were observed in DM mice. Thus, these narcolepsy signs are neither caused nor abrogated by the absence of histamine. Conversely, the lack of histamine produced obesity in HDC-KO and to a greater extent also in DM. Moreover, the regularity of breath duration during R was significantly increased in either HDC-KO or DM relative to that in congenic wild-type mice. Defects of histamine transmission may thus modulate the metabolic and respiratory phenotype of murine narcolepsy.
Assuntos
Histamina/metabolismo , Narcolepsia/metabolismo , Narcolepsia/patologia , Neurônios/metabolismo , Orexinas/deficiência , Fenótipo , Transdução de Sinais , Animais , Peso Corporal , Sistema Cardiovascular/fisiopatologia , Cataplexia/metabolismo , Cataplexia/patologia , Cataplexia/fisiopatologia , Ingestão de Energia , Feminino , Técnicas de Inativação de Genes , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/genética , Masculino , Camundongos , Respiração , Sono , VigíliaRESUMO
Histamine is a biogenic amine that is widely distributed and has multiple functions, but the role it plays in acute myocardial infarction (AMI) remains unclear. In this study, we investigated the origin and contribution of endogenous histamine to AMI. Histidine decarboxylase (HDC) is the unique enzyme responsible for histamine generation. Using HDC-EGFP bacterial artificial chromosome (BAC) transgenic mice in which EGFP expression is controlled by the HDC promoter, we identified HDC expression primarily in CD11b(+)Gr-1(+) immature myeloid cells (IMCs) that markedly increase in the early stages of AMI. Deficiency of histamine in HDC knockout mice (HDC(-/-)) reduced cardiac function and exacerbated the injury of infarcted heart. Furthermore, administering either an H1 receptor antagonist (pyrilamine) or an H2 receptor antagonist (cimetidine) demonstrated a protective effect of histamine against myocardial injury. The results of in vivo and in vitro assays showed that histamine deficiency promotes the apoptosis of cardiomyocytes and inhibits macrophage infiltration. In conclusion, CD11b(+)Gr-1(+) IMCs are the predominant HDC-expressing sites in AMI, and histamine plays a protective role in the process of AMI through inhibition of cardiomyocyte apoptosis and facilitation of macrophage infiltration.
Assuntos
Apoptose/efeitos dos fármacos , Histamina/farmacologia , Histidina Descarboxilase/genética , Macrófagos/imunologia , Infarto do Miocárdio/patologia , Doença Aguda , Animais , Linhagem Celular , Cimetidina/farmacologia , Creatina Quinase Forma MB/análise , Modelos Animais de Doenças , Traumatismos Cardíacos/etiologia , Traumatismos Cardíacos/prevenção & controle , Histamina/análise , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/metabolismo , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Regiões Promotoras Genéticas , Pirilamina/farmacologiaRESUMO
3-iodothyronamine (T1AM) and its oxidative product, 3-iodotyhyroacetic acid (TTA1A), are known to stimulate learning and induce hyperalgesia in mice. We investigated whether i)TA1 may be generated in vivo from T1AM, ii) T1AM shares with TA1 the ability to activate the histaminergic system. Tandem mass spectrometry was used to measure TA1 and T1AM levels in i) the brain of mice following intracerebroventricular (i.c.v.) injection of T1AM (11µgkg(-1)), with or without pretreatment with clorgyline, (2.5mgkg(-1) i.p.), a monoamine oxidase inhibitor; ii) the medium of organotypic hippocampal slices exposed to T1AM (50nM). In addition, learning and pain threshold were evaluated by the light-dark box task and the hot plate test, respectively, in mice pre-treated subcutaneously with pyrilamine (10mgkg(-1)) or zolantidine (5mgkg(-1)), 20min before i.c.v. injection of T1AM (1.32 and 11µgkg(-1)). T1AM-induced hyperalgesia (1.32 and 11µgkg(-1)) was also evaluated in histidine decarboxylase (HDC(-/-)) mice. T1AM and TA1 brain levels increased in parallel in mice injected with T1AM with the TA1/T1AM averaging 1.7%. Clorgyline pre-treatment reduced the increase in both T1AM and TA1. TA1 was the main T1AM metabolite detected in the hippocampal preparations. Pretreatment with pyrilamine or zolantidine prevented the pro-learning effect of 1.32 and 4µgkg(-1) T1AM while hyperalgesia was conserved at the dose of 11µgkg(-1) T1AM. T1AM failed to induce hyperalgesia in HDC(-/-) mice at all the doses. In conclusion, TA1 generated from T1AM, but also T1AM, appears to act by modulating the histaminergic system.
Assuntos
Hipocampo/metabolismo , Histamina/metabolismo , Transdução de Sinais , Hormônios Tireóideos/metabolismo , Tironinas/metabolismo , Tironinas/farmacocinética , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Biotransformação , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Antagonistas dos Receptores Histamínicos/farmacologia , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/genética , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Hiperalgesia/prevenção & controle , Injeções Intraventriculares , Masculino , Camundongos da Linhagem 129 , Camundongos Knockout , Inibidores da Monoaminoxidase/farmacologia , Oxirredução , Limiar da Dor/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas em Tandem , Tironinas/administração & dosagem , Tironinas/toxicidadeRESUMO
Regulatory T cells (Tregs) suppress effector T cells and ameliorate contact hypersensitivity (CH); however, the role of Tregs in chronic allergic contact dermatitis (CACD) has not been assessed. Repeated elicitation of CH has been used to produce CACD models in mice. We previously showed that the presence of histamine facilitates the creation of eczematous lesions in this model using histidine decarboxylase (HDC) (-/-) mice. Therefore, the effects of histamine on Tregs in the CACD model were investigated in this study. CACD was developed by repeated epicutaneous application of 2, 4, 6-trinitro-1-chlorobenzene (TNCB) on HDC (+/+) and HDC (-/-) murine skin to assess the effects of histamine in CACD. Histamine aggravated CACD in the murine model and suppressed the number of Tregs in the skin. Histamine also suppressed the level of TGF-ß1 in this model. Recombinant TGF-ß1 or anti-TGF-ß1 antibody was injected into the dorsal dermis of HDC (+/+) mice daily just before TNCB challenge to determine the effects of histamine-regulated TGF-ß on the Treg population in CACD. Recombinant TGF-ß1 injection promoted the infiltration of Tregs in the skin and the production of IL-10; however, anti-TGF-ß1 antibody injection suppressed the number of Tregs in the skin and the production of IL-10. Histamine suppresses the number of Tregs in CACD, and this effect is mediated by TGF-ß.
Assuntos
Dermatite Alérgica de Contato/imunologia , Histamina/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta1/imunologia , Animais , Doença Crônica , Dermatite Alérgica de Contato/etiologia , Dermatite Alérgica de Contato/patologia , Modelos Animais de Doenças , Feminino , Antagonistas dos Receptores Histamínicos H1/farmacologia , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/genética , Interleucina-10/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cloreto de Picrila/toxicidade , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Histamínicos , Receptores Histamínicos H4 , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Fator de Crescimento Transformador beta1/metabolismoRESUMO
The role of histamine in the retina is not well understood, despite it regulating a number of functions within the brain, including sleep, feeding, energy balance, and anxiety. In this study we characterized the structure and function of the retina in mice that lacked expression of the rate limiting enzyme in the formation of histamine, histidine decarboxylase (Hdc-/- mouse). Using laser capture microdissection, Hdc mRNA expression was assessed in the inner and outer nuclear layers of adult C57Bl6J wildtype (WT) and Hdc(-/-)-retinae. In adult WT and Hdc(-/-)-mice, retinal fundi were imaged, retinal structure was assessed using immunocytochemistry and function was probed by electroretinography. Blood flow velocity was assessed by quantifying temporal changes in the dynamic fluorescein angiography in arterioles and venules. In WT retinae, Hdc gene expression was detected in the outer nuclear layer, but not the inner nuclear layer, while the lack of Hdc expression was confirmed in the Hdc-/- retina. Preliminary examination of the fundus and retinal structure of the widely used Hdc-/- mouse strain revealed discrete lesions across the retina that corresponded to areas of photoreceptor abnormality reminiscent of the rd8 (Crb1) mutation. This was confirmed after genotyping and the strain designated Hdcrd8/rd8. In order to determine the effect of the lack of Hdc-alone on the retina, Hdc-/- mice free of the Crb1 mutation were bred. Retinal fundi appeared normal in these animals and there was no difference in retinal structure, macrogliosis, nor any change in microglial characteristics in Hdc-/- compared to wildtype retinae. In addition, retinal function and retinal blood flow dynamics showed no alterations in the Hdc-/- retina. Overall, these results suggest that histamine plays little role in modulating retinal structure and function.
Assuntos
Histamina/metabolismo , Histidina Descarboxilase/deficiência , Retina/metabolismo , Animais , Contagem de Células , Histidina Descarboxilase/metabolismo , Mamíferos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Microglia/patologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Fluxo Sanguíneo Regional , Retina/patologia , Células Fotorreceptoras Retinianas Cones/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/metabolismoRESUMO
BACKGROUND AND PURPOSE: 3-Iodothyroacetic acid (TA1) is an end product of thyroid hormone metabolism. So far, it is not known if TA1 is present in mouse brain and if it has any pharmacological effects. EXPERIMENTAL APPROACH: TA1 levels in mouse brain were measured by HPLC coupled to mass spectrometry. After i.c.v. administration of exogenous TA1 (0.4, 1.32 and 4 µg·kg(-1) ) to mice, memory acquisition-retention (passive avoidance paradigm with a light-dark box), pain threshold to thermal stimulus (51.5°C; hot plate test) and plasma glucose (glucorefractometer) were evaluated. Similar assays were performed in mice pretreated with s.c. injections of the histamine H1 receptor antagonist pyrilamine (10 mg·kg(-1) ) or the H2 receptor antagonist zolantidine (5 mg·kg(-1) ). TA1 (1.32 and 4 µg·kg(-1) ) was also given i.c.v. to mice lacking histidine decarboxylase (HDC(-/-) ) and the corresponding WT strain. KEY RESULTS: TA1 was found in the brain of CD1 but not of HDC mice. Exogenous TA1 induced amnesia (at 0.4 µg·kg(-1) ), stimulation of learning (1.32 and 4 µg·kg(-1) ), hyperalgesia (0.4, 1.32 and 4 µg·kg(-1) ) and hyperglycaemia (1.32 and 4 µg·kg(-1) ). All these effects were modulated by pyrilamine and zolantidine. In HDC(-/-) mice, TA1 (1.32 and 4 µg·kg(-1) ) did not increase plasma glucose or induce hyperalgesia. CONCLUSIONS AND IMPLICATIONS: Behavioural and metabolic effects of TA1 disclosed interactions between the thyroid and histaminergic systems.
Assuntos
Comportamento Animal/efeitos dos fármacos , Histamina/metabolismo , Hormônios Tireóideos/metabolismo , Tironinas/farmacologia , Animais , Histidina Descarboxilase/deficiência , Histidina Descarboxilase/metabolismo , Camundongos , Camundongos Knockout , Hormônios Tireóideos/química , Tironinas/química , Tironinas/metabolismoRESUMO
Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.