RESUMO
Perinatal asphyxia (PA) is associated with long-term neuronal damage and cognitive deficits in adulthood, such as learning and memory disabilities. After PA, specific brain regions are compromised, including neocortex, hippocampus, basal ganglia, and ascending neuromodulatory pathways, such as dopamine system, explaining some of the cognitive disabilities. We hypothesize that other neuromodulatory systems, such as histamine system from the tuberomammillary nucleus (TMN), which widely project to telencephalon, shown to be relevant for learning and memory, may be compromised by PA. We investigated here the effect of PA on (i) Density and neuronal activity of TMN neurons by double immunoreactivity for adenosine deaminase (ADA) and c-Fos, as marker for histaminergic neurons and neuronal activity respectively. (ii) Expression of the histamine-synthesizing enzyme, histidine decarboxylase (HDC) by western blot and (iii) thioperamide an H3 histamine receptor antagonist, on an object recognition memory task. Asphyxia-exposed rats showed a decrease of ADA density and c-Fos activity in TMN, and decrease of HDC expression in hypothalamus. Asphyxia-exposed rats also showed a low performance in object recognition memory compared to caesarean-delivered controls, which was reverted in a dose-dependent manner by the H3 antagonist thioperamide (5-10mg/kg, i.p.). The present results show that the histaminergic neuronal system of the TMN is involved in the long-term effects induced by PA, affecting learning and memory.
Assuntos
Asfixia/tratamento farmacológico , Histamina/metabolismo , Região Hipotalâmica Lateral/metabolismo , Memória , Animais , Asfixia/metabolismo , Asfixia/patologia , Dopamina/metabolismo , Feminino , Antagonistas dos Receptores Histamínicos/farmacologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/patologia , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Receptores Histamínicos/efeitos dos fármacosRESUMO
Considerable evidence has been collected indicating that histamine can modulate proliferation of different normal and malignant cells. High histamine biosynthesis and content together with histamine receptors have been reported in different human neoplasias including melanoma, colon and breast cancer, as well as in experimental tumours in which histamine has been postulated to behave as an important paracrine and autocrine regulator of proliferation. The discovery of the human histamine H(4) receptor in different tissues has contributed to our understanding of histamine role in numerous physiological and pathological conditions revealing novel functions for histamine and opening new perspectives in histamine pharmacology research. In the present review we aimed to briefly summarize current knowledge on histamine and histamine receptor involvement in cancer before focusing on some recent evidence supporting the novel role of histamine H(4) receptor in cancer progression representing a promising molecular target and avenue for cancer drug development.
Assuntos
Sistemas de Liberação de Medicamentos , Neoplasias/fisiopatologia , Receptores Histamínicos/metabolismo , Animais , Antineoplásicos/farmacologia , Proliferação de Células , Desenho de Fármacos , Histamina/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/efeitos dos fármacos , Receptores Histamínicos H4RESUMO
Drugs with antihistamine action are the most commonly prescribed medication in daily dermatologic practice, both to adults and children. This article addresses new concepts of the role of histamine receptors (H1 receptors) and discusses the anti-inflammatory effects of these drugs. Second generation antihistamines differs from first generation because of their high specificity and affinity for peripheral H1-receptors. Second generation antihistamines are also less likely to produce sedation because they have less effect on the central nervous system. Although the efficacy of the various H1-antihistamines in the treatment of allergic patients is similar, even when comparing first- and second-generation drugs, these drugs are still very different in terms of their chemical structure, pharmacology and toxic properties. Consequently, knowledge of their pharmacokinetic and pharmacodynamic characteristics is essential for a better medical care, especially that offered to pregnant women, children, the elderly, and patients with comorbidities.
Assuntos
Antagonistas dos Receptores Histamínicos/farmacologia , Histamina/fisiologia , Receptores Histamínicos/efeitos dos fármacos , Receptores Histamínicos/fisiologia , Antagonistas dos Receptores Histamínicos/farmacocinética , HumanosRESUMO
As drogas com ação anti-histamínica estão entre as medicações mais comumente prescritas na prática dermatológica diária, tanto em adultos como em crianças. Este artigo aborda os novos conceitos da função dos receptores de histamina (receptores H1) e discute os efeitos anti-inflamatórios dessas drogas. A segunda geração de anti-histamínicos difere da primeira geração devido a sua elevada especificidade e afinidade pelos receptores H1 periféricos e devido a seu menor efeito no sistema nervoso central, tendo como resultado menores efeitos sedativos. Embora a eficácia dos diferentes anti-histamínicos H1 (anti-H1) no tratamento de doentes alérgicos seja similar, mesmo quando se comparam anti-H1 de primeira e de segunda geração, eles são muito diferentes em termos de estrutura química, farmacologia e propriedades tóxicas. Consequentemente o conhecimento de suas características farmacocinéticas e farmacodinâmicas é importante para a melhor prática médica, especialmente em gestantes, crianças, idosos e doentes com comorbidades.
Drugs with antihistamine action are the most commonly prescribed medication in daily dermatologic practice, both to adults and children. This article addresses new concepts of the role of histamine receptors (H1 receptors) and discusses the anti-inflammatory effects of these drugs. Second generation antihistamines differs from first generation because of their high specificity and affinity for peripheral H1-receptors. Second generation antihistamines are also less likely to produce sedation because they have less effect on the central nervous system. Although the efficacy of the various H1-antihistamines in the treatment of allergic patients is similar, even when comparing first- and second-generation drugs, these drugs are still very different in terms of their chemical structure, pharmacology and toxic properties. Consequently, knowledge of their pharmacokinetic and pharmacodynamic characteristics is essential for a better medical care, especially that offered to pregnant women, children, the elderly, and patients with comorbidities.
Assuntos
Humanos , Antagonistas dos Receptores Histamínicos/farmacologia , Histamina/fisiologia , Receptores Histamínicos/efeitos dos fármacos , Receptores Histamínicos/fisiologia , Antagonistas dos Receptores Histamínicos/farmacocinéticaRESUMO
Histamine was intensively studied at the beginning of the 20th century because of its important role in allergic and inflammation processes. In those days it was very difficult that researchers could envisage another impacting function for the imidazolamine in the living systems. Once the imidazolamine was found located in neuron compartment in the brain, increasing evidence supported many regulatory functions including its possible role in memory and learning. The specific participation of histamine in cognitive functions followed a slow and unclear pathway because the many different experimental learning models, pharmacologic approaches, systemic and localized applications of the histamine active compounds into the brain used by researchers showed facilitating or inhibitory effects on learning, generating an active issue that has extended up to present time. In this review, all these aspects are analyzed and discussed considering the many intracellular different mechanisms discovered for histamine, the specific histamine receptors and the compartmentalizing proprieties of the brain that might explain the apparent inconsistent effects of the imidazolamine in learning. In addition, a hypothetical physiologic role for histamine in memory is proposed under the standard theories of learning in experimental animals and humans.
Assuntos
Cognição/fisiologia , Histamina/farmacologia , Histamina/fisiologia , Aprendizagem/fisiologia , Animais , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Histamina/administração & dosagem , Humanos , Região Hipotalâmica Lateral/anatomia & histologia , Região Hipotalâmica Lateral/fisiologia , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Memória/fisiologia , Receptores Histamínicos/efeitos dos fármacos , Receptores Histamínicos/fisiologiaRESUMO
There is increasing evidence that describes a histamine role in normal and cancer cell proliferation. To better understand the importance of histamine in breast cancer development, the expression of histamine H3 (H3R) and H4 (H4R) receptors and their association with proliferating cell nuclear antigen (PCNA), histidine decarboxylase (HDC) and histamine content were explored in mammary biopsies. Additionally, we investigated whether H3R and H4R were implicated in the biological responses triggered by histamine in MDA-MB-231 breast cancer cells. The expression levels of H3R, H4R, PCNA, HDC and histamine content were determined by immunohistochemistry in 40 benign and malignant lesions. MDA-MB-231 cells proliferation (clonogenic assay and BrdU incorporation) and cell cycle distribution (flow cytometry) were evaluated upon treatment with histamine, H3R and H4R agonists and antagonists. Apoptosis was determined by Annexin staining and TUNEL assay. Cell migration was assessed by transwell system. Results indicate that H3R was detected in 67% (10/15) of benign lesions and in almost all carcinomas (24/25), being the level of its expression significantly higher in carcinomas (p = 0.0016). The non-tumoral breast tissue surrounding carcinomas revealed a lower H3R expression compared to the tumor cells. Only 13% (2/15) of the benign lesions expressed H4R compared to 44% (11/25) of the carcinomas. Interestingly, H3R expression was correlated in carcinomas with the expression of HDC and PCNA (p < 0.0001), and also histamine content (p = 0.0229). Accordingly, histamine increased MDA-MB-231 cells proliferation and also migration via H3R. In contrast, activation of H4R inhibited proliferation and this effect was associated with an arrest in the G(0)/G(1) phase of the cell cycle and an induction of apoptosis. Present findings demonstrate the presence of H3R and H4R in human mammary tissue and suggest that H3R may be involved in the regulation of breast cancer growth and progression representing a novel molecular target for new therapeutic approach.
Assuntos
Neoplasias da Mama/etiologia , Histamina/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Receptores Histamínicos H3/fisiologia , Receptores Histamínicos/fisiologia , Adulto , Idoso , Mama/química , Neoplasias da Mama/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Histamina/análise , Histidina Descarboxilase/análise , Humanos , Imidazóis/farmacologia , Pessoa de Meia-Idade , Antígeno Nuclear de Célula em Proliferação/análise , Receptores Acoplados a Proteínas G/análise , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Histamínicos/análise , Receptores Histamínicos/efeitos dos fármacos , Receptores Histamínicos H3/análise , Receptores Histamínicos H3/efeitos dos fármacos , Receptores Histamínicos H4 , Tioureia/análogos & derivados , Tioureia/farmacologiaRESUMO
La permeabilidad vascular puede ser modificada por la liberación de histamina endógena como resultado de la presencia de ciertos tiobarbitúricos (tiopental) en el organismo. Esta modificación en la permeabilidad es mediada por la activación del receptor histaminérgico H1, pero es incierta la participación del receptor H2. En este trabajo se evalúa la participación de receptores H1 y H2 durante los cambios de permeabilidad vascular inducidos por histamina, a través de la determinación de concentraciones séricas de albúmina, proteínas totales y globulinas, que indirectamente lo indican. Se formaron 5 grupos de organismos; un control y 4 experimentales denominados grupo A, B, C y D. A los organismos del grupo A se les aplicó histamina IV, 10 µg/Kg de peso, y finalmente al grupo D se le inyectó simultáneamente 0.16 mg/Kg de peso; al grupo C se le inyectó ranitidina IV, 0.13 mg/Kg de peso, y finalmente al grupo D se le inyectó simultáneamente 0.16 mg/Kg de peso y 0.13 mg/Kg de peso de astemizol y ranitidina IV, respectivamente. El grupo A mostró un decremento significativo en las concentraciones de albúmina, proteínas totales y globulinas. En los grupos B, C y D se observó una disminución en la concentración de proteínas totales y globulinas, pero no de albúmina. Estos resultados muestran que los receptores H1 y H2 están involucrados en el aumento de permeabilidad vascular a la albúmina, pero tal vez exista un proceso de permeabilidad diferencial en el cual el paso de globulinas desde la luz vascular hasta el intersticio esté regulado por otro mecanismo
Assuntos
Animais , Ratos , Permeabilidade Capilar/imunologia , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H2/efeitos dos fármacos , Ranitidina/imunologia , Tiopental/imunologia , Receptores Histamínicos/efeitos dos fármacos , Astemizol/imunologia , Albuminas/imunologiaAssuntos
Regulação Neoplásica da Expressão Gênica/genética , Genes ras/genética , Queratinócitos/metabolismo , Receptores Histamínicos/genética , Transdução de Sinais/genética , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Carcinógenos/toxicidade , Cimetidina/análogos & derivados , Cimetidina/metabolismo , AMP Cíclico/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes ras/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/metabolismo , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/metabolismo , Antagonistas dos Receptores H2 da Histamina/metabolismo , Fosfatos de Inositol/metabolismo , Queratinócitos/efeitos dos fármacos , Camundongos , Mutação/efeitos dos fármacos , Mutação/genética , Proteína Oncogênica p21(ras)/biossíntese , Proteína Oncogênica p21(ras)/genética , Pirilamina/metabolismo , Receptores Histamínicos/efeitos dos fármacos , Sistemas do Segundo Mensageiro , Transdução de Sinais/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
In this paper it was studied the role of histamine and histamine receptors in the hippocampus of rats on an active avoidance response induced by an ultrasonic tone. The animals had to learn to walk through a swinging door into a safe compartment only after the conditioning ultrasonic tone was on in order to avoid an electric shock to their feet. Trained animals were implanted in the ventral hippocampus with microinjection cannulae and injected twice with 1 microliter of saline solution containing pyrilamine (PYR, H1-HA antagonist), ranitidine (RAN, H2-HA antagonist) or histamine. The histamine antagonists were applied in a dose of 65.5 nmol each while histamine was administered in a dose of 45 nmol. The two variables measured were the time in sec the rats take to present the conditioned avoidance response and the accumulated percentage of conditioned avoidance response (CAR). Results showed that histamine administration significantly increased the latency time to escape and decreased the % CAR. These effects were not blocked by the administration of RAN. However, administration of PYR completely counteracted the HA effects. Present findings confirm our previous findings about the inhibitory effect of histamine on the hippocampal retrieval mechanisms and give further support to the hypothesis that HA acts on the memory processes in the hippocampal formation, by activation of H1-histamine receptors.
Assuntos
Hipocampo/metabolismo , Antagonistas dos Receptores Histamínicos/farmacologia , Memória/fisiologia , Receptores Histamínicos/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Eletrochoque , Hipocampo/efeitos dos fármacos , Histamina/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Masculino , Memória/efeitos dos fármacos , Microinjeções , Pirilamina/farmacologia , Ranitidina/farmacologia , Ratos , Receptores Histamínicos/efeitos dos fármacosRESUMO
The effect of histamine on [3H]norepinephrine ([3H]NE) release in uterine horns from mice in estrous and diestrous states was studied under two different experimental conditions: resting NE release and stimulus-evoked NE release. It was found that [3H]NE release was higher for the diestrous state under both resting and stimulus-evoked (100 mM K+ and electrical stimulus) conditions. Histamine only potentiated the stimulus-evoked [3H]NE outflow in uterine horns from mice in the diestrous state and from ovariectomized mice treated with progesterone. This effect was dose dependent and was antagonized by H1 but not by H2 or H3 antagonists. R-alpha-Methylhistamine, a H3 agonist, has no effect on stimulus-evoked [3H]NE release. According to these results, it could be concluded that: (a) histamine regulates the NE release from noradrenergic nerve terminals in uterine tissues; (b) this heterologous regulation depends on progesterone predominance and on terminal depolarization; and (c) presynaptic H1 receptors located on noradrenergic terminals could be responsible for such an effect.