RESUMEN
PURPOSE: We have previously shown that domperidone-induced short-term hyperprolactinemia reduces the lung's allergic inflammatory response in an ovalbumin antigenic challenge model. Since purinergic receptor P2X7R activity leads to proinflammatory cytokine release and is possibly related to the pathogenesis of allergic respiratory conditions, the present study was designed to investigate a possible involvement of purinergic and prolactin receptors in this phenomenon. METHODS: To induce hyperprolactinemia, domperidone was injected intraperitoneally in rats at a dose of 5.1 mg × kg-1 per day for 5 days. P2X7 expression was evaluated by lung immunohistochemistry while prolactin receptor expression in bronchoalveolar lavage leukocytes was analyzed through flow cytometry. RESULTS: Previous reports demonstrated that rats subjected to short-term hyperprolactinemia exhibited a decrease in leukocyte counts in bronchoalveolar lavage, especially granulocytes. Here, it is revealed that hyperprolactinemia promotes an increased expression of prolactin receptors in granulocytes. Also, increased expression of purinergic P2X7R observed in allergic animals was significantly reduced by hyperprolactinemia. CONCLUSIONS: Both purinergic and prolactin receptor expression changes occur during the anti-asthmatic effect of hyperprolactinemia.
Asunto(s)
Asma/metabolismo , Hiperprolactinemia/metabolismo , Pulmón/metabolismo , Receptores Purinérgicos P2X7/biosíntesis , Animales , Asma/inducido químicamente , Asma/inmunología , Expresión Génica , Hiperprolactinemia/inmunología , Recuento de Leucocitos/tendencias , Pulmón/inmunología , Masculino , Ovalbúmina/toxicidad , Ratas , Ratas Wistar , Receptores Purinérgicos P2X7/genética , Factores de TiempoRESUMEN
The dopaminergic antagonist drug Domperidone has immunomodulatory effects. We investigated the effects of repeated Domperidone treatment in a model of Lypopolyssacharide (LPS)-induced acute lung inflammation. Adult C57BL/6J mice were treated with either Vehicle or Domperidone for 5days, and challenged intranasally with LPS in the following day. The behavior of mice was analyzed in the open field and elevated plus-maze test before and 24h after LPS challenge. The bronchoalveolar lavage fluid, blood and lung tissue were collected 24h and 48h after LPS challenge. Domperidone treatment increased LPS-induced tumor necrosis factor (TNF) and interleukin (IL)-6 production in the bronchoalveolar lavage fluid, without altering tissue damage and the number of immune cells in the lungs and circulation. Locomotor and anxiety-like behavior were unchanged after Domperidone and/or LPS treatment. Cytokine data indicate that Domperidone promotes a change in activity of other cell types, likely alveolar epithelial cells, without affecting immune cell migration in the present model. Due to the role of these cytokines in progression of inflammation, Domperidone treatment may exacerbate a subsequent inflammatory injury.
Asunto(s)
Lesión Pulmonar Aguda/inmunología , Domperidona/administración & dosificación , Antagonistas de Dopamina/administración & dosificación , Mucosa Respiratoria/fisiología , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Progresión de la Enfermedad , Domperidona/efectos adversos , Antagonistas de Dopamina/efectos adversos , Humanos , Mediadores de Inflamación/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Mucosa Respiratoria/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The wake-promoting drug Modafinil has been used for many years for treatment of Narcolepsy and Excessive Daytime Sleepiness, due to a dopamine-related psychostimulant action. Recent studies have indicated that Modafinil prevents neuroinflammation in animal models. Thus, the aim of the present study was to evaluate the effect of Modafinil pretreatment in the Lipopolysaccharide (LPS)-induced sickness and depressive-like behaviors. Adult male C57BL/6J mice were pretreated with Vehicle or Modafinil (90mg/Kg) and, 30min later, received a single saline or LPS (2mg/Kg) administration, and were submitted to the open field and elevated plus maze test 2h later. After 24h, mice were subjected to tail suspension test, followed by either flow cytometry with whole brain for CD11b+CD45+ cells or qPCR in brain areas for cytokine gene expression. Modafinil treatment prevented the LPS-induced motor impairment, anxiety-like and depressive-like behaviors, as well as the increase in brain CD11b+CD45high cells induced by LPS. Our results indicate that Modafinil pretreatment also decreased the IL-1ß gene upregulation caused by LPS in brain areas, which is possibly correlated with the preventive behavioral effects. The pharmacological blockage of the dopaminergic D1R by the drug SCH-23390 counteracted the effect of Modafinil on locomotion and anxiety-like behavior, but not on depressive-like behavior and brain immune cells. The dopaminergic D1 receptor signaling is essential to the Modafinil effects on LPS-induced alterations in locomotion and anxiety, but not on depression and brain macrophages. This evidence suggests that Modafinil treatment might be useful to prevent inflammation-related behavioral alterations, possibly due to a neuroimmune mechanism.
Asunto(s)
Compuestos de Bencidrilo/farmacología , Dopaminérgicos/farmacología , Conducta de Enfermedad/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Trastornos del Movimiento/tratamiento farmacológico , Receptores de Dopamina D1/metabolismo , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Ansiedad/patología , Benzazepinas/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Depresión/tratamiento farmacológico , Depresión/metabolismo , Depresión/patología , Modelos Animales de Enfermedad , Escherichia coli , Conducta de Enfermedad/fisiología , Lipopolisacáridos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones Endogámicos C57BL , Modafinilo , Actividad Motora/fisiología , Trastornos del Movimiento/etiología , Trastornos del Movimiento/metabolismo , Trastornos del Movimiento/patología , Neuroinmunomodulación/efectos de los fármacos , Neuroinmunomodulación/fisiología , Receptores de Dopamina D1/antagonistas & inhibidores , Promotores de la Vigilia/farmacologíaRESUMEN
The wake-promoting drug Modafinil has been used for treatment of sleep disorders, such as Narcolepsy, excessive daytime sleepiness and sleep apnea, due to its stimulant action. Despite the known effect of Modafinil on brain neurochemistry, particularly on brain dopamine system, recent evidence support an immunomodulatory role for Modafinil treatment in neuroinflammatory models. Here, we aimed to study the effects of in vitro and in vivo Modafinil treatment on activation, proliferation, cell viability, and cytokine production by immune cells in splenocytes culture from mice. The results show that in vitro treatment with Modafinil increased Interferon (IFN)-γ, Interleukin (IL)-2 and IL-17 production and CD25 expression by T cells. In turn, in vivo Modafinil treatment enhanced splenocyte production of IFN-γ, IL-6 and tumor necrosis factor (TNF), and increased the number of IFN-γ producing cells. Next, we addressed the translational value of the observed effects by testing PBMCs from Narcolepsy type 1 patients that underwent Modafinil treatment. We reported increased number of IFN-γ producing cells in PBMCs from Narcolepsy type 1 patients following continuous Modafinil treatment, corroborating our animal data. Taken together, our results show, for the first time, a pro-inflammatory action of Modafinil, particularly on IFN-mediated immunity, in mice and in patients with Narcolepsy type 1. The study suggests a novel effect of this drug treatment, which should be taken into consideration when given concomitantly with an ongoing inflammatory or autoimmune process.
Asunto(s)
Compuestos de Bencidrilo/farmacología , Factores Inmunológicos/farmacología , Interferones/metabolismo , Promotores de la Vigilia/farmacología , Animales , Compuestos de Bencidrilo/uso terapéutico , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Factores Inmunológicos/uso terapéutico , Masculino , Ratones Endogámicos C57BL , Modafinilo , Narcolepsia/sangre , Narcolepsia/tratamiento farmacológico , Narcolepsia/inmunología , Bazo/citología , Bazo/efectos de los fármacos , Bazo/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Promotores de la Vigilia/uso terapéuticoRESUMEN
OBJECTIVES: Cohabitation with Ehrlich tumor-bearing (ETB) mice induced behavioral, neurochemical, hormonal, and immune effects in the conspecifics as a consequence of stress-induced activation of the sympathetic nervous system (SNS) with catecholamine release. In the current study, the nonspecific ß-AR blocker d,l-propranolol and the specific ß2-AR blocker ICI-118.551 were employed as pharmacological tools to assess the extent to which catecholamines participated in the effects induced by cohabitation with ETB mice. METHODS: Two experiments were performed, 1 with d,l-propranolol treatment and the other with ICI-118.551. One mouse in the experimental group was called the "companion of the sick partner" (CSP) since it was forced to live in the same cage with 2 (experiment 1) or 1 (experiment 2) cage mate that had been i.p. injected with 5 × 106 Ehrlich tumor cells. RESULTS: The d,l-propranolol treatment, but not the ICI-118.551 treatment, attenuated the effects of cohabitation with 2 ETB mice on both open-field behavior and the hypothalamic levels and turnover rate of norepinephrine. The 2 ß-AR blockers were unable to change the serum corticosterone levels and adrenal weights of the CSP mice; however, these drugs abrogated the effects of cohabitation on neutrophil oxidative burst and phagocytosis. Finally, an increase in the 5-HT turnover rate was observed in the olfactory bulb of CSP mice compared to their respective controls, an effect that was not modified by ß-AR blockade. CONCLUSION: These results confirm and strengthen our hypothesis that the SNS is involved in the effects induced by cohabitation with ETB mice and point towards ß2-AR participation in the immune effects analyzed.
Asunto(s)
Adrenérgicos/farmacología , Carcinoma de Ehrlich/inmunología , Carcinoma de Ehrlich/psicología , Relaciones Interpersonales , Glándulas Suprarrenales/efectos de los fármacos , Animales , Carcinoma de Ehrlich/tratamiento farmacológico , Carcinoma de Ehrlich/metabolismo , Catecolaminas/metabolismo , Corticosterona/sangre , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Femenino , Citometría de Flujo , Conducta de Enfermedad/efectos de los fármacos , RatonesRESUMEN
AIMS: To evaluate the influence of lactation on lung immune function during allergic inflammation. MAIN METHODS: Female rats, 60-90days old, were divided into three groups: no lung allergy virgins (N group), ovalbumin (OVA)-immunized and sensitized virgins (V group), and OVA-immunized and sensitized lactating females (L group). On gestation day (GD) 10, all animals in L group received a subcutaneous injection of 0.1mg·kg(-1) OVA plus aluminum hydroxide. On GD17, the L group received a subcutaneous booster injection of 10µg OVA plus 10mg aluminum hydroxide. After 7days, an inhalatory challenge with 1% OVA was given in 15min sessions for 3 consecutive days. Animals from the V group received the same treatment, meaning both tests and time intervals between OVA treatment and inhalatory challenge were the same as in the L group. Twenty-four hours after the last inhalation session, the animals were euthanized, and the following tests were performed: total and differential bronchoalveolar lavage (BAL) and femoral marrow lavage (FML) leukocyte counts, quantification of tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ) levels in BAL fluid, and quantification of plasma corticosterone and catecholamine levels. KEY FINDINGS: The L group presented lower BAL total leukocyte counts and decreases in the number of eosinophils and macrophages compared with the V group. They also expressed higher BAL IFN-γ and lower plasma corticosterone levels. Plasma norepinephrine levels were higher in the L group than in the N and V groups. SIGNIFICANCE: Lactating female rats presented less intense allergic lung inflammation. Our findings suggest that lactation may protect females from asthmatic crises.