Stress induced cognitive deficit is differentially modulated in BALB/c and C57Bl/6 mice. Correlation with Th1/Th2 balance after stress exposure

Stress and balance of Th1/Th2 immunity has been implicated in psychiatric disorders. In addition, two genetically different inbred strains of mice, C57BL/6 and BALB/c, which have different balance of Th1/Th2 immunity show distinct behavioral responses, neurodevelopment and neurochemistry parameters. Here, we perform a comparative study on chronic mild stress (CMS) effects upon learning and memory and immunity in both strains. Stressed BALB/c, but not C57Bl/6 mice, showed a poor learning performance in both open field and Y-maze. Also, CMS induced a decrease in number of neurons and thickness on hippocampus of BALB/c mice, but not produces morphological changes in C57BL/6 hippocampus. Oxidative stress, evaluated by reactive oxygen species (ROS) production was increased in hippocampus of CMS-exposed BALB/c but not in stressed C57BL/6. Concerning to immune system, stressed BALB/c mice showed a diminished mitogeninduced T cell proliferation and an increase of B cell proliferation. Moreover, lymphocytes from CMSexposed BALB/c mice showed an increased Th2-type cytokines production (IL-4 and IL-10). On the contrary, lymphocytes from CMS-exposed C57BL/6 mice had an increase in T cell proliferation without changes in B cell proliferation. Also, these lymphocytes showed a higher Th1-type cytokine release (INF- and IL-2). These results suggest a differential effect of stress, being BALB/c more vulnerable to cognitive deficit  associated to stress exposition than C57BL/6 mice. This effect could be related to a differential regulation of Th1/ Th2 cytokine balance, suggesting a better learning performance in individuals that produce Th1 type cytokine after stress exposition.Fil: Palumbo, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Canzobre, Mariela Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Pascuan, Cecilia Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Rios, Hugo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Wald, Miriam Ruth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Genaro, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

Niacin modulates pro-inflammatory cytokine secretion. A potential mechanism involved in its anti-atherosclerotic effect

The pathogenesis of atherosclerosis includes the assignment of a critical role to cells of the monocyte/macrophage lineage and to pro-inflammatory cytokines. Niacin is known to improve lipid metabolism and to produce beneficial modification of cardiovascular risk factors. The aim of this work was to investigate if Niacin is able to modulate pro-inflammatory cytokine production in macrophages in a murine model of atherosclerosis. For this purpose C57Bl/6J mice fed with atherogenic diet (AGD) or with conventional chow diet were used. The AGD group showed an increase in body weight and in total plasma cholesterol, with no differences in triglyceride or HDL levels. Lesions in arterial walls were observed. The characterization of Niacin receptor showed an increase in the receptor number of macrophages from the AGD group. Macrophages from control and AGD animals treated in vitro with an inflammatory stimulus showed elevated levels of IL-6, IL-1 and TNF-α, that were even higher in macrophages from AGD mice. Niacin was able to decrease the production of pro-inflammatory cytokines in stimulated macrophages. Similar effect of Niacin was observed in an in vivo model of inflammation. These results show an attenuating inflammatory mechanism for this therapeutic agent and would point out its potential action in plaque stabilization and in the prevention of atherosclerosis progression. Furthermore, the present results provide the basis for future studies on the potential contribution of Niacin to antiinflammatory therapies.Fil: Lipszyc, P.. Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología; Argentina;Fil: Cremaschi, Graciela Alicia. Pontificia Universidad Católica Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina;Fil: Zorrilla Zubilete, María Aurelia. Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología; Argentina;Fil: Aon Bertolino, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas (i); Argentina;Fil: Capani, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas (i); Argentina;Fil: Genaro, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina; Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología; Argentina;Fil: Wald, Miriam Ruth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina; Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología; Argentina

Influence of castration on the response of the rat vas deferens to fluoxetine

Antidepressant drugs such as desipramine and fluoxetine increase norepinephrine (NE) contractile response in rat vas deferens by inhibiting neuronal amine uptake. Fluoxetine, unlike other antidepressants, also inhibits calcium fluxes, which results in an inhibition of maximal NE effect. Since the contractile response of the reproductive tract is under the influence of testosterone, the effect of fluoxetine could be modified according to the endocrine status of the animal. In the present study we evaluated the influence of castration and testosterone replacement (1 mg per 100 g body wt.) on the peripheral action of fluoxetine. Castration was followed by a decrease in vas deferens weight and the appearance of spontaneous activity. Testosterone replacement reversed these effects. Concentration-response curves to NE and calcium were obtained in the absence and the presence of fluoxetine in vasa deferentia from normal, castrated and testosterone-treated castrated rats. After castration the effect of fluoxetine on vas deferens contractility was markedly altered. The spontaneous activity that appears after castration was prevented by fluoxetine and the stimulatory effect on NE-induced contractions was not observed. In contrast, the inhibitory action of fluoxetine on maximal NE effect was increased. Testosterone replacement restored vas deferens response to NE in the presence of fluoxetine. Fluoxetine did not modify the binding parameters of [3H]prazosin in vasa deferentia from normal or castrated animals. Cocaine shifted the NE concentration-response curve to the left in all groups, suggesting that the changes in fluoxetine effect following castration were not the result of an alteration of the neuronal uptake mechanism. The nitric oxide synthase inhibitor L-NMMA did not modify vas deferens response to NE in castrated animals either in the absence or presence of fluoxetine. An increased sensitivity to the inhibitory effect of fluoxetine was observed in the calcium concentration-response curves in vasa deferentia from castrated rats, an effect that was reversed by testosterone replacement. The results suggest that the alteration in the responsiveness of vasa deferentia from castrated rats to calcium could be responsible for increased sensitivity to the inhibitory effect of fluoxetine. It is concluded that vas deferens contractile response is testosterone dependent and that this behaviour modifies the effect of drugs such as fluoxetine that have dual effect on contractility. (C) 2000 Academic Press.Fil: Busch, Lucila. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Farmacología; ArgentinaFil: Wald, Miriam Ruth. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Borda, Enri Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Farmacología; Argentin

Fluoxetine modulates norepinephrine contractile effect on rat vas deferens

The aim of this study was to evaluate whether the antidepressant drug fluoxetine could modify rat vas deferens response to norepinephrine (NE), and to compare its effect with that of desipramine and cocaine. Results showed that 10-5 M fluoxetine produced a super-sensibility of vas deferens to NE. This result was the same as those obtained for 10-6 M desipramine or cocaine. Since the effect was Na+- and Cl--dependent, an inhibitory mechanism of neuronal NE transport was suggested. Fluoxetine did not modify [3H]prazosin k(d) or B(max) in rat vas deferens, reinforcing the hypothesis of a pre-synaptic site of action. On the other hand fluoxetine inhibited NE maximal effect. This inhibitory effect could be related to an antagonism of calcium entry through the voltage-dependent calcium channel, since it was partially reverted by increasing calcium concentration and, besides, the drug was able to inhibit the calcium concentration-response curve also. Contractions induced by 5-hydroxytryptamine (5-HT) were not modified in the presence of fluoxetine. It is concluded that fluoxetine modulates rat vas deferens response to low NE concentrations in the same manner as the selective inhibitor of NE neuronal uptake desipramine. This peripheral effect could participate in the modulation of the male reproductive tract observed by these drugs when used in clinical trials.Fil: Busch, Lucila. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Farmacología; ArgentinaFil: Wald, Miriam Ruth. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sterin, Leonor Josefina. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Borda, Enri Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Odontología. Cátedra de Farmacología; Argentin

Chronic Stress and Glucocorticoid Receptor Resistance in Asthma

Purpose: Chronic and persistent exposure to negative stress can lead to adverse consequences on health. Particularly, psychosocial factors were found to increase the risk and outcome of respiratory diseases like asthma. Glucocorticoids (GCs) are the most efficient anti-inflammatory therapy for asthma. However, a significant proportion of patients don't respond adequately to GC administration. GC sensitivity is modulated by genetic and acquired disease-related factors. Additionally, it was proposed that endogenous corticosteroids may limit certain actions of synthetic GCs, contributing to insensitivity. Psychological and physiological stresses activate the hypothalamic-pituitary-adrenal axis, increasing cortisol levels. Here, we review the mechanism involved in altered GC sensitivity in asthmatic patients under stressful situations. Strategies for modulation GC sensitivity and improving GC therapy are discussed. Methods: PubMed was searched for publications on psychological chronic stress and asthma, GC resistance in asthma, biological mechanisms for GC resistance, and drugs for steroid-resistant asthma, including highly potent GCs. Findings: GC resistance in patients with severe disease remains a major clinical problem. In asthma, experimental and clinical evidence suggests that chronic stress induces inflammatory changes, contributing to a worse GC response. GC resistant patients can be treated with other broad-spectrum anti-inflammatory drugs, but these generally have major side effects. Different mechanisms of GC resistance have been described and might be useful for developing new therapeutic strategies against it. Novel drugs, such as highly potent GCs, phosphoinositide 3-kinase-delta inhibitors that reestablish histone deacetylase-2 function, decrease of GC receptor phosphorylation by p38 mitogen-activated protein kinase inhibitors, or phosphatase activators, are currently in clinical development and might be combined with GC therapy in the future. Furthermore, microRNAs (small noncoding RNA molecules) operate as posttranscriptional regulators, providing another level of control of GC receptor levels. Empirical results allow postulating that the detection and study of microRNAs might be a promising approach to better characterize and treat asthmatic patients. Implications: Many molecular and cellular pathobiological mechanisms are responsible of GC resistance. Therefore detecting specific biomarkers to help identify patients who would benefit from new therapies is crucial. Stress consitutes a negative aspect of current lifestyles that increase asthma morbidity and mortality. Adequate stress management could be an important and positive intervention.Fil: Palumbo, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; ArgentinaFil: Prochnik, Andrés. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Wald, Miriam Ruth. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Genaro, María Viviana. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología; Argentin

Chronic stress and glucocorticoid receptor resistance in asthma

Abstract: Purpose: Chronic and persistent exposure to negative stress can lead to adverse consequences on health. Particularly, psychosocial factors were found to increase the risk and outcome of respiratory diseases like asthma. Glucocorticoids (GCs) are the most efficient anti-inflammatory therapy for asthma. However, a significant proportion of patients don’t respond adequately to GC administration. GC sensitivity is modulated by genetic and acquired disease-related factors. Additionally, it was proposed that endogenous corticosteroids may limit certain actions of synthetic GCs, contributing to insensitivity. Psychological and physiological stresses activate the hypothalamic-pituitary-adrenal axis, increasing cortisol levels. Here, we review the mechanism involved in altered GC sensitivity in asthmatic patients under stressful situations. Strategies for modulation GC sensitivity and improving GC therapy are discussed. Methods: PubMed was searched for publications on psychological chronic stress and asthma, GC resistance in asthma, biological mechanisms for GC resistance, and drugs for steroid-resistant asthma, including highly potent GCs. Findings: GC resistance in patients with severe disease remains a major clinical problem. In asthma, experimental and clinical evidence suggests that chronic stress induces inflammatory changes, contributing to a worse GC response. GC resistant patients can be treated with other broad-spectrum anti-inflammatory drugs, but these generally have major side effects. Different mechanisms of GC resistance have been described and might be useful for developing new therapeutic strategies against it. Novel drugs, such as highly potent GCs, phosphoinositide 3-kinase-delta inhibitors that reestablish histone deacetylase-2 function, decrease of GC receptor phosphorylation by p38 mitogenactivated protein kinase inhibitors, or phosphatase activators, are currently in clinical development and might be combined with GC therapy in the future. Furthermore, microRNAs (small noncoding RNA molecules) operate as posttranscriptional regulators, providing another level of control of GC receptor levels. Empirical results allow postulating that the detection and study of microRNAs might be a promising approach to better characterize and treat asthmatic patients. Implications: Many molecular and cellular pathobiological mechanisms are responsible of GC resistance. Therefore detecting specific biomarkers to help identify patients who would benefit from new therapies is crucial. Stress consitutes a negative aspect of current lifestyles that increase asthma morbidity and mortality. Adequate stress management could be an important and positive intervention. Key words: asthma, chronic stress, glucocorticoid resistance, pharmacologic strategies

Immune Alterations Induced by Chronic Noise Exposure: Comparison with Restraint Stress in BALB/c and C57Bl/6 Mice

Exposure to loud noise levels represents a problem in all regions of the world. Noise exposure is known to affect auditory structures in living organisms. However, it should not be ignored that many of the effects of noise are extra-auditory. In particular, it has been proposed that noise could affect immune system similarly to other stressors. Nevertheless, only few studies so far have investigated the effects of noise on the immune function. The aim of the present work was to investigate the effect of chronic (2 wk) noise (95-97 dB) exposure on immune responses in BALB/c and C57 mice. To ascertain if the effect of noise is similar to other psychological stressors, the effect of chronic restraint –applied for the same time- on immune response was also analyzed. It was found that chronic noise impaired immune-related endpoints in vivo and ex vivo depending on the strain used. Noise, but not restraint, affected C57Bl/6 mouse T-cell-dependent antibody production and ex vivo stimulated T-cell proliferation but had no effect on these parameters in BALB/c mice or their cells. In fact, none of the stressors altered T-cell responses associated with the BALB/c mice. Further, noise exposure induced a decrease in corticosterone and catecholamines levels in BALB/c mice. In contrast, no differences were seen in these parameters for those BALB/c mice under restraint or for that matter C57Bl/6 mice exposed to restraint or noise. The results of these studies indicate that noise could seriously affect immune responses in susceptible individuals. In addition, it may also be concluded that noise possibility should not be considered a classic stressor.Fil: Pascuan, Cecilia Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina;Fil: Urán, Soledad Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina;Fil: Gonzalez Murano, Maria Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina;Fil: Wald, Miriam Ruth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina;Fil: Guelman, Laura Ruth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina;Fil: Genaro, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina

Current understanding of the roles of gut–brain axis in the cognitive deficits caused by perinatal stress exposure

Abstract: Abstract: The term ‘perinatal environment’ refers to the period surrounding birth, which plays a crucial role in brain development. It has been suggested that dynamic communication between the neuro–immune system and gut microbiota is essential in maintaining adequate brain function. This interaction depends on the mother’s status during pregnancy and/or the newborn environment. Here, we show experimental and clinical evidence that indicates that the perinatal period is a critical window in which stress-induced immune activation and altered microbiota compositions produce lasting behavioral consequences, although a clear causative relationship has not yet been established. In addition, we discuss potential early treatments for preventing the deleterious effect of perinatal stress exposure. In this sense, early environmental enrichment exposure (including exercise) and melatonin use in the perinatal period could be valuable in improving the negative consequences of early adversities. The evidence presented in this review encourages the realization of studies investigating the beneficial role of melatonin administration and environmental enrichment exposure in mitigating cognitive alteration in offspring under perinatal stress exposure. On the other hand, direct evidence of microbiota restoration as the main mechanism behind the beneficial effects of this treatment has not been fully demonstrated and should be explored in future studies

Current Understanding of the Roles of Gut–Brain Axis in the Cognitive Deficits Caused by Perinatal Stress Exposure

The term ‘perinatal environment’ refers to the period surrounding birth, which plays a crucial role in brain development. It has been suggested that dynamic communication between the neuro–immune system and gut microbiota is essential in maintaining adequate brain function. This interaction depends on the mother’s status during pregnancy and/or the newborn environment. Here, we show experimental and clinical evidence that indicates that the perinatal period is a critical window in which stress-induced immune activation and altered microbiota compositions produce lasting behavioral consequences, although a clear causative relationship has not yet been established. In addition, we discuss potential early treatments for preventing the deleterious effect of perinatal stress exposure. In this sense, early environmental enrichment exposure (including exercise) and melatonin use in the perinatal period could be valuable in improving the negative consequences of early adversities. The evidence presented in this review encourages the realization of studies investigating the beneficial role of melatonin administration and environmental enrichment exposure in mitigating cognitive alteration in offspring under perinatal stress exposure. On the other hand, direct evidence of microbiota restoration as the main mechanism behind the beneficial effects of this treatment has not been fully demonstrated and should be explored in future studies.Fil: Rubinstein Guichon, Mara Roxana. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Burgueño, Adriana Laura. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Quiroga, Sofía. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Wald, Miriam Ruth. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Genaro, Ana Maria. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentin