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.

Sexual dimorphism modulates metabolic and cognitive alterations under HFD nutrition and chronic stress exposure in mice. Correlation between spatial memory impairment and BDNF mRNA expression in hippocampus and spleen.

AIMS: The accumulated evidence suggests that lifestyle - specifically dietary habits and stress exposure - plays a detrimental role in health. The purpose of the present study was to analyze the interplay of stress, diet, and sex in metabolic and cognitive alterations. MAIN METHODS: For this purpose, one-month-old C57Bl/6J mice were fed with a standard diet or high-fat diet (HFD). After eight weeks, one subgroup of mice from each respective diet was exposed to 20 weeks of chronic mild stress (CMS), whilst the others were left undisturbed. KEY FINDINGS: After 28 weeks of HFD feeding, mice from both sexes were overweight, with an increase in caloric intake and abdominal and subcutaneous fat pads. Stress exposure induced a decrease in body weight, related to a decrease in caloric efficiency in both males and females. Results indicate that males are more susceptible than the females in modulating metabolic and cognitive functions under HFD and CMS. Although both sexes demonstrated HFD-induced weight gain, fat accumulation, insulin resistance, high cholesterol, only males exposed to CMS but not females have (i) impaired glucose tolerance with higher glucose level; (ii) significant prolonged latency in Barnes test, suggesting cognitive impairment; (iii) increased IFN-gamma expression in hippocampus, suggesting greater neuroinflammatory response; (iv) poorer cognitive performance related to a decrease in hippocampal and spleen BDNF mRNA expression. SIGNIFICANCE: The main finding in this study is the presence of a sexual dimorphism in modulating metabolic and cognitive functions under HFD and CMS, showing males are more susceptible than females. In addition, poorer cognitive performance was related to a decrease in hippocampal BDNF mRNA expression. Interestingly, these changes were observed in the spleen as well.

Immunomodulation induced by central nervous system-related peptides as a therapeutic strategy for neurodegenerative disorders.

Neurodegenerative diseases (NDD) are disorders characterized by the progressive loss of neurons affecting motor, sensory, and/or cognitive functions. The incidence of these diseases is increasing and has a great impact due to their high morbidity and mortality. Unfortunately, current therapeutic strategies only temporarily improve the patients' quality of life but are insufficient for completely alleviating the symptoms. An interaction between the immune system and the central nervous system (CNS) is widely associated with neuronal damage in NDD. Usually, immune cell infiltration has been identified with inflammation and is considered harmful to the injured CNS. However, the immune system has a crucial role in the protection and regeneration of the injured CNS. Nowadays, there is a consensus that deregulation of immune homeostasis may represent one of the key initial steps in NDD. Dr. Michal Schwartz originally conceived the concept of "protective autoimmunity" (PA) as a well-controlled peripheral inflammatory reaction after injury, essential for neuroprotection and regeneration. Several studies suggested that immunizing with a weaker version of the neural self-antigen would generate PA without degenerative autoimmunity. The development of CNS-related peptides with immunomodulatory neuroprotective effect led to important research to evaluate their use in chronic and acute NDD. In this review, we refer to the role of PA and the potential applications of active immunization as a therapeutic option for NDD treatment. In particular, we focus on the experimental and clinical promissory findings for CNS-related peptides with beneficial immunomodulatory effects.

Prenatal stress promotes insulin resistance without inflammation or obesity in C57BL/6J male mice.

During gestation, stress exposure increases the risk of developing cognitive and physiological alterations in either the long or short term. Among them, metabolic alterations have been described. Adipose tissue is responsible for the secretion of several factors involved in controlling body weight and energy expenditure, the regulation of insulin sensitivity, and the development of inflammation, among others. Moreover, the liver regulates glucose homeostasis and lipid metabolism, playing an essential role in developing insulin resistance. In this work, we analyzed if prenatal stress leads to alterations in metabolism and the relationship between these alterations and gene expression in the adipose tissue and the liver. Prenatal stress-exposed animals developed disturbances in the glucose and insulin response curve, showing in both tests higher glycemia than the control group. However, they did not exhibit increased body weight. At the same time, in the adipose tissue, we observed an increase in mRNA expression of Leptin and Resistin and a decrease in Adiponectin. In the liver, we observed a lower mRNA expression of several genes involved in glucose metabolism and fatty acid oxidation, such as Sirt1, Pgc1α, Pparα, among others. In both tissues, we observed a lower expression of inflammatory genes. These results suggest that prenatal stress exposure produces insulin resistance at both physiological and molecular levels without pro-inflammatory signaling or obesity.

Influence of prenatal stress on metabolic abnormalities induced by postnatal intake of a high-fat diet in BALB/c mice.

Prenatal insults during fetal development result in increased likelihood of developing chronic disease. Obesity, the biggest risk factor for the development of metabolic disease, is affected by several genetic and environmental factors. High-fat diet (HFD) consumption is usually linked with the development of obesity. The main goal of this study was to analyze the impact of the exposure to a HFD in prenatally stressed animals. For this purpose, we subjected pregnant BALB/c mice to restraint stress for 2 h a day between gestational day (GD) 14 and GD 21. Prenatally stressed and control offspring of both sexes were postnatally exposed to a HFD for 24 weeks. We found that prenatal stress (PS) per se produced disturbances in males such as increased total blood cholesterol and triglycerides, with a decrease in mRNA expression of sirtuin-1. When these animals were fed a HFD, we observed a rise in glucose and insulin levels and an increase in visceral adipose tissue gene expression of leptin, resistin, and interleukin-1 beta. Although females proved to be more resilient to PS consequences, when they were fed a HFD, they showed significant metabolic impairment. In addition to the changes observed in males, females also presented an increase in body weight and adiposity and a rise in cholesterol levels.

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.

Systematic review and meta-analysis on the relationship between prenatal stress and metabolic syndrome intermediate phenotypes.

BACKGROUND: Metabolic Syndrome (MetS) can be considered as a consequence of a complex interplay between genetic and environmental factors and can be influenced by changes in the environment early in life. Prenatal stress (PS) exposure likely represents an important adverse intrauterine environment that may impact the biology of the developing organism. The aim of this study was to quantitatively synthesize the available data on the effects of PS on offspring's obesity, estimated indirectly by body mass index (BMI) and body fat; blood pressure, plasma glucose and blood lipid concentrations (triglycerides and high-density lipoprotein cholesterol). METHODS: Literature searches for eligible studies on PubMed were conducted until October 8, 2018. Full text review yielded 24 publications for inclusion into the systematic review. Meta-analyses were performed for the outcomes BMI and body fat. 62 effect sizes from 19 studies together with relevant moderators were collected. Summary estimates were calculated by using random-effects model. RESULTS: The combined standardized mean difference (d) for the relation between BMI and PS indicated that despite significant heterogeneity, stress exposure of expectant mothers was associated with increased BMI of their offspring [d (95% CI) = 0.268 (0.191; 0.345)]. Both objective and subjective stress have been linked to increased overweight. Preliminary results of the relationship between PS and body fat suggested that the contribution of PS to body fat should be at least further considered [d (95% CI) = 0.167 (0.016; 0.317)]. Evidence from a limited number of published studies do not sustains an effect on blood pressure, glucose metabolism or circulating lipids, however these outcomes have only been scarcely investigated. CONCLUSIONS: A direct association between PS and BMI was found and further studies are needed to confirm the relationship between maternal stress during gestation and body fat. Overall, findings suggest that PS could contribute to alterations to the post-natal offspring phenotype.

Prenatal stress and later metabolic consequences: Systematic review and meta-analysis in rodents.

BACKGROUND: Numerous rodent studies have evaluated the effects of maternal stress (MS) on later in life susceptibility to Metabolic Syndrome (MetS) intermediate phenotypes with varying results. The aim of this study was to quantitatively synthesize the available data on the effects of MS on offspring obesity, estimated indirectly by body mass (BM), body fat (BF) and plasma leptin; systolic blood pressure (SBP); plasma glucose (and insulin) and blood lipid concentrations. METHODS: Literature was screened and summary estimates of the effect of MS outcomes were calculated by using random-effects models. Data on the effects of exogenous corticosteroid administration (or inhibition of 11ß-HSD2) during pregnancy in rodents was analysed separately to characterize the direct phenotypic effects of prenatal corticosteroid excess (PCE). RESULTS: We conducted 14 separate meta-analyses and synthesized relevant data on outcomes scarcely reported in literature. Both MS and PCE were associated with low birth weight without rapid catch-up growth resulting in decreased body mass later in life. Our analysis also revealed significant and contradictory effects on offspring adiposity. Little evidence was found for effects on glucose metabolism and blood lipids. We identified increased SBP in offspring exposed to PCE; however, there is not enough data to draw any conclusion about effects of MS on SBP. CONCLUSIONS: Neonatal weight proved to be decreased in offspring prenatally exposed to stress or corticosteroids, but laboratory rodents in the absence of a challenging environment did not show catch-up growth. The available evidence is inconclusive regarding the effect on adiposity revealing clear methodological and knowledge gaps. This meta-analysis also confirmed a significant positive association between PCE and SBP. Nevertheless, additional studies should address the association with MS.

Beneficial Effect of Fluoxetine and Sertraline on Chronic Stress-Induced Tumor Growth and Cell Dissemination in a Mouse Model of Lymphoma: Crucial Role of Antitumor Immunity.

Clinical data and experimental studies have suggested a relationship between psychosocial factors and cancer prognosis. Both, stress effects on the immune system and on tumor biology were analyzed independently. However, there are few studies regarding the stress influence on the interplay between the immune system and tumor biology. Moreover, antidepressants have been used in patients with cancer to alleviate mood disorders. Nevertheless, there is contradictory evidence about their action on cancer prognosis. In this context, we investigated the effect of chronic stress on tumor progression taking into account both its influence on the immune system and on tumor biology. Furthermore, we analyzed the action of selective serotonin reuptake inhibitors, fluoxetine and sertraline, in these effects. For this purpose, C57BL/6J mice submitted or not to a chronic stress model and treated or not with fluoxetine or sertraline were subcutaneously inoculated with EL4 cells to develop solid tumors. Our results indicated that chronic stress leads to an increase in both tumor growth and tumor cell dissemination. The analysis of cell cycle regulatory proteins showed that stress induced an increase in the mRNA levels of cyclins A2, D1, and D3 and a decrease in mRNA levels of cell cycle inhibitors p15, p16, p21, p27, stimulating cell cycle progression. Moreover, an augment of mRNA levels of metalloproteases (MMP-2 and MMP-9), a decrease of inhibitors of metalloproteases mRNA levels (TIMP 1, 2, and 3), and an increase in migration ability were found in tumors from stressed animals. In addition, a significant decrease of antitumor immune response in animals under stress was found. Adoptive lymphoid cell transfer experiments indicated that the reduced immune response in stressed animals influenced both the tumor growth and the metastatic capacity of tumor cells. Finally, we found an important beneficious effect of fluoxetine or sertraline treatment on cancer progression. Our results emphasize the crucial role of the immune system in tumor progression under stress situations. Although a direct effect of stress and drug treatment on tumor biology could not be ruled out, the beneficial effect of fluoxetine and sertraline appears to be mainly due to a restoration of antitumor immune response.

Altered interferon-γ expression in lymphocytes as a potential peripheral marker of chronic stress-induced cognitive deficit.

It is known that long-term exposure to stressful situations can produce severe consequences affecting behavioral, endocrine and immunological parameters. We have previously shown that stressed BALB/c mice had poor learning performance, which was reverted by glatiramer acetate treatment through a mechanism that likely involved the regulation of the cytokine balance and adult neurogenesis. In addition, recent results suggest that cytokine and neurotrophin expression in the hippocampus displayed similar tendencies as those in the serum. However, if lymphoid cells could be good candidates as peripheral markers of memory impairment have not yet been investigated. For this purpose, we analyzed the spatial memory and the neutrophin and cytokine mRNA levels in lymph nodes and hippocampus in mice submitted to chronic stress treated or not with glatiramer acetate. Results indicated that there was a correlation between the cytokine and neurotrophin mRNA levels in the hippocampus and in the peripheral lymph nodes, and the cognitive performance in BALB/c mice. In particular, our results suggest that altered IFN-γ levels could be used as peripheral biomarker of cognitive deficit and treatment response.

Immunomodulatory effects of fluoxetine: A new potential pharmacological action for a classic antidepressant drug?

Selective serotonin reuptake inhibitors are frequently used antidepressants. In particular, fluoxetine is usually chosen for the treatment of the symptoms of depression, obsessive-compulsive, panic attack and bulimia nervosa. Antidepressant therapy has been associated with immune dysfunction. However, there is contradictory evidence about the effect of fluoxetine on the immune system. Experimental findings indicate that lymphocytes express the serotonin transporter. Moreover it has been shown that fluoxetine is able to modulate the immune function through a serotonin-dependent pathway and through a novel independent mechanism. In addition, several studies have shown that fluoxetine can alter tumor cell viability. Thus, it was recently demonstrated in vivo that chronic fluoxetine treatment inhibits tumor growth by increasing antitumor T-cell activity. Here we briefly review some of the literature referring to how fluoxetine is able to modify, for better or worse, the functionality of the immune system. These results of our analysis point to the relevance of the novel pharmacological action of this drug as an immunomodulator helping to treat several pathologies in which immune deficiency and/or deregulation is present.

Involvement of Nitric Oxide, Neurotrophins and HPA Axis in Neurobehavioural Alterations Induced by Prenatal Stress.

Several studies suggest that negative emotions during pregnancy generate adverse effects on the cognitive, behavioural and emotional development of the descendants. The psychoneuroendocrine pathways involve the transplacentary passage of maternal glucocorticoids in order to influence directly on fetal growth and brain development.Nitric oxide is a gaseous neurotransmitter that plays an important role in the control of neural activity by diffusing into neurons and participates in learning and memory processes. It has been demonstrated that nitric oxide is involved in the regulation of corticosterone secretion. Thus, it has been found that the neuronal isoform of nitric oxide synthase (nNOS) is an endogenous inhibitor of glucocorticoid receptor (GR) in the hippocampus and that nNOS in the hippocampus may participate in the modulation of hypothalamic-pituitary-adrenal axis activity via GR.Neurotrophins are a family of secreted growth factors consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and NT4. Although initially described in the nervous system, they regulate processes such as cell survival, proliferation and differentiation in several other compartments. It has been demonstrated that the NO-citrulline cycle acts together with BDNF in maintaining the progress of neural differentiation.In the present chapter, we explore the interrelation between nitric oxide, glucocorticoids and neurotrophins in brain areas that are key structures in learning and memory processes. The participation of this interrelation in the behavioural and cognitive alterations induced in the offspring by maternal stress is also addressed.

Involvement of nitric oxide in improving stress-induced behavioural alteration by glatiramer acetate treatment in female BALB/c mice.

RATIONALE: Oxidative stress and neurotrophins are among the most important factors involved in several pathophysiological brain processes. In addition, long-term exposure to stressful situations has deleterious effects on behaviour. We have previously shown that stressed female BALB/c mice show poor learning performance and that this behaviour is reversed by glatiramer acetate (GA) treatment. OBJECTIVES: We investigated the involvement of the hippocampal oxidative status and neurotrophin levels in cognitive deficit and the improvement of this deficit by GA treatment in chronic stressed BALB/c mice. METHODS: Female BALB/c mice were exposed to a chronic mild stress (CMS) model for 9 weeks. During the last 3 weeks of the stress exposure, one group of mice was subcutaneously injected four times with 100 µg GA/mouse. Following this period, behavioural studies were performed. The mice were then sacrificed, and biochemical studies were performed on the hippocampus. RESULTS: The stressed mice exhibited a significant decline in their performance in the open-field and in object-in-place tasks. This decline was accompanied by an increase in reactive oxygen species (ROS) and a decrease in nitric oxide (NO) production by neuronal nitric oxide synthase (nNOS). Neither antioxidant defences nor neurotrophin protein levels were involved in this process. Interestingly, the administration of GA re-established the normal levels of ROS, restored nNOS activity and improved learning performance. CONCLUSIONS: The GA treatment improved learning and memory in female BALB/c mice under chronic stress through a mechanism that involves the regulation of NO production, which in turn modulates the ROS levels.

Prevalencia de automedicación de antiinflamatorios y analgésicos en la práctica ambulatoria / Pravalence of self-medication of anti-inflamatory and analgesic in ambulatory practice

La automedicación con AINEs y analgésicos es una práctica extendida tanto en países desarrollados como en desarrollo. Existen pocas intervenciones educacionales para disminuir esta práctica común y riesgosa. El objetivo primario del presente estudio fue determinar la prevalencia de automedicación en pacientes que son atendidos en instituciones públicas o privadas de la Ciudad de Buenos Aires. Para ello se reclutaron 1486 pacientes ambulatorios y se determinó la prevalencia y factores asociados. Resultados: La prevalencia de automedicación en la Ciudad de Buenos Aires fue del 34,6% siendo mayor en las mujeres, ancianos y pacientes atendidos en el ámbito público.

Self-medication is extensively practised in both developed andunderdeveloped countries. There are few educational interventionsto diminish this common and risky practice. The primary objectiveof this trial was to determine the prevalence of self-medicationin patients of public and private institutions of Buenos Aires City.For that reason, 1486 outpatients were recruited to evaluate theprevalence and associated factors. Results: The prevalence of selfmedicationin Buenos Aires city was 34.6%. It was more importantin females, and in public institutions.

Prenatal stress induces up-regulation of glucocorticoid receptors on lymphoid cells modifying the T-cell response after acute stress exposure in the adult life.

It has been demonstrated that a short-duration stress (acute stress) may result in immunopreparatory or immunoenhancing physiological conditions. The aim of the present study was to investigate whether exposure to prenatal restraint stress (PRS) influences the impact of acute stress on the T-cell response in the adult life. We found that female mice exposed to PRS (PS mice) did not exhibit changes in the T-cell-dependent IgG antibody production with respect to prenatally non-stressed mice (no-PS mice). However, no-PS mice exposed to acute stress showed an increase of antibody production after antigen stimulation. In contrast, PS mice exhibited a decreased response after an acute situation. Spleen catecholamines and plasma corticosterone levels were increased in acute stress in both PS and no-PS mice. Nevertheless, lymphocyte response to hormones was altered in PS mice. Particularly, inhibitory effect of corticosterone was higher on lymphocytes from PS mice. In addition, an increase in protein levels and mRNA expression of glucocorticoid receptor was found in lymphoid cells from PS mice. These results show that prenatal stress alters the immune intrinsic regulatory mechanism that in turn induces an increased vulnerability to any stressful situation able to modify immune homeostasis.

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 a 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 weeks) noise (95-97 dBA) 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 end-points 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.

Effects of oligoelements Se, Zn, and Mn plus Lachesis muta venom in experimental scleroderma.

Scleroderma, sclerosis of the skin, is a severe autoimmune disease refractant to all kind of treatments. To study the in vivo effects of a combination of three oligoelements selenium (Se), zinc (Zn), and manganese (Mn) plus Lachesis muta venom (O-LM) on the bleomycin (BLM)-induced scleroderma mouse experimental model. C3H mice were randomly divided into four groups: control (phosphate-buffered saline (PBS)), O-LM, BLM, and BLM + O-LM. All administrations were performed subcutaneously into the back of mice. BLM was injected 5 days per week for three consecutive weeks and O-LM was administered simultaneously with BLM from the beginning of the experiments and lasted for 3 weeks after the final BLM or PBS injection (for O-LM and BLM + O-LM groups), when animals were sacrificed and histopathological, immunohistochemical, thiobarbituric acid reactive species (TBARS) evaluation, and autoantibodies detection were determined. O-LM significantly reduced BLM-induced enhanced dermal thickness (605 ± 47 vs. 956 ± 59 µm, P < 0.01), collagen deposition, and mast cells infiltration (43.1 ± 1.0 vs. 102 ± 14.1 mast cells, P < 0.05). O-LM administration significantly blocked BLM-induced oxidative damage and the enhanced immunoreactive fibroblasts for α-smooth muscle actin while reduced BLM-induced autoantibodies that strongly react mainly with skin and spleen. O-LM significantly reduced BLM-induced scleroderma through the modulation of antioxidant and immunological pathways.

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 anti-inflammatory therapies.