Imipramine attenuates anxiety- and depressive-like effects of acute and prolonged ethanol-abstinence in male rats by modulating SERT and GR expression in the dorsal hippocampus.

AIMS: Considering that serotoninergic agents attenuate symptoms of anxiety and are used to treat depression, we investigated whether subchronic treatment with imipramine, a serotonin/noradrenaline reuptake inhibitor, would prevent the anxiogenic-like behaviour induced by acute and/or chronic ethanol withdrawal. We also investigated whether those changes were related to the disfunctioning of hypothalamic-pituitary-adrenal (HPA) axis and serotonergic neurotransmission. MAIN METHODS: 264 Male Wistar rats were treated with ethanol 6% (vol./vol.) for 21 days. Acute ethanol withdrawal was induced by abrupt discontinuation of treatment and sustained for 48 h. Protracted abstinence was sustained for an additional period of 21 days. Behavioural tests included the Elevated Plus Maze (EPM) or Light/Dark Box (LDB) after acute abstinence, and the Forced Swim Test (FST) after protracted abstinence. Imipramine (15 mg/kg, i.p.) was administered 24, 19 and 1 h before EPM or LDB tests. KEY FINDINGS: Acute abstinence decreased exploration of the open arms of the EPM, without changing exploration of LDB. Additionally, chronic abstinent rats displayed more time immobile in the FST, when compared to control animals. These effects were attenuated by imipramine treatment, without changing basal response. Imipramine prevented protracted abstinence -induced decrease in glucocorticoid receptor (GR) and serotonin transporter (SERT) expression in the dorsal hippocampus. SIGNIFICANCE: Our findings indicate that chronic ethanol withdrawal affects the hippocampal serotonergic system by decreasing serotonin transporter expression. It also disturbs the HPA axis functioning through an imbalance on GR and mineralocorticoid (MR) expression.

Cholecalciferol abolishes depressive-like behavior and hippocampal glucocorticoid receptor impairment induced by chronic corticosterone administration in mice.

Several attempts have been made to understand the role of cholecalciferol (vitamin D3) in the modulation of neuropsychiatric disorders. Notably, the deficiency of vitamin D3 is considered a pandemic and has been postulated to enhance the risk of major depressive disorder (MDD). Therefore, this study aims to investigate the antidepressant-like effect of cholecalciferol in a mouse model of depression induced by corticosterone, and the possible role of glucocorticoid receptors (GR), NLRP3 and autophagic pathways in this effect. Corticosterone administration (20 mg/kg, p.o., for 21 days) significantly increased the immobility time and grooming latency, as well as reduced the total time spent grooming in mice subjected to the tail suspension test (TST) and splash test (ST), respectively. Importantly, these behavioral alterations were associated with reduced GR immunocontent in the hippocampus of mice. Conversely, the repeated administration of cholecalciferol (2.5 µg/kg, p.o.) in the last 7 days of corticosterone administration was effective to prevent the increased immobility time in the TST and the reduced time spent grooming in the ST, and partially abolished the increase in the grooming latency induced by corticosterone, suggesting its antidepressant-like effect. These behavioral effects were similar to those exerted by fluoxetine (10 mg/kg, p.o.). Moreover, the corticosterone-induced reduction on hippocampal GR immunocontent was not observed in mice treated with cholecalciferol. Additionally, cholecalciferol treatment per se reduced the immunocontent of NLRP3 inflammasome-related proteins ASC, caspase-1, and TXNIP in the hippocampus of mice. No alterations on hippocampal immunocontent of the autophagic-related proteins phospho-mTORC1, beclin-1, and LC3A/B were observed following cholecalciferol treatment and/or corticosterone administration. Collectively, our results provide insights into the effects of cholecalciferol in depression-related behaviors that seem to be related, at least in part, to GR modulation.

Anti-proliferative and anti-inflammatory effects of 3ß,6ß,16ß-Trihydroxylup-20(29)-ene on cutaneous inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: 3ß,6ß,16ß-Trihydroxylup-20(29)-ene (TTHL) is a triterpene isolated from the flowers of Combretum leprosum, a plant used in folk medicine in the north of Brazil for the treatment of skin disorders. AIM OF THE STUDY: In the present study, TTHL was evaluated as a potential topical anti-inflammatory and anti-proliferative agent through in vivo and in vitro models. MATERIAL AND METHODS: Anti-inflammmatory and anti-proliferative effects of TTHL were assessed using Swiss mice in acute and chronic models of skin inflammation induced by 12-O-tetradecanoylphorbol-acetate (TPA) application. Anti-proliferative activity was proved through in vitro experiments with the HaCaT human keratinocyte cell line. RESULTS: Treatment with TTHL inhibited inflammatory parameters such as oedema formation and cellular infiltration in acute and chronic models. In the chronic model, TTHL also inhibited epidermal hyperproliferation, as evidenced by reduction of epidermis thickness and proliferating cell nuclear antigen expression. The anti-proliferative effect was confirmed by the capability of TTHL in reducing the proliferation and inducing cell apoptosis of HaCaT cells. Suggesting a mechanism of action, TTHL showed activation of corticosteroid receptors, but without the induction of corticosteroid-related cutaneous side effects. CONCLUSION: Our results demonstrate consistent anti-inflammatory and anti-proliferative activity and assign TTHL as a valuable tool in the development of a new treatment for skin inflammatory and proliferative diseases, such as psoriasis.

GR-independent down-modulation on GM-CSF bone marrow-derived dendritic cells by the selective glucocorticoid receptor modulator Compound A.

Dendritic cells (DC) initiate the adaptive immune response. Glucocorticoids (GCs) down-modulate the function of DC. Compound A (CpdA, (2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride) is a plant-derived GR-ligand with marked dissociative properties. We investigated the effects of CpdA on in vitro generated GM-CSF-conditioned bone marrow-derived DC (BMDC). CpdA-exposed BMDC exhibited low expression of cell-surface molecules and diminution of the release of proinflammatory cytokines upon LPS stimulation; processes associated with BMDC maturation and activation. CpdA-treated BMDC were inefficient at Ag capture via mannose receptor-mediated endocytosis and displayed reduced T-cell priming. CpdA prevented the LPS-induced rise in pErk1/2 and pP38, kinases involved in TLR4 signaling. CpdA fully inhibited LPS-induced pAktSer473, a marker associated with the generation of tolerogenic DC. We used pharmacological blockade and selective genetic loss-of-function tools and demonstrated GR-independent inhibitory effects of CpdA in BMDC. Mechanistically, CpdA-mediated inactivation of the NF-κB intracellular signaling pathway was associated with a short-circuiting of pErk1/2 and pP38 upstream signaling. Assessment of the in vivo function of CpdA-treated BMDC pulsed with the hapten trinitrobenzenesulfonic acid showed impaired cell-mediated contact hypersensitivity. Collectively, we provide evidence that CpdA is an effective BMDC modulator that might have a benefit for immune disorders, even when GR is not directly targeted.

Impaired brain StAR and HSP70 gene expression in zebrafish exposed to Methyl-Parathion based insecticide.

Fish production ponds and natural water body areas located in close proximity to agricultural fields receive water with variable amounts of agrochemicals, and consequently, compounds that produce adverse effects may reach nontarget organisms. The aim of this study was to investigate whether waterborne methyl-parathion-based insecticide (MPBI) affected gene expression patterns of brain glucocorticoid receptor (GR), steroidogenic acute regulatory protein (StAR), and heat shock protein 70 (hsp70) in adult zebrafish (Danio rerio) exposed to this chemical for 96 h. Treated fish exposed to MPBI-contaminated water showed an inhibition of brain StAR and hsp70 gene expression. Data demonstrated that MPBI produced a decrease brain StAR and hsp70 gene expression.

Maternal separation in early life modifies anxious behavior and Fos and glucocorticoid receptor expression in limbic neurons after chronic stress in rats: effects of tianeptine.

Early-life adversity can lead to long-term consequence persisting into adulthood. Here, we assess the implications of an adverse early environment on vulnerability to stress during adulthood. We hypothesized that the interplay between early and late stress would result in a differential phenotype regarding the number of neurons immunoreactive for glucocorticoid receptor (GR-ir) and neuronal activity as assessed by Fos immunoreactivity (Fos-ir) in brain areas related to stress responses and anxiety-like behavior. We also expected that the antidepressant tianeptine could correct some of the alterations induced in our model. Male Wistar rats were subjected to daily maternal separation (MS) for 4.5 h during the first 3 weeks of life. As adults, the rats were exposed to chronic stress for 24 d and they were treated daily with tianeptine (10 mg/kg intraperitoneal) or vehicle (isotonic saline). Fos-ir was increased by MS in all structures analyzed. Chronic stress reduced Fos-ir in the hippocampus, but increased it in the paraventricular nucleus. Furthermore, chronic stress increased GR-ir in hippocampus (CA1) and amygdala in control non-MS rats. By contrast, when MS and chronic stress were combined, GR-ir was decreased in these structures. Additionally, whereas tianeptine did not affect Fos-ir, it regulated GR-ir in a region-dependent manner, in hippocampus and amygdala opposing in some cases the stress or MS effects. Furthermore, tianeptine reversed the MS- or stress-induced anxious behavior. The interplay between MS and chronic stress observed indicates that MS rats have a modified phenotype, which is expressed when they are challenged by stress in later life.

Exercise reverses OVA-induced inhibition of glucocorticoid receptor and increases anti-inflammatory cytokines in asthma.

The purpose of this study was to determine the effect of aerobic exercise training (AT) on the expression of glucocorticoid receptors (GR) and anti-inflammatory cytokines in an asthma model. BALB/c mice were divided into groups control (CT; nonsensitized/nontrained), aerobic training (AT; nonsensitized/trained), ovalbumin (OVA; sensitized/not trained), and OVA+AT (sensitized/trained). OVA groups received OVA by inhalation, and the AT groups completed 1, 3, or 7 days of exercise (60 min/session). Expression of GR, IL-4, IL-5, IL-10, IL-1ra, NF-κB, TGF-ß, VEGF, ICAM-1, VCAM-1; eosinophils counting; and airway remodeling (AR) features [airway smooth muscle (ASM) and epithelial thickness and collagen fiber deposition] were quantified. OVA sensitization induced a decrease in the expression of GR and increases in the eosinophil, IL-4, IL-5, NF-κB, TGF-ß, VEGF, ICAM-1, VCAM-1, and AR features (P < 0.05). After 3 days, AT reversed the OVA-induced reduction in the expression of GR, and subsequently induced increases in the expression of IL-10 and IL-1ra (seventh day). In contrast, the eosinophil migration, the expression of NF-κB, IL-4, IL-5, TGF-ß, RANTES, VEGF, ICAM-1, VCAM-1, and the AR features (P < 0.05) were reduced. AT increases the expression of GR and anti-inflammatory cytokines (IL-10 and IL-1ra) and reduces the expression of inflammatory mediators and airway inflammation in an animal model of asthma.

A double-hit model of stress dysregulation in rats: implications for limbic corticosteroid receptors and anxious behavior under amitriptyline treatment.

Adversity during early life can lead to diverging endocrine and behavioral responses to stress in adulthood. In our laboratory, we evaluated the long-term effects of early life adversity and its interaction with chronic stress during adulthood. We propose this as a model of vulnerability to dysregulation of the stress response. We hypothesized that rats subjected to both protocols would show differential expression of corticosteroid receptors measured as number of neurons immunoreactive for glucocorticoid receptors (GR) or mineralocorticoid receptors (MR), in limbic areas related to the control of anxiety-like behavior. We also evaluated the effect of amitriptyline expecting to prevent the outcomes of the model. Male Wistar rats were separated from the mother (MS) for 4.5 h every day for the first 3 weeks of life. From postnatal day 50, rats were subjected to chronic variable stress (CVS) during 24 d (five types of stressor at different times of day). During the stress protocol, the rats were administered amitriptyline (10 mg/kg i.p.) daily. MS evoked lower MR expression in the central amygdaloid nucleus and this was reversed by amitriptyline. Furthermore, CVS increased MR immunoreactivity in the hippocampal area CA2 and increased anxious behavior; both effects were prevented by the antidepressant. When MS was combined with CVS during adulthood, there was a reduction of locomotor activity, with no corrective effect of amitriptyline. The differential effects among groups could mean that MS would promote an alternative phenotype that is expressed when facing CVS (a double hit) later in life.

Effects of methotrexate on the expression of the translational isoforms of glucocorticoid receptors α and ß: correlation with methotrexate efficacy in rheumatoid arthritis patients.

OBJECTIVES: To test the effect of MTX on the expression of glucocorticoid receptor (GR) α and ß isoforms AB, C and D in peripheral blood mononuclear cells (PBMCs) in culture, from newly diagnosed RA patients and to evaluate whether the test results correlate with patients' subsequent response to MTX treatment. METHODS: Twenty patients with early active RA were enrolled. Patients who had previously received any DMARD or cytotoxic agent, or who had received CSs in the 6 months before enrolment were excluded. PBMCs from all patients were obtained and cultured in the presence and absence of MTX (10(-4), 10(-6) and 10(-8) M). The expression of GR isoforms was evaluated by western blot. After blood samples were taken, patients entered a 24-week study receiving MTX, diclofenac and prednisone (10 mg/day). At Week 24, the ACR core set of disease activity measures was calculated and a correlation between the MTX effect on patients' PBMC GR expression in vitro and the ACR response was evaluated. RESULTS: MTX 10(-6) M in the culture medium induced the expression of the PBMC isoform AB of GRα (P = 0.009). Other GR isoforms were unaffected. The magnitude of the induced expression correlated with the ACR response to treatment at Week 24 of therapy (r = 0.92, P = 0.00003). CONCLUSION: MTX in vitro induces greater expression of GRαAB isoform in PBMC from RA patients who later respond to MTX treatment than in non-responding patients. This may have clinical applications for predicting MTX efficacy in RA patients.

Cognitive enhancers: focus on modulatory signaling influencing memory consolidation.

Biological research has unraveled many of the molecular and cellular mechanisms involved in the formation of long-lasting memory, providing new opportunities for the development of cognitive-enhancing drugs. Studies of drug enhancement of cognition have benefited from the use of pharmacological treatments given after learning, allowing the investigation of mechanisms regulating the consolidation phase of memory. Modulatory systems influencing consolidation processes include stress hormones and several neurotransmitter and neuropeptide systems. Here, we review some of the findings on memory enhancement by drug administration in animal models, and discuss their implications for the development of cognitive enhancers.

Amitriptyline and acute inflammation: a study using intravital microscopy and the carrageenan-induced paw edema model.

BACKGROUND/AIMS: Antidepressants are reported to exhibit antiinflammatory effects. However, mechanisms involved in this action have not been elucidated. Thus, the objectives of the present study were (a) to evaluate the effects of amitriptyline on the acute inflammatory process, and (b) to investigate the participation of α(1)-adrenergic receptors and glucocorticoids as possible mechanisms implicated in the amitriptyline action on inflammation. METHODS AND RESULTS: Single and multiple doses of amitriptyline were administered to rats submitted to the carrageenan-induced paw edema model. The results showed a significant antiedematous reaction to amitriptyline, mainly when administered at each elimination half-life. The next step was to evaluate its effects on leukocyte behavior, using intravital microscopy. Amitriptyline produced a significant effect on leukocyte behavior. To investigate possible mechanisms involved, a glucocorticoid receptor antagonist (RU-486) and an α(1)-adrenergic receptor antagonist (prazosin) were used. RU-486 administration lacked the ability to decrease the amitriptyline antiinflammatory effects in the carrageenan-induced paw edema model. Prazosin pretreatment potentiated the amitriptyline antiinflammatory effect without presenting an effect per se. CONCLUSION: The present study shows the ability of amitriptyline to decrease edema and affect leukocyte behavior in an acute inflammatory process; and, for the first time to our knowledge, we suggest the involvement of α(1)-adrenoceptors in the antiinflammatory effects of amitriptyline.

Revisiting steroid treatment for septic shock: molecular actions and clinical effects--a review.

Corticosteroids are widely used to treat a diversity of pathological conditions including allergic, autoimmune and some infectious diseases. These drugs have complex mechanisms of action involving both genomic and non-genomic mechanisms and interfere with different signal transduction pathways in the cell. The use of corticosteroids to treat critically ill patients with acute respiratory distress syndrome and severe infections, such as sepsis and pneumonia, is still a matter of intense debate in the scientific and medical community with evidence both for and against its use in these patients. Here, we review the basic molecular mechanisms important for corticosteroid action as well as current evidence for their use, or not, in septic patients. We also present an analysis of the reasons why this is still such a controversial point in the literature.

Revisiting steroid treatment for septic shock: molecular actions and clinical effects - a review

Corticosteroids are widely used to treat a diversity of pathological conditions including allergic, autoimmune and some infectious diseases. These drugs have complex mechanisms of action involving both genomic and non-genomic mechanisms and interfere with different signal transduction pathways in the cell. The use of corticosteroids to treat critically ill patients with acute respiratory distress syndrome and severe infections, such as sepsis and pneumonia, is still a matter of intense debate in the scientific and medical community with evidence both for and against its use in these patients. Here, we review the basic molecular mechanisms important for corticosteroid action as well as current evidence for their use, or not, in septic patients. We also present an analysis of the reasons why this is still such a controversial point in the literature.

Simultaneous evaluation of in vivo glucocorticoid sensitivity and expression of glucocorticoid receptor alpha-isoform in rheumatoid arthritis patients.

OBJECTIVES: To analyze glucocorticoid (GC) sensitivity using intravenous very low dose dexamethasone suppression test (IV-VLD-DST) in patients with rheumatoid arthritis (RA) and its correlation with glucocorticoid receptor alpha-isoform (GRalpha) gene expression. METHODS: We evaluated 20 healthy controls and 32 RA patients with Health Assessment Questionnaire (HAQ) and Disease Activity Score 28 joints (DAS) scores and IV-VLD-DST and GRalpha expression in mononuclear cells. RESULTS: Basal cortisol and the percentage of cortisol reduction after IV-VLD-DST were lower in RA patients than in controls, whereas GRalpha expression was similar among groups. In the RA group there was an inverse correlation between GRalpha expression and the percentage of cortisol suppression that was not observed in controls. There was a direct relationship between DAS and GRalpha expression. CONCLUSIONS: Mechanisms involved in GC resistance observed in patients with RA are possibly not at the level of GRalpha gene expression, since it was similar among groups and GRalpha increased with disease activity.

Simultaneous evaluation of in vivo glucocorticoid sensitivity and expression of glucocorticoid receptor alpha-isoform in rheumatoid arthritis patients / Avaliação concomitante da sensibilidade in vivo aos glicocorticóides e da expressão da isoforma alfa do receptor de glicocorticóide em pacientes com artrite reumatóide

OBJECTIVES: To analyze glucocorticoid (GC) sensitivity using intravenous very low dose dexamethasone suppression test (IV-VLD-DST) in patients with rheumatoid arthritis (RA) and its correlation with glucocorticoid receptor alpha-isoform (GRα) gene expression. METHODS: We evaluated 20 healthy controls and 32 RA patients with Health Assessment Questionnaire (HAQ) and Disease Activity Score 28 joints (DAS) scores and IV-VLD-DST and GRα expression in mononuclear cells. RESULTS: Basal cortisol and the percentage of cortisol reduction after IV-VLD-DST were lower in RA patients than in controls, whereas GRα expression was similar among groups. In the RA group there was an inverse correlation between GRα expression and the percentage of cortisol suppression that was not observed in controls. There was a direct relationship between DAS and GRα expression. CONCLUSIONS: Mechanisms involved in GC resistance observed in patients with RA are possibly not at the level of GRα gene expression, since it was similar among groups and GRα increased with disease activity.

OBJETIVOS: Determinar a sensibilidade aos glicocorticóides (GC) utilizando teste de supressão com dexametasona em doses muito baixas (IV-VLD-DST) em pacientes com artrite reumatóide (AR) e sua correlação com a expressão gênica da isoforma alfa do receptor glicocorticóide (GRα). MÉTODOS: Foram avaliados 20 controles saudáveis e 32 pacientes com AR com Health Assessment Questionnaire (HAQ) e Disease Activity Score 28 joints (DAS), IV-VLD-DST e expressão do GRα em células mononucleares. RESULTADOS: Cortisol basal e porcentagem de redução do cortisol após IV-VLD-DST foram menores no grupo AR do que nos controles, enquanto a expressão de GRα foi similar entre eles. No grupo com AR, ocorreu correlação negativa entre a expressão do GRα e a porcentagem de supressão do cortisol, enquanto nos controles não houve correlação. Ocorreu relação direta entre DAS e expressão de GRα . CONCLUSÕES: Sugerimos que os mecanismos envolvidos na resistência aos GC observada na AR não estejam ao nível da expressão gênica do GRα, já que esta é igual entre os grupos e aumenta com a gravidade da doença.

Impaired hypothalamic-pituitary-adrenal axis activity in patients with multiple sclerosis.

OBJECTIVE: To investigate hypothalamic-pituitary-adrenal axis activity in well-defined multiple sclerosis (MS) patient subgroups. METHODS: A total of 173 patients with clinically definite MS were studied: 40 with primary progressive, 41 with secondary progressive, 58 with relapsing-remitting in remission, and 34 with relapsing-remitting during acute relapse. Sixty healthy subjects served as controls. No patients were receiving steroid or other immunomodulatory therapy. Plasma cortisol, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEAS), as well as urine cortisol levels, were measured using commercial radioimmunoassays. Glucocorticoid receptor (GR)-binding assay in peripheral blood mononuclear cells (PBMCs) was performed using [(3)H]dexamethasone (Dex). PBMC production of the proinflammatory peptide corticotrophin-releasing hormone (CRH), interleukin (IL)-1beta, IL-6, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha was evaluated using enzyme-linked immunosorbent spot assay. RESULTS: All four groups of patients displayed significantly higher cortisol, ACTH, and DHEAS plasma concentrations and urine cortisol values than controls. Although 62% of MS patients did not suppress Dex, suppression test results did not correlate with IL-1beta, IL-6, IFN-gamma, or TNF-alpha production. GR-binding assays showed no differences in binding sites between patients and controls; however, all MS groups showed decreased GR affinity and sensitivity compared with controls. The numbers of IL-1beta-, IL-6-, and TNF-alpha-secreting cells increased significantly in relapsing-remitting MS patients only during exacerbations; in contrast, IFN-gamma-secreting cells increased during both exacerbations and remission. Finally, PBMC CRH-secreting cell numbers were considerably greater in all forms of MS. CONCLUSIONS: Patients with multiple sclerosis show hypothalamic-pituitary-adrenal axis hyperactivity, with lymphocytes expressing similar glucocorticoid receptor numbers to controls; however, binding affinity and glucocorticoid sensitivity of these lymphocytes seem to be reduced.

Mechanism of action of glucocorticoids in nasal polyposis.

UNLABELLED: Glucocorticoids (GC) are the drugs of choice for the clinical treatment of nasal polyposis, according to the medical literature. Its mechanism of action in the regression of clinical symptoms and polyps, however, is not fully understood. The topical and/or systemic use of glucocorticoids lead to variable expression of cytokines, chemokines and lymphokines, as well as changes in cells. It is known that GC suppresses the expression of pro-inflammatory cytokines, chemokines and adhesion molecules such as ICAM-1 and E-selectin; GC also stimulate the transcription of anti-inflammatory cytokines such as TGF-b. GC suppress pro-fibrotic cytokines related to polyp growth, such as IL-11, the basic fibroblast growth factor (b-FGF), and the vascular endotelial growth factor (VEGF). The action of GC depends fundamentally on their interaction with receptors (GR); certain subjects have a degree of resistance to its effect, which appears to be related with the presence of a b isoform of GR. GC also act variably on the genes involved in immunoglobulin production, presentation, and antigen processing. AIM: We present a review of the literature on the mechanisms of GC action in nasal polyosis. CONCLUSION: Understanding the mechanism of action of GC in nasal polyposis will aid in the development of new, more efficient, drugs.

A very low dose intravenous dexamethasone suppression test as an index of glucocorticoid sensitivity.

BACKGROUND/AIMS: The wide variability of responses to corticotherapy suggests a role for individual recognition of steroid sensitivity in order to customize treatment. Oral dexamethasone (DEX) administration may be hindered by the rate of its intestinal absorption and the liver first-passage effect. In this study we suggest that an intravenous very low dose DEX suppression test (VLD IV-DST) can be used as an index for glucocorticoid (GC) sensitivity. METHODS: We evaluated 87 normal subjects: 44 prepubertal children, 23 adolescents and 20 adults with a VLD IV-DST using 20 mug/m(2) of DEX (dose able to recognize GC sensitivity). Cortisol was initially measured at several time-points after DEX prompting us to establish its nadir and subsequent simplification of the test by measuring cortisol at baseline and after 120 min. RESULTS: Baseline cortisol was similar in adolescents and in adults, but lower in children. There was a spectrum of individual responses in all age groups. The percent reduction of cortisol after 120 min was different in these three age groups, with median values of 44.4% in children, 25.9% in adolescents and 61.6% in adults. CONCLUSION: This simplified VLD IV-DST using 20 mug/m(2) of DEX is useful to evaluate individual sensitivity to GC in different age groups.

Effects of pre-natal glucocorticoids on testicular development in sheep.

We tested the hypothesis that acute pre-natal exposure to high levels of synthetic glucocorticoid (betamethasone) would alter fetal testicular development through actions on gonadal glucocorticoid receptors (GRs). Pregnant Merino ewes bearing singleton male fetuses (n = 24) were allocated randomly among four equal groups to be injected intramuscularly with saline or betamethasone (0.5 mg/kg) either on day 109 of gestation or on both day 109 and day 116 of gestation. Fetal testes were collected at post-mortem, 5 days after each treatment. The volume of interstitial tissue and the volume, length and diameter of the sex cords were measured, and Sertoli cells and gonocytes were counted. For cord volume and interstitial tissue volume, control testes demonstrated maturational changes as fetal age advanced from 109 to 116 days of gestation. For that period, the single injection of betamethasone significantly reduced Leydig cell proliferation (P < 0.05), but had no effect on Sertoli cell numbers. Immunohistochemistry was used to localize GR and proliferating cell nuclear antigen in testicular cells. GR immunoexpression in Leydig cells was higher in fetuses exposed to betamethasone at 109 days of gestation than in control fetuses. Sertoli cells showed low levels of GR. It was concluded that, during mid-gestation, a brief period of glucocorticoid treatment could affect testicular development in male sheep fetuses. The mechanism probably involves direct effects on Leydig cells, as these cells express extra-GR in response to the treatment. Sertoli cells seem to produce less GR than Leydig cells, perhaps explaining their lack of response to betamethasone. These outcomes may have important implications for future fertility in male offspring.

Mecanismos de ação dos corticosteróides na polipose rinossinusal: [revisão] / Mechanism of action of glucocorticoids in nasal polyposis: [review]

Os glicocorticóides (GC) são drogas de escolha no tratamento clínico da polipose nasossinusal conforme recomendação da literatura. Entretanto, seus mecanismos de ação nas regressões dos sintomas clínicos e dos pólipos não são totalmente compreendidos. Sabe-se que a administração tópica e ou sistêmica dos glicocorticóides leva a variações na expressão de citocinas, quimiocinas e linfocinas, além das alterações celulares. Assim, os GC suprimem a expressão de citocinas pró-inflamatórias, de quimiocinas, de moléculas de adesão, além de estimular a transcrição de citocinas antiinflamatórias. Citocinas pró-fibróticas como a IL-11, fator básico de crescimento do fibroblasto (b-FGF) e fator de crescimento endotelial vascular (VEGF), relacionados com o crescimento do pólipo, também são suprimidos pela ação do GC. Tal ação depende fundamentalmente da interação com os seus receptores (GR), pois alguns indivíduos apresentam algum grau de resistência celular ao seu efeito, que parece estar relacionada com a presença da isoforma b do GR. Genes envolvidos nas fases de produção de imunoglobulinas, apresentação e processamento do antígeno também sofrem ação dos GC de forma variada. OBJETIVOS: Fazer uma revisão da literatura sobre os mecanismos de ação do GC na PNS. CONCLUSÃO: A compreensão desses mecanismos implicará no desenvolvimento de drogas mais eficazes na sua terapêutica.

Glucocorticoids (GC) are the drugs of choice for the clinical treatment of nasal polyposis, according to the medical literature. Its mechanism of action in the regression of clinical symptoms and polyps, however, is not fully understood. The topical and/or systemic use of glucocorticoids lead to variable expression of cytokines, chemokines and lymphokines, as well as changes in cells. It is known that GC suppresses the expression of pro-inflammatory cytokines, chemokines and adhesion molecules such as ICAM-1 and E-selectin; GC also stimulate the transcription of anti-inflammatory cytokines such as TGF-b. GC suppress pro-fibrotic cytokines related to polyp growth, such as IL-11, the basic fibroblast growth factor (b-FGF), and the vascular endotelial growth factor (VEGF). The action of GC depends fundamentally on their interaction with receptors (GR); certain subjects have a degree of resistance to its effect, which appears to be related with the presence of a b isoform of GR. GC also act variably on the genes involved in immunoglobulin production, presentation, and antigen processing. AIM: We present a review of the literature on the mechanisms of GC action in nasal polyosis. CONCLUSION: Understanding the mechanism of action of GC in nasal polyposis will aid in the development of new, more efficient, drugs.