Brain Glucocorticoid Receptors and Their Role in Behavioural Teratogenicity of Synthetic Glucocorticoids

Author(s):  
O. Benešová ◽  
A. Pavlík
2016 ◽  
Vol 229 (1) ◽  
pp. R17-R28 ◽  
Author(s):  
Kerryn M Taylor ◽  
David W Ray ◽  
Paula Sommer

Proper expression of the glucocorticoid receptor (GR) plays an essential role in the development of the lung. GR expression and signalling in the lung is manipulated by administration of synthetic glucocorticoids (Gcs) for the treatment of neonatal, childhood and adult lung diseases. In lung cancers, Gcs are also commonly used as co-treatment during chemotherapy. This review summarises the effect of Gc monotherapy and co-therapy on lung cancers in vitro, in mouse models of lung cancer, in xenograft, ex vivo and in vivo. The disparity between the effects of pre-clinical and in vivo Gc therapy is commented on in light of the recent discovery of GR as a novel tumour suppressor gene.


2020 ◽  
Vol 24 (4) ◽  
pp. 9-20
Author(s):  
Ya. F. Zverev ◽  
A. Ya. Rykunova

The review is devoted to the consideration of the most common drugs currently used in the treatment of primary nephrotic syndrome. Mechanisms of pharmacological activity of glucocorticosteroids, ACTH, calcineurin inhibitors cyclosporine A and tacrolimus, alkylating compounds cyclophosphamide and chlorambucil, mycophenolate mofetil, levamisole, abatacept, rituximab and a number of other recently created monoclonal antibodies. An attempt is made to separate the immune and non-immune mechanisms of action of the most common drugs, concerning both the impact on the immunogenetics of the noted diseases and the direct impact on the podocytes that provide permeability of the glomerular filtration barrier and the development of proteinuria. It is shown that the immune mechanisms of corticosteroids are caused by interaction with glucocorticoid receptors of lymphocytes, and nonimmune – with stimulation of the same receptors in podocytes. It was found that the activation of adrenocorticotropic hormone melanocortin receptors contributes to the beneficial effect of the drug in nephrotic syndrome. It is discussed that the immune mechanism of calcineurin inhibitors is provided by the suppression of tissue and humoral immunity, and the non-immune mechanism is largely due to the preservation of the activity of podocyte proteins such as synaptopodin and cofilin. Evidence is presented to show that the beneficial effect of rituximab in glomerulopathies is related to the interaction of the drug with the protein SMPDL-3b in lymphocytes and podocytes. The mechanisms of action of mycophenolate mofetil, inhibiting the activity of the enzyme inosine 5-monophosphate dehydrogenase, which causes the suppression of the synthesis of guanosine nucleotides in both lymphocytes and glomerular mesangium cells, are considered. It is emphasized that the effect of levamisole in nephrotic syndrome is probably associated with the normalization of the ratio of cytokines produced by various T-helpers, as well as with an increase in the expression and activity of glucocorticoid receptors. The mechanisms of pharmacological activity of a number of monoclonal antibodies, as well as galactose, the beneficial effect of which may be provided by binding to the supposed permeability factor produced by lymphocytes, are considered.


Author(s):  
Saniya Hashim Khan ◽  
Sheraz Khan ◽  
Inamullah Khan ◽  
Narmeen Hashim

Background: Chronic stress elevates the cortisol beyond normal levels, which affects cognition including learning & memory. This injurious effect is primarily mediated via over excitation of metabotropic glucocorticoid receptors (mGR). Methods: The present study was aimed appraise the neuroprotective effects of naturally occurring molecule β-1,3-glucan by interfering with stress-cortisol-mGR axis. Our data of virtual screening (in silico) exhibited the promising interactions of βglucan with the mGR. Therefore, the study was extended to evaluate its efficacy (2.5, 5 and 10 mg/kg/ i.p) in an animal model of chronic unpredictable mild stress (CUMS, 28 days) induced memory impairment. Results: Results of the current study revealed the β-glucan provided dose dependent protection against deleterious effects of stress on learning and memory associated parameters observed in Morris water maze (MWM) task. At higher tested doses, it has also significantly antagonized the stress induced weight loss and corticosterone elevation. Conclusion: From these findings, it can be deduced that the β-glucan possesses therapeutic potential against stress induced memory impairment, and this effect can be attributed to its normalizing effect on corticosterone levels.


Author(s):  
Leandro F. Vendruscolo ◽  
George F. Koob

Alcohol use disorder is a chronically relapsing disorder that involves (1) compulsivity to seek and take alcohol, (2) difficulty in limiting alcohol intake, and (3) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) in the absence of alcohol. Alcohol addiction encompasses a three-stage cycle that becomes more intense as alcohol use progresses: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These stages engage neuroadaptations in brain circuits that involve the basal ganglia (reward hypofunction), extended amygdala (stress sensitization), and prefrontal cortex (executive function disorder). This chapter discusses key neuroadaptations in the hypothalamic and extrahypothalamic stress systems and the critical role of glucocorticoid receptors. These neuroadaptations contribute to negative emotional states that powerfully drive compulsive alcohol drinking and seeking. These changes in association with a disruption of prefrontal cortex function that lead to cognitive deficits and poor decision making contribute to the chronic relapsing nature of alcohol dependence.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Aya Sasaki ◽  
Margaret E. Eng ◽  
Abigail H. Lee ◽  
Alisa Kostaki ◽  
Stephen G. Matthews

AbstractSynthetic glucocorticoids (sGC) are administered to women at risk of preterm delivery, approximately 10% of all pregnancies. In animal models, offspring exposed to elevated glucocorticoids, either by administration of sGC or endogenous glucocorticoids as a result of maternal stress, show increased risk of developing behavioral, endocrine, and metabolic dysregulation. DNA methylation may play a critical role in long-lasting programming of gene regulation underlying these phenotypes. However, peripheral tissues such as blood are often the only accessible source of DNA for epigenetic analyses in humans. Here, we examined the hypothesis that prenatal sGC administration alters DNA methylation signatures in guinea pig offspring hippocampus and whole blood. We compared these signatures across the two tissue types to assess epigenetic biomarkers of common molecular pathways affected by sGC exposure. Guinea pigs were treated with sGC or saline in late gestation. Genome-wide modifications of DNA methylation were analyzed at single nucleotide resolution using reduced representation bisulfite sequencing in juvenile female offspring. Results indicate that there are tissue-specific as well as common methylation signatures of prenatal sGC exposure. Over 90% of the common methylation signatures associated with sGC exposure showed the same directionality of change in methylation. Among differentially methylated genes, 134 were modified in both hippocampus and blood, of which 61 showed methylation changes at identical CpG sites. Gene pathway analyses indicated that prenatal sGC exposure alters the methylation status of gene clusters involved in brain development. These data indicate concordance across tissues of epigenetic programming in response to alterations in glucocorticoid signaling.


2021 ◽  
Vol 22 (11) ◽  
pp. 6054
Author(s):  
Ioanna Kokkinopoulou ◽  
Paraskevi Moutsatsou

Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid hormones. Glucocorticoids (GCs) regulate the mitochondrially encoded oxidative phosphorylation gene expression and mitochondrial energy metabolism. The identification of Glucocorticoid Response Elements (GREs) in mitochondrial sequences and the detection of Glucocorticoid Receptor (GR) in mitochondria of different cell types gave support to hypothesis that mitochondrial GR directly regulates mitochondrial gene expression. Numerous studies have revealed changes in mitochondrial gene expression alongside with GR import/export in mitochondria, confirming the direct effects of GCs on mitochondrial genome. Further evidence has made clear that mitochondrial GR is involved in mitochondrial function and apoptosis-mediated processes, through interacting or altering the distribution of Bcl2 family members. Even though its exact translocation mechanisms remain unknown, data have shown that GR chaperones (Hsp70/90, Bag-1, FKBP51), the anti-apoptotic protein Bcl-2, the HDAC6- mediated deacetylation and the outer mitochondrial translocation complexes (Tom complexes) co-ordinate GR mitochondrial trafficking. A role of mitochondrial GR in stress and depression as well as in lung and hepatic inflammation has also been demonstrated.


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