@article{Menke2019, author = {Menke, Andreas}, title = {Is the HPA axis as target for depression outdated, or is there a new hope?}, series = {Frontiers in Psychiatry}, volume = {10}, journal = {Frontiers in Psychiatry}, number = {101}, issn = {1664-0640}, doi = {10.3389/fpsyt.2019.00101}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195780}, year = {2019}, abstract = {Major depressive disorder (MDD) is a very common stress-related mental disorder that carries a huge burden for affected patients and the society. It is associated with a high mortality that derives from suicidality and the development of serious medical conditions such as heart diseases, diabetes, and stroke. Although a range of effective antidepressants are available, more than 50\% of the patients do not respond to the first treatment they are prescribed and around 30\% fail to respond even after several treatment attempts. The heterogeneous condition of MDD, the lack of biomarkers matching patients with the right treatments and the situation that almost all available drugs are only targeting the serotonin, norepinephrine, or dopamine signaling, without regulating other potentially dysregulated systems may explain the insufficient treatment status. The hypothalamic-pituitary-adrenal (HPA) axis is one of these other systems, there is numerous and robust evidence that it is implicated in MDD and other stress-related conditions, but up to date there is no specific drug targeting HPA axis components that is approved and no test that is routinely used in the clinical setting identifying patients for such a specific treatment. Is there still hope after these many years for a breakthrough of agents targeting the HPA axis? This review will cover tests detecting altered HPA axis function and the specific treatment options such as glucocorticoid receptor (GR) antagonists, corticotropin-releasing hormone 1 (CRH1) receptor antagonists, tryptophan 2,3-dioxygenase (TDO) inhibitors and FK506 binding protein 5 (FKBP5) receptor antagonists.}, language = {en} } @article{PishvaDrukkerViechtbaueretal.2014, author = {Pishva, Ehsan and Drukker, Marjan and Viechtbauer, Wolfgang and Decoster, Jeroen and Collip, Dina and van Winkel, Ruud and Wichers, Marieke and Jacobs, Nele and Thiery, Evert and Derom, Catherine and Geschwind, Nicole and van den Hove, Daniel and Lataster, Tineke and Myin-Germeys, Inez and van Os, Jim and Rutten, Bart P. F. and Kenis, Gunter}, title = {Epigenetic Genes and Emotional Reactivity to Daily Life Events: A Multi-Step Gene-Environment Interaction Study}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {6}, issn = {1932-6203}, doi = {10.1371/journal.pone.0100935}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115956}, pages = {e100935}, year = {2014}, abstract = {Recent human and animal studies suggest that epigenetic mechanisms mediate the impact of environment on development of mental disorders. Therefore, we hypothesized that polymorphisms in epigenetic-regulatory genes impact stress-induced emotional changes. A multi-step, multi-sample gene-environment interaction analysis was conducted to test whether 31 single nucleotide polymorphisms (SNPs) in epigenetic-regulatory genes, i.e. three DNA methyltransferase genes DNMT1, DNMT3A, DNMT3B, and methylenetetrahydrofolate reductase (MTHFR), moderate emotional responses to stressful and pleasant stimuli in daily life as measured by Experience Sampling Methodology (ESM). In the first step, main and interactive effects were tested in a sample of 112 healthy individuals. Significant associations in this discovery sample were then investigated in a population-based sample of 434 individuals for replication. SNPs showing significant effects in both the discovery and replication samples were subsequently tested in three other samples of: (i) 85 unaffected siblings of patients with psychosis, (ii) 110 patients with psychotic disorders, and iii) 126 patients with a history of major depressive disorder. Multilevel linear regression analyses showed no significant association between SNPs and negative affect or positive affect. No SNPs moderated the effect of pleasant stimuli on positive affect. Three SNPs of DNMT3A (rs11683424, rs1465764, rs1465825) and 1 SNP of MTHFR (rs1801131) moderated the effect of stressful events on negative affect. Only rs11683424 of DNMT3A showed consistent directions of effect in the majority of the 5 samples. These data provide the first evidence that emotional responses to daily life stressors may be moderated by genetic variation in the genes involved in the epigenetic machinery.}, language = {en} } @article{ReschkeSalvadorSchlegeletal.2022, author = {Reschke, Moritz and Salvador, Ellaine and Schlegel, Nicolas and Burek, Malgorzata and Karnati, Srikanth and Wunder, Christian and F{\"o}rster, Carola Y.}, title = {Isosteviol sodium (STVNA) reduces pro-inflammatory cytokine IL-6 and GM-CSF in an in vitro murine stroke model of the blood-brain barrier (BBB)}, series = {Pharmaceutics}, volume = {14}, journal = {Pharmaceutics}, number = {9}, issn = {1999-4923}, doi = {10.3390/pharmaceutics14091753}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286275}, year = {2022}, abstract = {Early treatment with glucocorticoids could help reduce both cytotoxic and vasogenic edema, leading to improved clinical outcome after stroke. In our previous study, isosteviol sodium (STVNA) demonstrated neuroprotective effects in an in vitro stroke model, which utilizes oxygen-glucose deprivation (OGD). Herein, we tested the hypothesis that STVNA can activate glucocorticoid receptor (GR) transcriptional activity in brain microvascular endothelial cells (BMECs) as previously published for T cells. STVNA exhibited no effects on transcriptional activation of the glucocorticoid receptor, contrary to previous reports in Jurkat cells. However, similar to dexamethasone, STVNA inhibited inflammatory marker IL-6 as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. Based on these results, STVNA proves to be beneficial as a possible prevention and treatment modality for brain ischemia-reperfusion injury-induced blood-brain barrier (BBB) dysfunction.}, language = {en} } @article{SalvadorShityakovFoerster2013, author = {Salvador, Ellaine and Shityakov, Sergey and F{\"o}rster, Carola}, title = {Glucocorticoids and endothelial cell barrier function}, series = {Cell and Tissue Research}, volume = {355}, journal = {Cell and Tissue Research}, number = {3}, doi = {10.1007/s00441-013-1762-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132091}, pages = {597-605}, year = {2013}, abstract = {Glucocorticoids (GCs) are steroid hormones that have inflammatory and immunosuppressive effects on a wide variety of cells. They are used as therapy for inflammatory disease and as a common agent against edema. The blood brain barrier (BBB), comprising microvascular endothelial cells, serves as a permeability screen between the blood and the brain. As such, it maintains homeostasis of the central nervous system (CNS). In many CNS disorders, BBB integrity is compromised. GC treatment has been demonstrated to improve the tightness of the BBB. The responses and effects of GCs are mediated by the ubiquitous GC receptor (GR). Ligand-bound GR recognizes and binds to the GC response element located within the promoter region of target genes. Transactivation of certain target genes leads to improved barrier properties of endothelial cells. In this review, we deal with the role of GCs in endothelial cell barrier function. First, we describe the mechanisms of GC action at the molecular level. Next, we discuss the regulation of the BBB by GCs, with emphasis on genes targeted by GCs such as occludin, claudins and VE-cadherin. Finally, we present currently available GC therapeutic strategies and their limitations.}, language = {en} } @article{TeloracPrykhozhijSchoeneetal.2016, author = {Telorac, Jonas and Prykhozhij, Sergey V. and Sch{\"o}ne, Stefanie and Meierhofer, David and Sauer, Sascha and Thomas-Chollier, Morgane and Meijsing, Sebastiaan H.}, title = {Identification and characterization of DNA sequences that prevent glucocorticoid receptor binding to nearby response elements}, series = {Nucleic Acids Research}, volume = {44}, journal = {Nucleic Acids Research}, number = {13}, doi = {10.1093/nar/gkw203}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166330}, pages = {6142-6156}, year = {2016}, abstract = {Out of the myriad of potential DNA binding sites of the glucocorticoid receptor (GR) found in the human genome, only a cell-type specific minority is actually bound, indicating that the presence of a recognition sequence alone is insufficient to specify where GR binds. Cooperative interactions with other transcription factors (TFs) are known to contribute to binding specificity. Here, we reasoned that sequence signals preventing GR recruitment to certain loci provide an alternative means to confer specificity. Motif analyses uncovered candidate Negative Regulatory Sequences (NRSs) that interfere with genomic GR binding. Subsequent functional analyses demonstrated that NRSs indeed prevent GR binding to nearby response elements. We show that NRS activity is conserved across species, found in most tissues and that they also interfere with the genomic binding of other TFs. Interestingly, the effects of NRSs appear not to be a simple consequence of changes in chromatin accessibility. Instead, we find that NRSs interact with proteins found at sub-nuclear structures called paraspeckles and that these proteins might mediate the repressive effects of NRSs. Together, our studies suggest that the joint influence of positive and negative sequence signals partition the genome into regions where GR can bind and those where it cannot.}, language = {en} } @article{WiechmannRoehSaueretal.2019, author = {Wiechmann, Tobias and R{\"o}h, Simone and Sauer, Susann and Czamara, Darina and Arloth, Janine and K{\"o}del, Maik and Beintner, Madita and Knop, Lisanne and Menke, Andreas and Binder, Elisabeth B. and Proven{\c{c}}al, Nadine}, title = {Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus}, series = {Clinical Epigenetics}, volume = {11}, journal = {Clinical Epigenetics}, doi = {10.1186/s13148-019-0682-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233673}, year = {2019}, abstract = {Background Epigenetic mechanisms may play a major role in the biological embedding of early-life stress (ELS). One proposed mechanism is that glucocorticoid (GC) release following ELS exposure induces long-lasting alterations in DNA methylation (DNAm) of important regulatory genes of the stress response. Here, we investigate the dynamics of GC-dependent methylation changes in key regulatory regions of the FKBP5 locus in which ELS-associated DNAm changes have been reported. Results We repeatedly measured DNAm in human peripheral blood samples from 2 independent cohorts exposed to the GC agonist dexamethasone (DEX) using a targeted bisulfite sequencing approach, complemented by data from Illumina 450K arrays. We detected differentially methylated CpGs in enhancers co-localizing with GC receptor binding sites after acute DEX treatment (1 h, 3 h, 6 h), which returned to baseline levels within 23 h. These changes withstood correction for immune cell count differences. While we observed main effects of sex, age, body mass index, smoking, and depression symptoms on FKBP5 methylation levels, only the functional FKBP5 SNP (rs1360780) moderated the dynamic changes following DEX. This genotype effect was observed in both cohorts and included sites previously shown to be associated with ELS. Conclusion Our study highlights that DNAm levels within regulatory regions of the FKBP5 locus show dynamic changes following a GC challenge and suggest that factors influencing the dynamics of this regulation may contribute to the previously reported alterations in DNAm associated with current and past ELS exposure.}, language = {en} }