@article{NeuhausSchlundtFehrholzetal.2015,
  author    = {Neuhaus, Winfried and Schlundt, Marian and Fehrholz, Markus and Ehrke, Alexander and Kunzmann, Steffen and Liebner, Stefan and Speer, Christian P. and F{\"o}rster, Carola Y.},
  title     = {Multiple Antenatal Dexamethasone Treatment Alters Brain Vessel Differentiation in Newborn Mouse Pups},
  series = {PLoS One},
  volume    = {10},
  journal   = {PLoS One},
  number    = {8},
  doi       = {10.1371/journal.pone.0136221},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125471},
  pages     = {e0136221},
  year      = {2015},
  abstract  = {Antenatal steroid treatment decreases morbidity and mortality in premature infants through the maturation of lung tissue, which enables sufficient breathing performance. However, clinical and animal studies have shown that repeated doses of glucocorticoids such as dexamethasone and betamethasone lead to long-term adverse effects on brain development. Therefore, we established a mouse model for antenatal dexamethasone treatment to investigate the effects of dexamethasone on brain vessel differentiation towards the blood-brain barrier (BBB) phenotype, focusing on molecular marker analysis. The major findings were that in total brains on postnatal day (PN) 4 triple antenatal dexamethasone treatment significantly downregulated the tight junction protein claudin-5, the endothelial marker Pecam-1/CD31, the glucocorticoid receptor, the NR1 subunit of the N-methyl-D-aspartate receptor, and Abc transporters (Abcb1a, Abcg2 Abcc4). Less pronounced effects were found after single antenatal dexamethasone treatment and in PN10 samples. Comparisons of total brain samples with isolated brain endothelial cells together with the stainings for Pecam-1/CD31 and claudin-5 led to the assumption that the morphology of brain vessels is affected by antenatal dexamethasone treatment at PN4. On the mRNA level markers for angiogenesis, the sonic hedgehog and the Wnt pathway were downregulated in PN4 samples, suggesting fundamental changes in brain vascularization and/or differentiation. In conclusion, we provided a first comprehensive molecular basis for the adverse effects of multiple antenatal dexamethasone treatment on brain vessel differentiation.},
  language  = {en}
}
@article{ShityakovFoerster2014,
  author    = {Shityakov, Sergey and F{\"o}rster, Carola},
  title     = {In silico predictive model to determine vector-mediated transport properties for the blood-brain barrier choline transporter},
  series = {Advances and Applications in Bioinformatics and Chemistry},
  volume    = {7},
  journal   = {Advances and Applications in Bioinformatics and Chemistry},
  doi       = {10.2147/AABC.S63749},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120200},
  pages     = {23-36},
  year      = {2014},
  abstract  = {The blood-brain barrier choline transporter (BBB-ChT) may have utility as a drug delivery vector to the central nervous system (CNS). We therefore initiated molecular docking studies with the AutoDock and AutoDock Vina (ADVina) algorithms to develop predictive models for compound screening and to identify structural features important for binding to this transporter. The binding energy predictions were highly correlated with r2=0.88, F=692.4, standard error of estimate =0.775, and P-value<0.0001 for selected BBB-ChT-active/inactive compounds (n=93). Both programs were able to cluster active (Gibbs free energy of binding <-6.0 kcal*mol-1) and inactive (Gibbs free energy of binding >-6.0 kcal*mol-1) molecules and dock them significantly better than at random with an area under the curve value of 0.86 and 0.84, respectively. In ranking smaller molecules with few torsional bonds, a size-related bias in scoring producing false-negative outcomes was detected. Finally, important blood-brain barrier parameters, such as the logBBpassive and logBBactive values, were assessed to predict compound transport to the CNS accurately. Knowledge gained from this study is useful to better understand the binding requirements in BBB-ChT, and until such time as its crystal structure becomes available, it may have significant utility in developing a highly predictive model for the rational design of drug-like compounds targeted to the brain.},
  language  = {en}
}
@article{RosenbaumSchickWollbornetal.2016,
  author    = {Rosenbaum, Corinna and Schick, Martin Alexander and Wollborn, Jakob and Heider, Andreas and Scholz, Claus-J{\"u}rgen and Cecil, Alexander and Niesler, Beate and Hirrlinger, Johannes and Walles, Heike and Metzger, Marco},
  title     = {Activation of Myenteric Glia during Acute Inflammation In Vitro and In Vivo},
  series = {PLoS One},
  volume    = {11},
  journal   = {PLoS One},
  number    = {3},
  doi       = {10.1371/journal.pone.0151335},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146544},
  pages     = {e0151335},
  year      = {2016},
  abstract  = {Background Enteric glial cells (EGCs) are the main constituent of the enteric nervous system and share similarities with astrocytes from the central nervous system including their reactivity to an inflammatory microenvironment. Previous studies on EGC pathophysiology have specifically focused on mucosal glia activation and its contribution to mucosal inflammatory processes observed in the gut of inflammatory bowel disease (IBD) patients. In contrast knowledge is scarce on intestinal inflammation not locally restricted to the mucosa but systemically affecting the intestine and its effect on the overall EGC network. Methods and Results In this study, we analyzed the biological effects of a systemic LPS-induced hyperinflammatory insult on overall EGCs in a rat model in vivo, mimicking the clinical situation of systemic inflammation response syndrome (SIRS). Tissues from small and large intestine were removed 4 hours after systemic LPS-injection and analyzed on transcript and protein level. Laser capture microdissection was performed to study plexus-specific gene expression alterations. Upon systemic LPS-injection in vivo we observed a rapid and dramatic activation of Glial Fibrillary Acidic Protein (GFAP)-expressing glia on mRNA level, locally restricted to the myenteric plexus. To study the specific role of the GFAP subpopulation, we established flow cytometry-purified primary glial cell cultures from GFAP promotor-driven EGFP reporter mice. After LPS stimulation, we analyzed cytokine secretion and global gene expression profiles, which were finally implemented in a bioinformatic comparative transcriptome analysis. Enriched GFAP+ glial cells cultured as gliospheres secreted increased levels of prominent inflammatory cytokines upon LPS stimulation. Additionally, a shift in myenteric glial gene expression profile was induced that predominantly affected genes associated with immune response. Conclusion and Significance Our findings identify the myenteric GFAP-expressing glial subpopulation as particularly susceptible and responsive to acute systemic inflammation of the gut wall and complement knowledge on glial involvement in mucosal inflammation of the intestine.},
  language  = {en}
}