Control of the Blood–Brain Barrier by Glucocorticoids and the Cells of the Neurovascular Unit

Abstract

The blood-brain barrier is built up by endothelial cells lining the cerebral capillaries whereby the physical diffusion barrier is formed by tight junctions sealing the intercellular clefts. Chemical factors being released endogenously to the blood stream may regulate the barrier tightness. However, since tight junctions of the cerebral capillaries are more complex compared to those of other vessels, it becomes evident that the cells of the neurovascular unit play an important role in the induction and the maintenance of the barrier properties. Astrocytes and pericytes interact with the endothelial cells whereby the contact zone is built up by the extracellular matrix. Thus, in addition to chemical mediators released from either cells of the cerebrovascular unit leading to a crosstalk between those cells, the presence of given molecules of the extracellular matrix and also their assembly have to be considered in the transfer of signals able to induce or modulate the barrier. Here we report and summarize recent evidence that external factors like glucocorticoids act in concert with astroyctes in a co-culture system of primary porcine endothelial cells with astrocytes, but only if astrocytes are able to contact the endothelial cells. Moreover, evidence will be given to show that astrocytic and also the pericytic extracellular matrix produced by those cells are able to induce the barrier by an upregulation of the tight junction proteins occludin, claudin-5 and ZO-1, both on mRNA and at the protein level.

Maternal glucocorticoid exposure alters tight junction protein expression in the brain of fetal sheep

“…Furthermore, maternal treatment with glucocorticoids at 70% gestation results in decreases in barrier permeability in fetuses of ewes after both single and multiple courses of glucocorticoids, but treatment with multiple courses does not accentuate the decreases in permeability observed after the single course of treatment (39). The site of action of glucocorticoids on the blood-brain barrier in the fetus (39,44,45 (17), occludin and claudin-5 (but not claudin-1) in a human immortalized model of the blood-brain barrier (16), and occludin, claudin-5, and ZO-1 in primary cultures of porcine brain capillary endothelial cells (29). In addition, glucocorticoid-related increases in TJ protein expression are associated with increases in transendothelial electrical resistance and decreases in paracellular permeability in vitro (16,17,29,36).…”

“…The site of action of glucocorticoids on the blood-brain barrier in the fetus (39,44,45 (17), occludin and claudin-5 (but not claudin-1) in a human immortalized model of the blood-brain barrier (16), and occludin, claudin-5, and ZO-1 in primary cultures of porcine brain capillary endothelial cells (29). In addition, glucocorticoid-related increases in TJ protein expression are associated with increases in transendothelial electrical resistance and decreases in paracellular permeability in vitro (16,17,29,36). Furthermore, in vivo treatment of adult mice with dexamethasone for 4 days resulted in increased occludin immunostaining that was specific to the brain endothelium (18).…”

Effects of prednisolone on the dystrophin-associated proteins in the blood–brain barrier and skeletal muscle of dystrophic mdx mice

“…In fact, binding of the activated glucocorticoid receptor to putative glucocorticoid-responsive elements in the occludin promoter has been described. 38,59,60 Dexamethasone prevents alteration of TJ-associated proteins in bacterially infected epithelial choroidal cells by restoring the occludin phosphorylation degree via attenuation of ERK activation and MMP-3 expression. 61 It is noteworthy that the inhibition of the ERK pathways blocks the production of MMPs, which in Prednisolone in mdx mice R Tamma et al turn cleave occludin in the epithelial cells after induced apoptosis.…”

“…Because of this finding, our results suggest a role for these two types of cells in glucorticoid responsiveness in the brain. 60 AQP4 is important for the integrity of BBB function, and its expression on the perivascular glial endfeet is altered in pathological brain conditions. [68][69][70] AQP4 is dynamically regulated in different ways.…”

Impact of Manganese on and Transfer across Blood-Brain and Blood-Cerebrospinal Fluid Barrier in Vitro

“…BBB Co-culture Model-A co-culture model of PBCECs and CCF-STTG1 was used as described previously (23). CCF-STTG1 (CCL-1718 TM , American Type Culture Collection) cells were cultured in RPMI 1640 medium (Biochrom) containing 10% FBS (PAA Laboratories, Pasching, Austria), 1.4 mM L-glutamine (Biochrom), 100 units of penicillin/ml and 100 g of streptomycin/ml (PAA Laboratories) at 37°C with 5% CO 2 and 100% humidity.…”