scholarly journals A circadian clock regulates efflux by the blood-brain barrier in mice and human cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shirley L. Zhang ◽  
Nicholas F. Lahens ◽  
Zhifeng Yue ◽  
Denice M. Arnold ◽  
Peter P. Pakstis ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Blood Brain Barrier ◽  
Active Phase ◽  
Brain Barrier ◽  
Microvascular Endothelial Cell ◽  
Circadian Regulation ◽  
Neural Function ◽  
Regulation Of Transcription ◽  
Intracellular Magnesium ◽  
Blood Brain

AbstractThe blood-brain barrier (BBB) is critical for neural function. We report here circadian regulation of the BBB in mammals. Efflux of xenobiotics by the BBB oscillates in mice, with highest levels during the active phase and lowest during the resting phase. This oscillation is abrogated in circadian clock mutants. To elucidate mechanisms of circadian regulation, we profiled the transcriptome of brain endothelial cells; interestingly, we detected limited circadian regulation of transcription, with no evident oscillations in efflux transporters. We recapitulated the cycling of xenobiotic efflux using a human microvascular endothelial cell line to find that the molecular clock drives cycling of intracellular magnesium through transcriptional regulation of TRPM7, which appears to contribute to the rhythm in efflux. Our findings suggest that considering circadian regulation may be important when therapeutically targeting efflux transporter substrates to the CNS.

scholarly journals A circadian clock in the blood-brain barrier regulates xenobiotic efflux from the brain

2017 ◽  
Author(s):  
Shirley L. Zhang ◽  
Zhifeng Yue ◽  
Denice M. Arnold ◽  
Amita Sehgal
Keyword(s):  
Gap Junctions ◽  
Blood Brain Barrier ◽  
Time Of Day ◽  
Brain Barrier ◽  
Circadian Regulation ◽  
List Type ◽  
Intracellular Magnesium ◽  
Therapeutic Implications ◽  
Blood Brain ◽  
The Central Nervous System

HighlightsThe Drosophila BBB displays a circadian rhythm of permeabilityCyclic efflux driven by a clock in the BBB underlies the permeability rhythmCircadian control is non-cell-autonomous via gap junction regulation of [Mg2+]iAn anti-seizure drug is more effective when administered at nightSummaryEndogenous circadian rhythms are thought to modulate responses to external factors, but mechanisms that confer time-of-day differences in organismal responses to environmental insults / therapeutic treatments are poorly understood. Using a xenobiotic, we find that permeability of the Drosophila “blood”-brain barrier (BBB) is higher at night. The permeability rhythm is driven by circadian regulation of efflux and depends upon a molecular clock in the perineurial glia of the BBB, although efflux transporters are restricted to subperineurial glia (SPG). We show that transmission of circadian signals across the layers requires gap junctions, which are expressed cyclically. Specifically, during nighttime gap junctions reduce intracellular magnesium ([Mg2+]i), a positive regulator of efflux, in SPG. Consistent with lower nighttime efflux, nighttime administration of the anti-epileptic phenytoin is more effective at treating a Drosophila seizure model. These findings identify a novel mechanism of circadian regulation and have therapeutic implications for drugs targeted to the central nervous system.

scholarly journals Blood-Brain Barrier and Exercise – a Short Review

2008 ◽  
Vol 19 (1) ◽  
pp. 83-92 ◽  
Author(s):  
Katarzyna Nierwińska ◽  
Elżbieta Malecka ◽  
Małgorzata Chalimoniuk ◽  
Aleksandra Żebrowska ◽  
Józef Langfort
Keyword(s):  
Blood Brain Barrier ◽  
Brain Injuries ◽  
Marked Change ◽  
Short Review ◽  
Brain Barrier ◽  
Neural Function ◽  
Normal Brain ◽  
Cns Injury ◽  
Blood Brain ◽  
Bbb Permeability

Blood-Brain Barrier and Exercise – a Short ReviewBlood-brain barier (BBB) segregates central nervous system (CNS) from the circulating blood. BBB is formed by the brain capillary endothelial cells with complex tight junctions between them as well as by astrocytes and pericytes. BBB is responsible for transport of selected chemicals into and out of the CNS as well as for its protection from fluctuations in plasma composition following meals, during exercise and from circulating agents such as neurotransmitters, xenobiotics and other potentially harmful substances capable to disturb neural function. BBB may be compromised during CNS injury, infection, fever and in some nerodegenerative diseases. The increase of BBB permeability was observed also during exercise as documented by changes of plasma S-100 protein levels, used as a peripheral marker of BBB integrity. Marked change in BBB integrity during exercise may disturb normal brain function and contribute to the development of central fatigue. Moreover, serum S-100β may indicate level of injury in individuals suffering brain injuries during sports. There are also data suggesting that acute effect of physical exercise on serum S100β levels may not be related with CNS injury. Further studies to establish whether training and which type of it may modulate BBB permeability are needed.

scholarly journals Human Brain Endothelial CXCR2 is Inflammation-Inducible and Mediates CXCL5- and CXCL8-Triggered Paraendothelial Barrier Breakdown

2019 ◽  
Vol 20 (3) ◽  
pp. 602 ◽  
Author(s):  
Axel Haarmann ◽  
Michael Schuhmann ◽  
Christine Silwedel ◽  
Camelia-Maria Monoranu ◽  
Guido Stoll ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Tight Junction ◽  
Human Brain ◽  
Blood Brain Barrier ◽  
Barrier Function ◽  
Morphological Changes ◽  
Brain Barrier ◽  
Microvascular Endothelial Cell ◽  
Inflammatory Conditions ◽  
Blood Brain

Chemokines (C-X-C) motif ligand (CXCL) 5 and 8 are overexpressed in patients with multiple sclerosis, where CXCL5 serum levels were shown to correlate with blood–brain barrier dysfunction as evidenced by gadolinium-enhanced magnetic resonance imaging. Here, we studied the potential role of CXCL5/CXCL8 receptor 2 (CXCR2) as a regulator of paraendothelial brain barrier function, using the well-characterized human cerebral microvascular endothelial cell line hCMEC/D3. Low basal CXCR2 mRNA and protein expression levels in hCMEC/D3 were found to strongly increase under inflammatory conditions. Correspondingly, immunohistochemistry of brain biopsies from two patients with active multiple sclerosis revealed upregulation of endothelial CXCR2 compared to healthy control tissue. Recombinant CXCL5 or CXCL8 rapidly and transiently activated Akt/protein kinase B in hCMEC/D3. This was followed by a redistribution of tight junction-associated protein zonula occludens-1 (ZO-1) and by the formation of actin stress fibers. Functionally, these morphological changes corresponded to a decrease of paracellular barrier function, as measured by a real-time electrical impedance-sensing system. Importantly, preincubation with the selective CXCR2 antagonist SB332235 partially prevented chemokine-induced disturbance of both tight junction morphology and function. We conclude that human brain endothelial CXCR2 may contribute to blood–brain barrier disturbance under inflammatory conditions with increased CXCL5 and CXCL8 expression, where CXCR2 may also represent a novel pharmacological target for blood–brain barrier stabilization.

scholarly journals Effect of heat stress on blood-brain barrier integrity in iPS cell-derived microvascular endothelial cell models

PLoS ONE ◽  
2019 ◽  
Vol 14 (9) ◽  
pp. e0222113 ◽  
Author(s):  
Tomoko Yamaguchi ◽  
Kentaro Shimizu ◽  
Yasuhiro Kokubu ◽  
Misae Nishijima ◽  
Shuko Takeda ◽  
...  
Keyword(s):  
Heat Stress ◽  
Endothelial Cell ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Microvascular Endothelial Cell ◽  
Cell Models ◽  
Ips Cell ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Blood Brain Barrier Integrity

scholarly journals The Role of Brain Microvascular Endothelial Cell and Blood-Brain Barrier Dysfunction in Schizophrenia

2020 ◽  
Vol 6 (1-2) ◽  
pp. 30-46
Author(s):  
Sovannarath Pong ◽  
Rakesh Karmacharya ◽  
Marianna Sofman ◽  
Jeffrey R. Bishop ◽  
Paulo Lizano
Keyword(s):  
Blood Brain Barrier ◽  
Association Studies ◽  
Central Element ◽  
Brain Barrier ◽  
Microvascular Endothelial Cell ◽  
Genome Wide Association Studies ◽  
Barrier Dysfunction ◽  
Blood Brain ◽  
Microvascular Endothelial

Background: Despite decades of research, little clarity exists regarding pathogenic mechanisms related to schizophrenia. Investigations on the disease biology of schizophrenia have primarily focused on neuronal alterations. However, there is substantial evidence pointing to a significant role for the brain’s microvasculature in mediating neuroinflammation in schizophrenia. Summary: Brain microvascular endothelial cells (BMEC) are a central element of the microvasculature that forms the blood-brain barrier (BBB) and shields the brain against toxins and immune cells via paracellular, transcellular, transporter, and extracellular matrix proteins. While evidence for BBB dysfunction exists in brain disorders, including schizophrenia, it is not known if BMEC themselves are functionally compromised and lead to BBB dysfunction. Key Messages: Genome-wide association studies, postmortem investigations, and gene expression analyses have provided some insights into the role of the BBB in schizophrenia pathophysiology. However, there is a significant gap in our understanding of the role that BMEC play in BBB dysfunction. Recent advances differentiating human BMEC from induced pluripotent stem cells (iPSC) provide new avenues to examine the role of BMEC in BBB dysfunction in schizophrenia.

High glucose-induced effects on Na+-K+-Cl- cotransport and Na+/H+ exchange of blood-brain barrier endothelial cells: involvement of SGK1, PKCβII and SPAK/OSR1

2021 ◽  
Author(s):  
Nicholas R. Klug ◽  
Olga V. Chechneva ◽  
Benjamin Y. Hung ◽  
Martha E. O'Donnell
Keyword(s):  
Blood Brain Barrier ◽  
High Glucose ◽  
Artery Occlusion ◽  
Brain Barrier ◽  
Microvascular Endothelial Cell ◽  
Edema Formation ◽  
Kinase C ◽  
Blood Brain ◽  
Transport Of Ions ◽  
Cerebral Artery Occlusion

Hyperglycemia exacerbates edema formation and worsens neurological outcome in ischemic stroke. Edema formation in the early hours of stroke involves transport of ions and water across an intact blood-brain barrier (BBB), and swelling of astrocytes. We showed previously that high glucose (HG) exposures of 24 hours to 7 days increase abundance and activity of BBB Na+-K+-2Cl- cotransport (NKCC) and Na+/H+ exchange 1 (NHE1). Further, bumetanide and HOE-642 inhibition of these transporters significantly reduces edema and infarct following middle cerebral artery occlusion in hyperglycemic rats, suggesting that NKCC and NHE1 are effective therapeutic targets for reducing edema in hyperglycemic stroke. The mechanisms underlying hyperglycemia effects on BBB NKCC and NHE1 are not known. In the present study we investigated whether serum-glucocorticoid regulated kinase 1 (SGK1) and protein kinase C beta II (PKCβII) are involved in HG effects on BBB NKCC and NHE1. We found transient increases in phosphorylated SGK1 and PKCβII within the first hour of HG exposure, after 5-60 min for SGK1 and 5 min for PKCβII. However, no changes were observed in cerebral microvascular endothelial cell SGK1 or PKCβII abundance or phosphorylation (activity) after 24 or 48 hr HG exposures. Further, we found that HG-induced increases in NKCC and NHE1 abundance were abolished by inhibition of SGK1 but not PKCβII, whereas the increases in NKCC and NHE activity were abolished by inhibition of either kinase. Finally, we found evidence that STE20/SPS1-related proline/alanine-rich kinase and oxidative stress-responsive kinase-1 (SPAK/OSR1) participate in the HG-induced effects on BBB NKCC.

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