Evaluation of Soluble Junctional Adhesion Molecule-A as a Biomarker of Human Brain Endothelial Barrier Breakdown

Haarmann, Axel; Deiß, Annika; Prochaska, Jürgen H.; Foerch, Christian; Weksler, Babette B.; Romero, Ignacio A.; Couraud, Pierre‐Olivier; Stoll, Guido; Rieckmann, Peter; Buttmann, Mathias

doi:10.1371/journal.pone.0013568

Cited by 39 publications

(35 citation statements)

References 42 publications

(70 reference statements)

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“…JAM-1 is believed to mediate early attachment of adjacent endothelial cells during BBB development through homophilic interactions and loss of JAMs is associated with BBB breakdown (19-22). For example, studies in an immortalized human brain endothelial cell line (hCMEC/d3) showed that inflammatory stimuli triggered movement of JAM away from the TJ, an observation that directly correlated with increased dextran leak across the BBB (23). Of particular note, JAMs are also implicated in the regulation of transendothelial migration of leukocytes (20, 24).…”

Section: Components Of the Nvumentioning

confidence: 99%

Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

Sanchez-Covarrubias¹,

Slosky²,

Thompson³

et al. 2014

CPD

200

137

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The blood-brain barrier (BBB) and blood-cerebrospinal fluid (BCSF) barriers are critical determinants of CNS homeostasis. Additionally, the BBB and BCSF barriers are formidable obstacles to effective CNS drug delivery. These brain barrier sites express putative influx and efflux transporters that precisely control permeation of circulating solutes including drugs. The study of transporters has enabled a shift away from “brute force” approaches to delivering drugs by physically circumventing brain barriers towards chemical approaches that can target specific compounds of the BBB and/or BCSF barrier. However, our understanding of transporters at the BBB and BCSF barriers has primarily focused on understanding efflux transporters that efficiently prevent drugs from attaining therapeutic concentrations in the CNS. Recently, through the characterization of multiple endogenously expressed uptake transporters, this paradigm has shifted to the study of brain transporter targets that can facilitate drug delivery (i.e., influx transporters). Additionally, signaling pathways and trafficking mechanisms have been identified for several endogenous BBB/BCSF transporters, thereby offering even more opportunities to understand how transporters can be exploited for optimization of CNS drug delivery. This review presents an overview of the BBB and BCSF barrier as well as the many families of transporters functionally expressed at these barrier sites. Furthermore, we present an overview of various strategies that have been designed and utilized to deliver therapeutic agents to the brain with a particular emphasis on those approaches that directly target endogenous BBB/BCSF barrier transporters.

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Section: Components Of the Nvumentioning

confidence: 99%

Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

Sanchez-Covarrubias¹,

Slosky²,

Thompson³

et al. 2014

CPD

200

137

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“…One was a human brain microvascular endothelial cell line which was established as a model for the blood brain barrier (BBB) [13][14][15]. These cells are stitched together by tight junctions that are composed of several transmembrane proteins forming a complex BBB [16][17][18].…”

Section: Methodsmentioning

confidence: 99%

Ultrasound fails to induce proliferation of human brain and mouse endothelial cell lines

Rodemer¹,

Jenne²,

Fatar³

et al. 2012

AIP Conference Proceedings

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Abstract. Both in vitro and in vivo studies suggest that ultrasound (US) is capable of inducing angiogenesis. There is no information, however, on whether ultrasound can induce proliferation of brain endothelial cells. We therefore explored the angiogenic potential of ultrasound on a novel immortalised human brain endothelial cell line (hCMEC/D3) and on mouse brain microvascular endothelial cells (bEND3). Ultrasound failed to enhance cell proliferation in both cell lines at all acoustic pressures studied. Endothelial cell damage occurred at 0.24 MPa with significantly slower proliferation. Cells growing in Opticell™ dishes did not show damage or reduced proliferation at these pressures.

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“…Additionally, loss of JAM protein expression is directly correlated with BBB disruption and injury (Yeung et al 2008; Hoffman et al 2009; Wang et al 2014). Additionally, studies in an immortalized human brain endothelial cell line (hCMEC/d3) showed that inflammatory stimulation led to increased paracellular solute diffusion, which correlated with JAM movement away from the tight junction, further suggesting a central role in maintaining BBB integrity (Haarmann et al 2010). …”

Section: The Blood-brain Barriermentioning

confidence: 99%

Targeting transporters: Promoting blood–brain barrier repair in response to oxidative stress injury

Ronaldson

Davis

2015

Brain Research

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The blood-brain barrier (BBB) is a physical and biochemical barrier that precisely regulates the ability of endogenous and exogenous substances to accumulate within brain tissue. It possesses structural and biochemical features (i.e., tight junction and adherens junction protein complexes, influx and efflux transporters) that work in concert to control solute permeation. Oxidative stress, a critical component of several diseases including cerebral hypoxia/ischemia and peripheral inflammatory pain, can cause considerable injury to the BBB and lead to significant CNS pathology. This suggests a critical need for novel therapeutic approaches that can protect the BBB in diseases with an oxidative stress component. Recent studies have identified molecular targets (i.e., endogenous transporters, intracellular signaling systems) that can be exploited for optimization of endothelial drug delivery or for control of transport of endogenous substrates such as the antioxidant glutathione (GSH). In particular, targeting transporters offers a unique approach to protect BBB integrity by promoting repair of cell-cell interactions at the level of the brain microvascular endothelium. This review summarizes current knowledge in this area and emphasizes those targets that present considerable opportunity for providing BBB protection and/or promoting BBB repair in the setting of oxidative stress.

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Evaluation of Soluble Junctional Adhesion Molecule-A as a Biomarker of Human Brain Endothelial Barrier Breakdown

Cited by 39 publications

References 42 publications

Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

Ultrasound fails to induce proliferation of human brain and mouse endothelial cell lines

Targeting transporters: Promoting blood–brain barrier repair in response to oxidative stress injury

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