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Leiden, Netherlands

Mizee M.R.,VU University Amsterdam | Nijland P.G.,VU University Amsterdam | van der Pol S.M.A.,VU University Amsterdam | Drexhage J.A.R.,VU University Amsterdam | And 6 more authors.
Acta Neuropathologica | Year: 2014

Multiple sclerosis (MS) lesions are characterized by the presence of activated astrocytes, which are thought to actively take part in propagating lesion progression by secreting pro-inflammatory mediators. Conversely, reactive astrocytes may exert disease-dampening effects through the production of trophic factors and anti-inflammatory mediators. Astrocytic control of the blood–brain barrier (BBB) is crucial for normal brain homeostasis and BBB disruption is a well-established early event in MS lesion development. Here, we set out to unravel potential protective effects of reactive astrocytes on BBB function under neuroinflammatory conditions as seen in MS, where we focus on the role of the brain morphogen retinoic acid (RA). Immunohistochemical analysis revealed that retinaldehyde dehydrogenase 2 (RALDH2), a key enzyme for RA synthesis, is highly expressed by reactive astrocytes throughout white matter lesions compared to control and normal appearing white matter. In vitro modeling of reactive astrocytes resulted in increased expression of RALDH2, enhanced RA synthesis, and a protective role for astrocyte-derived RA on BBB function during inflammation-induced barrier loss. Furthermore, RA induces endothelial immune quiescence and decreases monocyte adhesion under inflammatory conditions. Finally, we demonstrated that RA attenuated oxidative stress in inflamed endothelial cells, through activation of the antioxidant transcription factor nuclear factor E2 related factor 2. In summary, RA synthesis by reactive astrocytes represents an endogenous protective response to neuroinflammation, possibly aimed at protecting the BBB against inflammatory insult. A better understanding of RA signaling in MS pathophysiology may lead to the discovery of novel targets to halt disease progression. © 2014, Springer-Verlag Berlin Heidelberg. Source

Lopez-Ramirez M.A.,Open University Milton Keynes | Lopez-Ramirez M.A.,Yale University | Wu D.,Open University Milton Keynes | Pryce G.,Queen Mary, University of London | And 12 more authors.
FASEB Journal | Year: 2014

Blood-brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuroinflammation at the BBB. miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis (EAE). In mice, loss of miR-155 reduced CNS extravasation of systemic tracers, both in EAE and in an acute systemic inflammation model induced by lipopolysaccharide. In cultured human brain endothelium, miR-155 was strongly and rapidly upregulated by inflammatory cytokines. miR-155 up-regulation mimicked cytokine-induced alterations in junctional organization and permeability, whereas inhibition of endogenous miR-155 partially prevented a cytokine-induced increase in permeability. Furthermore, miR-155 modulated brain endothelial barrier function by targeting not only cell-cell complex molecules such as annexin-2 and claudin-1, but also focal adhesion components such as DOCK-1 and syntenin-1. We propose that brain endothelial miR-155 is a negative regulator of BBB function that may constitute a novel therapeutic target for CNS neuroinflammatory disorders. © FASEB. Source

Wisniewska-Kruk J.,University of Amsterdam | Hoeben K.A.,University of Amsterdam | Vogels I.M.C.,University of Amsterdam | Gaillard P.J.,To BBB Technologies BV | And 4 more authors.
Experimental Eye Research | Year: 2012

Loss of blood-retinal barrier (BRB) properties is an important feature in the pathology of diabetic macular edema (DME), but cellular mechanisms underlying BRB dysfunction are poorly understood. Therefore, we developed and characterized a novel in vitro BRB model, based on primary bovine retinal endothelial cells (BRECs). These cells were shown to maintain specific in vivo BRB properties by expressing high levels of the endothelial junction proteins occludin, claudin-5, VE-cadherin and ZO-1 at cell borders, and the specific pumps glucose transporter-1 (GLUT1) and efflux transporter P-glycoprotein (MDR1). To investigate the influence of pericytes and astrocytes on BRB maintenance in vitro, we compared five different co-culture BRB models, based on BRECs, bovine retinal pericytes (BRPCs) and rat glial cells. Co-cultures of BRECs with BRPCs and glial cells showed the highest trans-endothelial resistance (TEER) as well as decreased permeability of tracers after vascular endothelial growth factor (VEGF) stimulation, suggesting a major role for these cell types in maintaining barrier properties. To mimic the in vivo situation of DME, we stimulated BRECs with VEGF, which downregulated MDR1 and GLUT1 mRNA levels, transiently reduced expression levels of endothelial junctional proteins and altered their organization, increased the number of intercellular gaps in BRECs monolayers and influence the permeability of the model to differently-sized molecular tracers. Moreover, as has been shown in vivo, expression of plasmalemma vesicle-associated protein (PLVAP) was increased in endothelial cells in the presence of VEGF. This in vitro model is the first co-culture model of the BRB that mimicks in vivo VEGF-dependent changes occurring in DME. © 2011 Elsevier Ltd. Source

Lindqvist A.,Uppsala University | Rip J.,To BBB Technologies BV | van Kregten J.,To BBB Technologies BV | Gaillard P.J.,To BBB Technologies BV | Hammarlund-Udenaes M.,Uppsala University
Pharmaceutical Research | Year: 2015

Purpose: The purpose of this study was to evaluate formulation factors causing improvement in brain delivery of a small peptide after encapsulation into a targeted nanocarrier in vivo. Methods: The evaluation was performed in rats using microdialysis, which enabled continuous sampling of the released drug in both the brain (striatum) and blood. Uptake in brain could thereby be studied in terms of therapeutically active, released drug. Results: We found that encapsulation of the peptide DAMGO in fast-releasing polyethylene glycol (PEG)ylated liposomes, either with or without the specific brain targeting ligand glutathione (GSH), doubled the uptake of DAMGO into the rat brain. The increased brain delivery was observed only when the drug was encapsulated into the liposomes, thus excluding any effects of the liposomes themselves on the blood–brain barrier integrity as a possible mechanism. The addition of a GSH coating on the liposomes did not result in an additional increase in DAMGO concentrations in the brain, in contrast to earlier studies on GSH coating. This may be caused by differences in the characteristics of the encapsulated compounds and the composition of the liposome formulations. Conclusions: We were able to show that encapsulation into PEGylated liposomes of a peptide with limited brain delivery could double the drug uptake into the brain without using a specific brain targeting ligand. © 2015 Springer Science+Business Media New York Source

Gaillard P.J.,To BBB Technologies BV | Visser C.C.,To BBB Technologies BV | Appeldoorn C.C.M.,To BBB Technologies BV | Rip J.,To BBB Technologies BV
Drug Discovery Today: Technologies | Year: 2012

The blood-brain barrier presents a significant hurdle in CNS drug development. Blood-to-brain delivery by effectively crossing this barrier allows therapeutics to reach a large area of the brain. Over the past decades several drug delivery technologies have been developed, some more successful than others, which we hold against 10 key development criteria. Adhering to these criteria will allow a more successful development of therapeutics for patients with devastating brain diseases. © 2011 Elsevier Ltd. All rights reserved. Source

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