scholarly journals Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

2020 ◽  
Vol 21 (2) ◽  
pp. 591 ◽  
Author(s):  
Wolfgang Löscher ◽  
Alon Friedman
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Defense Mechanism ◽  
Extracellular Fluid ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Brain Barrier ◽  
Transport Systems ◽  
Blood Brain ◽  
The Brain

The blood-brain barrier (BBB) is a dynamic, highly selective barrier primarily formed by endothelial cells connected by tight junctions that separate the circulating blood from the brain extracellular fluid. The endothelial cells lining the brain microvessels are under the inductive influence of neighboring cell types, including astrocytes and pericytes. In addition to the anatomical characteristics of the BBB, various specific transport systems, enzymes and receptors regulate molecular and cellular traffic across the BBB. While the intact BBB prevents many macromolecules and immune cells from entering the brain, following epileptogenic brain insults the BBB changes its properties. Among BBB alterations, albumin extravasation and diapedesis of leucocytes from blood into brain parenchyma occur, inducing or contributing to epileptogenesis. Furthermore, seizures themselves may modulate BBB functions, permitting albumin extravasation, leading to activation of astrocytes and the innate immune system, and eventually modifications of neuronal networks. BBB alterations following seizures are not necessarily associated with enhanced drug penetration into the brain. Increased expression of multidrug efflux transporters such as P-glycoprotein likely act as a ‘second line defense’ mechanism to protect the brain from toxins. A better understanding of the complex alterations in BBB structure and function following seizures and in epilepsy may lead to novel therapeutic interventions allowing the prevention and treatment of epilepsy as well as other detrimental neuro-psychiatric sequelae of brain injury.

scholarly journals Characterization of a Primate Blood-Brain Barrier Co-Culture Model Prepared from Primary Brain Endothelial Cells, Pericytes and Astrocytes

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1484
Author(s):  
Daisuke Watanabe ◽  
Shinsuke Nakagawa ◽  
Yoichi Morofuji ◽  
Andrea E. Tóth ◽  
Monika Vastag ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Transport Systems ◽  
Brain Endothelial Cells ◽  
Monkey Brain ◽  
Blood Brain ◽  
Culture Model ◽  
Culture Models ◽  
Human Primate

Culture models of the blood-brain barrier (BBB) are important research tools. Their role in the preclinical phase of drug development to estimate the permeability for potential neuropharmaceuticals is especially relevant. Since species differences in BBB transport systems exist, primate models are considered as predictive for drug transport to brain in humans. Based on our previous expertise we have developed and characterized a non-human primate co-culture BBB model using primary cultures of monkey brain endothelial cells, rat brain pericytes, and rat astrocytes. Monkey brain endothelial cells in the presence of both pericytes and astrocytes (EPA model) expressed enhanced barrier properties and increased levels of tight junction proteins occludin, claudin-5, and ZO-1. Co-culture conditions also elevated the expression of key BBB influx and efflux transporters, including glucose transporter-1, MFSD2A, ABCB1, and ABCG2. The correlation between the endothelial permeability coefficients of 10 well known drugs was higher (R2 = 0.8788) when the monkey and rat BBB culture models were compared than when the monkey culture model was compared to mouse in vivo data (R2 = 0.6619), hinting at transporter differences. The applicability of the new non-human primate model in drug discovery has been proven in several studies.

scholarly journals Modulating the Blood-Brain Barrier by Light Stimulation of Molecular-Targeted Nanoparticles

2020 ◽  
Author(s):  
Xiaoqing Li ◽  
Vamsidhara Vemireddy ◽  
Qi Cai ◽  
Hejian Xiong ◽  
Peiyuan Kang ◽  
...  
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Therapeutic Interventions ◽  
Brain Barrier ◽  
Light Stimulation ◽  
Targeted Nanoparticles ◽  
Blood Brain ◽  
The Brain ◽  
Stimulation Of

AbstractThe blood-brain barrier (BBB) tightly regulates the entry of molecules into the brain by tight junctions that seals the paracellular space and receptor-mediated transcytosis. It remains elusive to selectively modulate these mechanisms and to overcome BBB without significant neurotoxicity. Here we report that light stimulation of tight junction-targeted plasmonic nanoparticles selectively opens up the paracellular route to allow diffusion through the compromised tight junction and into the brain parenchyma. The BBB modulation does not impair vascular dynamics and associated neurovascular coupling, or cause significant neural injury. It further allows antibody and adeno-associated virus delivery into local brain regions. This novel method offers the first evidence of selectively modulating BBB tight junctions and opens new avenues for therapeutic interventions in the central nervous system.One Sentence SummaryGentle stimulation of molecular-targeted nanoparticles selectively opens up the paracellular pathway and allows macromolecules and gene therapy vectors into the brain.

Anthropogenic Iron Oxide Nanoparticles Induce Damage to Brain Microvascular Endothelial Cells Forming the Blood-Brain Barrier

2021 ◽  
Author(s):  
Lorena Gárate-Vélez ◽  
Claudia Escudero-Lourdes ◽  
Daniela Salado-Leza ◽  
Armando González-Sánchez ◽  
Ildemar Alvarado-Morales ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
Blood Brain ◽  
Fe3o4 Nps ◽  
Microvascular Endothelial ◽  
The Brain

Background: Iron nanoparticles, mainly in magnetite phase (Fe3O4 NPs), are released to the environment in areas with high traffic density and braking frequency. Fe3O4 NPs were found in postmortem human brains and are assumed to get directly into the brain through the olfactory nerve. However, these pollution-derived NPs may also translocate from the lungs to the bloodstream and then, through the blood-brain barrier (BBB), into the brain inducing oxidative and inflammatory responses that contribute to neurodegeneration. Objective: To describe the interaction and toxicity of pollution-derived Fe3O4 NPs on primary rat brain microvascular endothelial cells (rBMECs), main constituents of in vitro BBB models. Methods: Synthetic bare Fe3O4 NPs that mimic the environmental ones (miFe3O4) were synthesized by co-precipitation and characterized using complementary techniques. The rBMECs were cultured in Transwell® plates. The NPs-cell interaction was evaluated through transmission electron microscopy and standard colorimetric in vitro assays. Results: The miFe3O4 NPs, with a mean diameter of 8.45 ± 0.14 nm, presented both magnetite and maghemite phases, and showed super-paramagnetic properties. Results suggest that miFe3O4 NPs are internalized by rBMECs through endocytosis and that they are able to cross the cells monolayer. The lowest miFe3O4 NPs concentration tested induced mid cytotoxicity in terms of 1) membrane integrity (LDH release) and 2) metabolic activity (MTS transformation). Conclusion: Pollution-derived Fe3O4 NPs may interact and cross the microvascular endothelial cells forming the BBB and cause biological damage.

scholarly journals Impact of the Renin–Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives

2020 ◽  
Vol 21 (12) ◽  
pp. 4268 ◽  
Author(s):  
Fatima Y. Noureddine ◽  
Raffaele Altara ◽  
Fan Fan ◽  
Andriy Yabluchanskiy ◽  
George W. Booz ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Dementia ◽  
Blood Brain Barrier ◽  
Renin Angiotensin System ◽  
Brain Barrier ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Blood Brain ◽  
Body Tissues ◽  
The Brain

The effects of the renin–angiotensin system (RAS) surpass the renal and cardiovascular systems to encompass other body tissues and organs, including the brain. Angiotensin II (Ang II), the most potent mediator of RAS in the brain, contributes to vascular dementia via different mechanisms, including neuronal homeostasis disruption, vascular remodeling, and endothelial dysfunction caused by increased inflammation and oxidative stress. Other RAS components of emerging significance at the level of the blood–brain barrier include angiotensin-converting enzyme 2 (ACE2), Ang(1–7), and the AT2, Mas, and AT4 receptors. The various angiotensin hormones perform complex actions on brain endothelial cells and pericytes through specific receptors that have either detrimental or beneficial actions. Increasing evidence indicates that the ACE2/Ang(1–7)/Mas axis constitutes a protective arm of RAS on the blood–brain barrier. This review provides an update of studies assessing the different effects of angiotensins on cerebral endothelial cells. The involved signaling pathways are presented and help highlight the potential pharmacological targets for the management of cognitive and behavioral dysfunctions associated with vascular dementia.

scholarly journals Human pluripotent stem cell–derived brain pericyte–like cells induce blood-brain barrier properties

2019 ◽  
Vol 5 (3) ◽  
pp. eaau7375 ◽  
Author(s):  
Matthew J. Stebbins ◽  
Benjamin D. Gastfriend ◽  
Scott G. Canfield ◽  
Ming-Song Lee ◽  
Drew Richards ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Barrier Properties ◽  
Cell Types ◽  
Brain Barrier ◽  
Human Model ◽  
Blood Brain ◽  
Brain Pericytes

Brain pericytes play important roles in the formation and maintenance of the neurovascular unit (NVU), and their dysfunction has been implicated in central nervous system disorders. While human pluripotent stem cells (hPSCs) have been used to model other NVU cell types, including brain microvascular endothelial cells (BMECs), astrocytes, and neurons, hPSC-derived brain pericyte–like cells have not been integrated into these models. In this study, we generated neural crest stem cells (NCSCs), the embryonic precursor to forebrain pericytes, from hPSCs and subsequently differentiated NCSCs to brain pericyte–like cells. These cells closely resembled primary human brain pericytes and self-assembled with endothelial cells. The brain pericyte–like cells induced blood-brain barrier properties in BMECs, including barrier enhancement and reduced transcytosis. Last, brain pericyte–like cells were incorporated with iPSC-derived BMECs, astrocytes, and neurons to form an isogenic human model that should prove useful for the study of the NVU.

Metabolic fuel and amino acid transport into the brain in experimental hypothyroidism

1990 ◽  
Vol 122 (2) ◽  
pp. 156-162 ◽  
Author(s):  
Arshag D. Mooradian
Keyword(s):  
Amino Acids ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Transport Systems ◽  
Brain Uptake ◽  
Acid Transport ◽  
Brain Extraction ◽  
Blood Brain ◽  
Brain Uptake Index ◽  
The Brain

Abstract The effect of hypothyroidism in the adult rat on blood-brain barrier and muscle transport of hexoses, neutral amino acids, basic amino acids, monocarboxylic acids, and ketone bodies was examined using single arterial injection-tissue sampling technique. The cerebral blood flow and brain extraction of 3H2O (internal reference substance) was not altered in 3-month-old hypothyroid rats maintained on methimazole, 0.025% in the drinking water, for 7 weeks. The brain uptake index of D-β-hydroxybutyrate was significantly reduced in hypothyroid rats (2.4 ± 0.3 vs 4.6 ± 0.6% p<0.001). Hypothyroid rats given thyroid hormone replacement therapy had normal brain uptake of D-β-hydroxybutyrate (4.4 ± 0.8%). The brain uptake index of butyrate was also significantly reduced in hypothyroid rats (39.3 ± 2.1 vs 47.2 ± 0.74%, p<0.001). The brain uptake index of other test substances and muscle uptake of nutrients examined were not altered in hypothyroid rats. These studies indicate that of the four transport systems examined in two tissues, the blood-brain barrier monocarboxylic acid transport system is most susceptible to the hypothyroidism-induced changes.

scholarly journals Hypoxic-Ischaemic Encephalopathy and the Blood-Brain Barrier in Neonates

2017 ◽  
Vol 39 (1-4) ◽  
pp. 49-58 ◽  
Author(s):  
Wei Ling Amelia Lee ◽  
Adina T. Michael-Titus ◽  
Divyen K. Shah
Keyword(s):  
Blood Brain Barrier ◽  
Systemic Circulation ◽  
Brain Parenchyma ◽  
Cerebral Injury ◽  
Brain Barrier ◽  
Transport Systems ◽  
Permeability Barrier ◽  
Cell Based Therapy ◽  
Blood Brain ◽  
The Brain

This review aims to highlight a possible relationship between hypoxic-ischaemic encephalopathy (HIE) and the disruption of the blood-brain barrier (BBB). Inflammatory reactions perpetuate a large proportion of cerebral injury. The extent of injury noted in HIE is not only determined by the biochemical cascades that trigger the apoptosis-necrosis continuum of cell death in the brain parenchyma, but also by the breaching of the BBB by pro-inflammatory factors. We examine the changes that contribute to the breakdown of the BBB that occur during HIE at a macroscopic, cellular, and molecular level. The BBB is a permeability barrier which separates a large majority of brain areas from the systemic circulation. The concept of a physiological BBB is based at the anatomical level on the neurovascular unit (NVU). The NVU consists of various cellular components that jointly regulate the exchanges that occur at the interface between the systemic circulation and the brain parenchyma. There is increased understanding of the contribution of the components of the NVU, e.g., astrocytes and pericytes, to the maintenance of this physiological barrier. We also explore the development of therapeutic options in HIE, such as harnessing the transport systems in the BBB, to enable the delivery of large molecules with molecular Trojan horse technology, and the reinforcement of the physical barrier with cell-based therapy which utilizes endothelial progenitor cells and stem cells.

scholarly journals The Dual Role of Microglia in Blood-Brain Barrier Dysfunction after Stroke

2020 ◽  
Vol 18 (12) ◽  
pp. 1237-1249 ◽  
Author(s):  
Ruiqing Kang ◽  
Marcin Gamdzyk ◽  
Cameron Lenahan ◽  
Jiping Tang ◽  
Sheng Tan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Vital Role ◽  
Dual Role ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Blood Brain ◽  
M2 Microglia ◽  
The Brain

It is well-known that stroke is one of the leading causes of death and disability all over the world. After a stroke, the blood-brain barrier subsequently breaks down. The BBB consists of endothelial cells surrounded by astrocytes. Microglia, considered the long-living resident immune cells of the brain, play a vital role in BBB function. M1 microglia worsen BBB disruption, while M2 microglia assist in repairing BBB damage. Microglia can also directly interact with endothelial cells and affect BBB permeability. In this review, we are going to discuss the mechanisms responsible for the dual role of microglia in BBB dysfunction after stroke.

scholarly journals Human pluripotent stem cell-derived brain pericyte-like cells induce blood-brain barrier properties

2018 ◽  
Author(s):  
Matthew J. Stebbins ◽  
Benjamin D. Gastfriend ◽  
Scott G. Canfield ◽  
Ming-Song Lee ◽  
Drew Richards ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Pluripotent Stem Cells ◽  
Neurovascular Unit ◽  
Human Pluripotent Stem Cells ◽  
Brain Barrier ◽  
Blood Brain ◽  
Brain Pericytes ◽  
The Brain

ABSTRACTBrain pericytes play an important role in the formation and maintenance of the neurovascular unit (NVU), and their dysfunction has been implicated in central nervous system (CNS) disorders. While human pluripotent stem cells (hPSCs) have been used to model other components of the NVU including brain microvascular endothelial cells (BMECs), astrocytes, and neurons, cells having brain pericyte-like phenotypes have not been described. In this study, we generated neural crest stem cells (NCSCs), the embryonic precursor to forebrain pericytes, from human pluripotent stem cells (hPSCs) and subsequently differentiated NCSCs to brain pericyte-like cells. The brain pericyte-like cells expressed marker profiles that closely resembled primary human brain pericytes, and they self-assembled with endothelial cells to support vascular tube formation. Importantly, the brain pericyte-like cells induced blood-brain barrier (BBB) properties in BMECs, including barrier enhancement and reduction of transcytosis. Finally, brain pericyte-like cells were incorporated with iPSC-derived BMECs, astrocytes, and neurons to form an isogenic human NVU model that should prove useful for the study of the BBB in CNS health, disease, and therapy.

Sign in / Sign up

Export Citation Format

Share Document