Function and Biomarkers of the Blood-Brain Barrier in a Neonatal Germinal Matrix Haemorrhage Model

Germinal matrix haemorrhage (GMH), caused by rupturing blood vessels in the germinal matrix, is a prevalent driver of preterm brain injuries and death. Our group recently developed a model simulating GMH using intrastriatal injections of collagenase in 5-day-old rats, which corresponds to the brain development of human preterm infants. This study aimed to define changes to the blood-brain barrier (BBB) and to evaluate BBB proteins as biomarkers in this GMH model. Regional BBB functions were investigated using blood to brain 14C-sucrose uptake as well as using biotinylated BBB tracers. Blood plasma and cerebrospinal fluids were collected at various times after GMH and analysed with ELISA for OCLN and CLDN5. The immunoreactivity of BBB proteins was assessed in brain sections. Tracer experiments showed that GMH produced a defined region surrounding the hematoma where many vessels lost their integrity. This region expanded for at least 6 h following GMH, thereafter resolution of both hematoma and re-establishment of BBB function occurred. The sucrose experiment indicated that regions somewhat more distant to the hematoma also exhibited BBB dysfunction; however, BBB function was normalised within 5 days of GMH. This shows that GMH leads to a temporal dysfunction in the BBB that may be important in pathological processes as well as in connection to therapeutic interventions. We detected an increase of tight-junction proteins in both CSF and plasma after GMH making them potential biomarkers for GMH.

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Circulating Tight-Junction Proteins Are Potential Biomarkers for Blood-Brain Barrier Function in a Model of Neonatal Hypoxic/Ischemic Brain Injury

10.21203/rs.3.rs-90299/v1 ◽

2020 ◽

Author(s):

Axel Erik Andersson ◽

Carina Mallard ◽

Carl Joakim Ek

Keyword(s):

Brain Injury ◽

Blood Brain Barrier ◽

Brain Injuries ◽

Brain Barrier ◽

Neonatal Brain ◽

Ischemic Brain ◽

Blood Brain ◽

Hypoxia Ischemia ◽

The Brain ◽

Junction Proteins

Abstract BackgroundNeonatal hypoxia-ischemia often leads to lifelong disabilities with limited treatments currently available. The brain vasculature is an important factor in many neonatal brain pathologies but there is a lack of diagnostic tools to evaluate the brain vascular health of neonates in a clinical setting. Measurement of blood-brain barrier tight-junction proteins have shown promise as biomarkers for brain injury in the adult. Here we tested the biomarker potential of tight-junctions in the context of neonatal brain injury.MethodsThe levels of TJ-proteins (occluding, claudin-5, and zonula occludens-1) in both blood plasma and cerebrospinal fluid (CSF) as well as blood-brain barrier function were measured in a clinically relevant hypoxia/ischemia model in neonatal rats.ResultsTemporally acute elevated levels of occludin and claudin-5 could be measured in blood and CSF after hypoxia/ischemia with males generally having higher levels than females. The levels of claudin-5 in CSF correlated with the severity of the brain injury at 24h post- hypoxia/ischemia. Simultaneously, we detected early increase in blood-brain barrier-permeability at 6 and 24h after hypoxia/ischemia.ConclusionsLevels of circulating claudin-5 and occludin are increased after hypoxic/ischemic brain injuries and blood-brain barrier-impairment and have promise as early biomarkers for cerebral vascular health and as a tool for risk assessment of neonatal brain injuries.

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Circulating Tight-junction Proteins are Potential Biomarkers for Blood-Brain Barrier Function in a Model of Neonatal Hypoxic/Ischemic Brain Injury

10.21203/rs.3.rs-90299/v2 ◽

2021 ◽

Author(s):

Axel Erik Andersson ◽

Carina Mallard ◽

Carl Joakim Ek

Keyword(s):

Brain Injury ◽

Blood Brain Barrier ◽

Brain Injuries ◽

Vascular Dysfunction ◽

Brain Barrier ◽

Ischemic Brain ◽

Blood Brain ◽

Hypoxia Ischemia ◽

The Brain ◽

Junction Proteins

Abstract Background Neonatal encephalopathy often leads to lifelong disabilities with limited treatments currently available. The brain vasculature is an important factor in many neonatal neurological disorders but there is a lack of diagnostic tools to evaluate the brain vascular dysfunction of neonates in the clinical setting. Measurement of blood-brain barrier tight-junction proteins have shown promise as biomarkers for brain injury in the adult. Here we tested the biomarker potential of tight-junctions in the context of neonatal brain injury.Methods The levels of TJ-proteins (occluding, claudin-5, and zonula occludens protein 1) in both blood plasma and cerebrospinal fluid (CSF) as well as blood-brain barrier function via 14C-sucrose (342 Da) and Evans blue extravasation were measured in a hypoxia/ischemia brain-injury model in neonatal rats.Results Time-dependent changes of occludin and claudin-5 levels could be measured in blood and CSF after hypoxia/ischemia with males generally having higher levels than females. The levels of claudin-5 in CSF correlated with the severity of the brain injury at 24h post- hypoxia/ischemia. Simultaneously, we detected early increase in blood-brain barrier-permeability at 6 and 24h after hypoxia/ischemia.Conclusions Levels of circulating claudin-5 and occludin are increased after hypoxic/ischemic brain injuries and blood-brain barrier-impairment and have promise as early biomarkers for cerebral vascular dysfunction and as a tool for risk assessment of neonatal brain injuries.

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

10.1101/2020.10.05.326843 ◽

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21020591 ◽

2020 ◽

Vol 21 (2) ◽

pp. 591 ◽

Cited By ~ 17

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.

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Circulating tight-junction proteins are potential biomarkers for blood–brain barrier function in a model of neonatal hypoxic/ischemic brain injury

Fluids and Barriers of the CNS ◽

10.1186/s12987-021-00240-9 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

E. Axel Andersson ◽

Carina Mallard ◽

C. Joakim Ek

Keyword(s):

Brain Injury ◽

Blood Brain Barrier ◽

Brain Injuries ◽

Vascular Dysfunction ◽

Brain Barrier ◽

Neonatal Brain ◽

Ischemic Brain ◽

Blood Brain ◽

Hypoxia Ischemia ◽

The Brain

Abstract Background Neonatal encephalopathy often leads to lifelong disabilities with limited treatments currently available. The brain vasculature is an important factor in many neonatal neurological disorders but there is a lack of diagnostic tools to evaluate the brain vascular dysfunction of neonates in the clinical setting. Measurement of blood–brain barrier tight-junction (TJ) proteins have shown promise as biomarkers for brain injury in the adult. Here we tested the biomarker potential of tight-junctions in the context of neonatal brain injury. Methods The levels of TJ-proteins (occluding, claudin-5, and zonula occludens protein 1) in both blood plasma and cerebrospinal fluid (CSF) as well as blood–brain barrier function via 14C-sucrose (342 Da) and Evans blue extravasation were measured in a hypoxia/ischemia brain-injury model in neonatal rats. Results Time-dependent changes of occludin and claudin-5 levels could be measured in blood and CSF after hypoxia/ischemia with males generally having higher levels than females. The levels of claudin-5 in CSF correlated with the severity of the brain injury at 24 h post- hypoxia/ischemia. Simultaneously, we detected early increase in blood–brain barrier-permeability at 6 and 24 h after hypoxia/ischemia. Conclusions Levels of circulating claudin-5 and occludin are increased after hypoxic/ischemic brain injuries and blood–brain barrier-impairment and have promise as early biomarkers for cerebral vascular dysfunction and as a tool for risk assessment of neonatal brain injuries.

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The Blood-Brain Barrier and Blood-Cerebral Spinal Fluid Barrier

Seminars in Cardiothoracic and Vascular Anesthesia ◽

10.1177/1089253206288992 ◽

2006 ◽

Vol 10 (2) ◽

pp. 128-131 ◽

Cited By ~ 25

Author(s):

Dixon M. Moody

Keyword(s):

Endothelial Cells ◽

Cerebrospinal Fluid ◽

Blood Brain Barrier ◽

Barrier Function ◽

Brain Injuries ◽

Brain Barrier ◽

Normal Brain ◽

Blood Brain ◽

Clinical Consequences ◽

The Brain

An intact blood-brain barrier and normal production, circulation, and absorption of cerebrospinal fluid are critical for normal brain function. Minor disruptions of barrier function are without clinical consequences. Major disruptions accompany most significant acute brain injuries. The anatomic location of the blood-brain barrier is the endothelial cells of arterioles, capillaries, veins, and the epithelial cell surface of the choroid plexus. However, endothelial cells require the presence of glial cells to maintain barrier function. During cardiopulmonary bypass, several factors may result in a temporary disruption of the barrier; the most important are systemic inflammatory response and focal ischemia due to emboli. Lacking a lymphatic system, the brain depends on the circulation of cerebrospinal fluid to remove the products of metabolism, and the circulation of cerebrospinal fluid depends on a vascular systolic pulse wave to drive this fluid antegrade along the brain paravascular spaces. Although it is not possible to identify this paravavscular space histologically, its presence is confirmed by tracer methods.

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Resveratrol defends blood-brain barrier integrity in experimental autoimmune encephalomyelitis mice

Journal of Neurophysiology ◽

10.1152/jn.00510.2016 ◽

2016 ◽

Vol 116 (5) ◽

pp. 2173-2179 ◽

Cited By ~ 30

Author(s):

Dong Wang ◽

Shi-Ping Li ◽

Jin-Sheng Fu ◽

Sheng Zhang ◽

Lin Bai ◽

...

Keyword(s):

Tight Junction ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Tight Junction Proteins ◽

Autoimmune Encephalomyelitis ◽

Arginase 1 ◽

Blood Brain ◽

Anti Inflammatory ◽

The Brain ◽

Junction Proteins

The mouse autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS), is primarily characterized as dysfunction of the blood-brain barrier (BBB). Resveratrol exhibits anti-inflammatory, antioxidative, and neuroprotective activities. We investigated the beneficial effects of resveratrol in protecting the integrity of the BBB in EAE mice and observed improved clinical outcome in the EAE mice after resveratrol treatment. Evans blue (EB) extravasation was used to detect the disruption of BBB. Western blot were used to detected the tight junction proteins and adhesion molecules zonula occludens-1 (ZO-1), occludin, ICAM-1, and VCAM-1. Inflammatory factors inducible nitric oxide synthase (iNOS), IL-1β, and arginase 1 were evaluated by quantitative RT-PCR (qPCR) and IL-10 by ELISA. NADPH oxidase (NOX) levels were evaluated by qPCR, and its activity was analyzed by lucigenin-derived chemiluminescence. Resveratrol at doses of 25 and 50 mg/kg produced a dose-dependent decrease in EAE paralysis and EB leakage, ameliorated EAE-induced loss of tight junction proteins ZO-1, occludin, and claudin-5, as well as repressed the EAE-induced increase in adhesion proteins ICAM-1 and VCAM-1. In addition, resveratrol suppressed the EAE-induced overexpression of proinflammatory transcripts iNOS and IL-1β and upregulated the expression of anti-inflammatory transcripts arginase 1 and IL-10 cytokine in the brain. Furthermore, resveratrol downregulated the overexpressed NOX2 and NOX4 in the brain and suppressed NADPH activity. Resveratrol ameliorates the clinical severity of MS through maintaining the BBB integrity in EAE mice.

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The Roles of the Microbiome in Alzheimer’s Disease

UTSC's Journal of Natural Sciences ◽

10.33137/jns.v2i1.35867 ◽

2021 ◽

Vol 2 (1) ◽

pp. 159-167

Author(s):

Zahin Hafiz ◽

Moina Malek ◽

William Ju

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Brain Barrier ◽

Metabolic Diseases ◽

The Other ◽

Therapeutic Interventions ◽

Brain Barrier ◽

Therapeutic Implications ◽

Blood Brain ◽

The Brain

The gut and the brain are in constant communication in a complex network known as the brain-gut axis. A growing body of research has found links between the brain-gut axis and Alzheimer’s Disease (AD). In this review, we will explore how the mammalian microbiome affects neuroinflammation and increases the permeability of the blood brain barrier in the context of AD. Research shows that the microbiome is associated with neuroinflammation in AD, which is presumably caused by the secretion of cytokines from specialized cells of the brain - microglia and astrocytes. On the other hand, metabolic diseases, caused by microbiota dysbiosis, can increase the permeability of the blood brain barrier. In addition, its higher permeability can allow blood plasma components to enter brain tissue and further develop AD pathology. Findings of the current research have tremendous therapeutic implications. Researchers have speculated whether the therapeutic modification of gut microbiota, through the use of antibiotics and probiotics, may show improvement in AD patients. Our understanding of the pathways and mechanisms involved in the brain-gut axis and AD is still very limited and requires further research before clinical and therapeutic interventions can occur.

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West Nile virus-induced disruption of the blood–brain barrier in mice is characterized by the degradation of the junctional complex proteins and increase in multiple matrix metalloproteinases

Journal of General Virology ◽

10.1099/vir.0.040899-0 ◽

2012 ◽

Vol 93 (6) ◽

pp. 1193-1203 ◽

Cited By ~ 90

Author(s):

Kelsey Roe ◽

Mukesh Kumar ◽

Stephanie Lum ◽

Beverly Orillo ◽

Vivek R. Nerurkar ◽

...

Keyword(s):

West Nile Virus ◽

Matrix Metalloproteinases ◽

Blood Brain Barrier ◽

Virus Replication ◽

Brain Barrier ◽

West Nile ◽

Altered Expression ◽

Blood Brain ◽

The Brain ◽

Junction Proteins

West Nile virus (WNV) encephalitis is characterized by neuroinflammation, neuronal loss and blood–brain barrier (BBB) disruption. However, the mechanisms associated with the BBB disruption are unclear. Complex interactions between the tight junction proteins (TJP) and the adherens junction proteins (AJP) of the brain microvascular endothelial cells are responsible for maintaining the BBB integrity. Herein, we characterized the relationship between the BBB disruption and expression kinetics of key TJP, AJP and matrix metalloproteinases (MMPs) in the mice brain. A dramatic increase in the BBB permeability and extravasation of IgG was observed at later time points of the central nervous system (CNS) infection and did not precede virus–CNS entry. WNV-infected mice exhibited significant reduction in the protein levels of the TJP ZO-1, claudin-1, occludin and JAM-A, and AJP β-catenin and vascular endothelial cadherin, which correlated with increased levels of MMP-1, -3 and -9 and infiltrated leukocytes in the brain. Further, intracranial inoculation of WNV also demonstrated increased extravasation of IgG in the brain, suggesting the role of virus replication in the CNS in BBB disruption. These data suggest that altered expression of junction proteins is a pathological event associated with WNV infection and may explain the molecular basis of BBB disruption. We propose that WNV initially enters CNS without altering the BBB integrity and later virus replication in the brain initiates BBB disruption, allowing enhanced infiltration of immune cells and contribute to virus neuroinvasion via the ‘Trojan-horse’ route. These data further implicate roles of multiple MMPs in the BBB disruption and strategies to interrupt this process may influence the WNV disease outcome.

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Ligand and Structure-based Modeling of Passive Diffusion through the Blood-Brain Barrier

Current Medicinal Chemistry ◽

10.2174/0929867324666171106163742 ◽

2018 ◽

Vol 25 (9) ◽

pp. 1073-1089 ◽

Cited By ~ 1

Author(s):

Santiago Vilar ◽

Eduardo Sobarzo-Sanchez ◽

Lourdes Santana ◽

Eugenio Uriarte

Keyword(s):

Blood Brain Barrier ◽

In Silico ◽

Passive Diffusion ◽

Brain Barrier ◽

Barrier Permeability ◽

Blood Brain Barrier Permeability ◽

Blood Brain ◽

Brain Barrier Permeability ◽

Different Types ◽

The Brain

Background: Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. Methods: We elaborated on ligand-based and structure-based models that have been described to predict the blood-brain barrier permeability. Results: Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability. We explained different types of descriptors that correlate with passive diffusion along with data analysis methods. Moreover, we discussed the applicability of other types of molecular structure-based simulations, such as molecular dynamics, and their implications in the prediction of passive diffusion. Challenges and limitations of experimental measurements of permeability and in silico predictive methods were also described. Conclusion: Improvements in the prediction of blood-brain barrier permeability from different types of in silico models are crucial to optimize the process of Central Nervous System drug discovery and development.

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