Oatp58Dc contributes to blood-brain barrier function by excluding organic anions from the Drosophila brain

2013 ◽  
Vol 305 (5) ◽  
pp. C558-C567 ◽  
Author(s):  
Sara Seabrooke ◽  
Michael J. O'Donnell
Keyword(s):  
Blood Brain Barrier ◽  
Organic Anion ◽  
Complex Structure ◽  
Critical Role ◽  
Organic Anions ◽  
Molecular Techniques ◽  
Brain Barrier ◽  
Blood Brain ◽  
Wide Range ◽  
The Brain

The blood-brain barrier (BBB) physiologically isolates the brain from the blood and, thus, plays a vital role in brain homeostasis. Ion transporters play a critical role in this process by effectively regulating access of chemicals to the brain. Organic anion-transporting polypeptides (Oatps) transport a wide range of amphipathic substrates and are involved in efflux of chemicals across the vertebrate BBB. The anatomic complexity of the vascularized vertebrate BBB, however, creates challenges for experimental analysis of these processes. The less complex structure of the Drosophila BBB facilitates measurement of solute transport. Here we investigate a physiological function for Oatp58Dc in transporting small organic anions across the BBB. We used genetic manipulation, immunocytochemistry, and molecular techniques to supplement a whole animal approach to study the BBB. For this whole animal approach, the traceable small organic anion fluorescein was injected into the hemolymph. This research shows that Oatp58Dc is involved in maintaining a chemical barrier against fluorescein permeation into the brain. Oatp58Dc expression was found in the perineurial and subperineurial glia, as well as in postmitotic neurons. We specifically targeted knockdown of Oatp58Dc expression in the perineurial and subperineurial glia to reveal that Oatp58Dc expression in the perineurial glia is necessary to maintain the barrier against fluorescein influx into the brain. Our results show that Oatp58Dc contributes to maintenance of a functional barrier against fluorescein influx past the BBB into the brain.

scholarly journals The Potential Roles of Blood–Brain Barrier and Blood–Cerebrospinal Fluid Barrier in Maintaining Brain Manganese Homeostasis

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1833
Author(s):  
Shannon Morgan McCabe ◽  
Ningning Zhao
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Blood Circulation ◽  
Critical Role ◽  
Systemic Circulation ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

Manganese (Mn) is a trace nutrient necessary for life but becomes neurotoxic at high concentrations in the brain. The brain is a “privileged” organ that is separated from systemic blood circulation mainly by two barriers. Endothelial cells within the brain form tight junctions and act as the blood–brain barrier (BBB), which physically separates circulating blood from the brain parenchyma. Between the blood and the cerebrospinal fluid (CSF) is the choroid plexus (CP), which is a tissue that acts as the blood–CSF barrier (BCB). Pharmaceuticals, proteins, and metals in the systemic circulation are unable to reach the brain and spinal cord unless transported through either of the two brain barriers. The BBB and the BCB consist of tightly connected cells that fulfill the critical role of neuroprotection and control the exchange of materials between the brain environment and blood circulation. Many recent publications provide insights into Mn transport in vivo or in cell models. In this review, we will focus on the current research regarding Mn metabolism in the brain and discuss the potential roles of the BBB and BCB in maintaining brain Mn homeostasis.

scholarly journals Global Perspective of Novel Therapeutic Strategies for the Management of NeuroAIDS

2018 ◽  
Vol 9 (1) ◽  
pp. 33-42 ◽  
Author(s):  
Swatantra Kumar ◽  
Vimal K Maurya ◽  
Himanshu R Dandu ◽  
Madan LB Bhatt ◽  
Shailendra K Saxena
Keyword(s):  
Antiretroviral Therapy ◽  
Blood Brain Barrier ◽  
Highly Active Antiretroviral Therapy ◽  
Complex Structure ◽  
Antiretroviral Drugs ◽  
Global Perspective ◽  
Brain Barrier ◽  
Asymptomatic Neurocognitive Impairment ◽  
Blood Brain ◽  
The Brain

AbstractAmong Human immunodeficiency virus (HIV) infected individuals, around two-thirds of patients present with neuroAIDS, where HIV-associated neurocognitive disorders (HAND), and HIV-associated dementia (HAD) are the most prevailing neurological complications. The neuropathology of neuroAIDS can be characterized by the presence of HIV infected macrophages and microglia in the brain, with the formation of multinucleated giant cells. Global predominant subtypes of HIV-1 clade B and C infections influence the differential effect of immune and neuronal dysfunctions, leading to clade-specific clinical variation in neuroAIDS patient cohorts. Highly active antiretroviral therapy (HAART) enhances the survival rate among AIDS patients, but due to the inability to cross the Blood-Brain-Barrier (BBB), incidence of neuroAIDS during disease progression may be envisaged. The complex structure of blood-brain-barrier, and poor pharmacokinetic profile coupled with weak bio-distribution of antiretroviral drugs, are the principle barriers for the treatment of neuroAIDS. In the combined antiretroviral therapy (cART) era, the frequency of HAD has decreased; however the incidence of asymptomatic neurocognitive impairment (ANI) and minor neurocognitive disorder (MND) remains consistent. Therefore, several effective novel nanotechnology based therapeutic approaches have been developed to improve the availability of antiretroviral drugs in the brain for the management of neuroAIDS.

scholarly journals Oxidative Stress Increases Blood–Brain Barrier Permeability and Induces Alterations in Occludin during Hypoxia–Reoxygenation

2010 ◽  
Vol 30 (9) ◽  
pp. 1625-1636 ◽  
Author(s):  
Jeffrey J Lochhead ◽  
Gwen McCaffrey ◽  
Colleen E Quigley ◽  
Jessica Finch ◽  
Kristin M DeMarco ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Brain Barrier ◽  
Critical Role ◽  
Brain Barrier ◽  
Central Component ◽  
Radical Scavenger ◽  
Cerebral Microvessels ◽  
Disease States ◽  
Blood Brain ◽  
The Brain

The blood–brain barrier (BBB) has a critical role in central nervous system homeostasis. Intercellular tight junction (TJ) protein complexes of the brain microvasculature limit paracellular diffusion of substances from the blood into the brain. Hypoxia and reoxygenation (HR) is a central component to numerous disease states and pathologic conditions. We have previously shown that HR can influence the permeability of the BBB as well as the critical TJ protein occludin. During HR, free radicals are produced, which may lead to oxidative stress. Using the free radical scavenger tempol (200 mg/kg, intraperitoneal), we show that oxidative stress produced during HR (6% O2 for 1 h, followed by room air for 20 min) mediates an increase in BBB permeability in vivo using in situ brain perfusion. We also show that these changes are associated with alterations in the structure and localization of occludin. Our data indicate that oxidative stress is associated with movement of occludin away from the TJ. Furthermore, subcellular fractionation of cerebral microvessels reveals alterations in occludin oligomeric assemblies in TJ associated with plasma membrane lipid rafts. Our data suggest that pharmacological inhibition of disease states with an HR component may help preserve BBB functional integrity.

Evaluation of the effect of stress on the blood–brain barrier: critical role of the brain perfusion time

2001 ◽  
Vol 905 (1-2) ◽  
pp. 21-25 ◽  
Author(s):  
Haim Ovadia ◽  
Oded Abramsky ◽  
Shaul Feldman ◽  
Joseph Weidenfeld
Keyword(s):  
Blood Brain Barrier ◽  
Critical Role ◽  
Brain Perfusion ◽  
Brain Barrier ◽  
Blood Brain ◽  
Perfusion Time ◽  
The Brain

scholarly journals Disruption in the Blood-Brain Barrier: The Missing Link between Brain and Body Inflammation in Bipolar Disorder?

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Jay P. Patel ◽  
Benicio N. Frey
Keyword(s):  
Bipolar Disorder ◽  
Blood Brain Barrier ◽  
Peripheral Blood ◽  
Critical Role ◽  
Brain Barrier ◽  
Inflammatory Conditions ◽  
Blood Brain ◽  
The Central Nervous System ◽  
The Brain

The blood-brain barrier (BBB) regulates the transport of micro- and macromolecules between the peripheral blood and the central nervous system (CNS) in order to maintain optimal levels of essential nutrients and neurotransmitters in the brain. In addition, the BBB plays a critical role protecting the CNS against neurotoxins. There has been growing evidence that BBB disruption is associated with brain inflammatory conditions such as Alzheimer’s disease and multiple sclerosis. Considering the increasing role of inflammation and oxidative stress in the pathophysiology of bipolar disorder (BD), here we propose a novel model wherein transient or persistent disruption of BBB integrity is associated with decreased CNS protection and increased permeability of proinflammatory (e.g., cytokines, reactive oxygen species) substances from the peripheral blood into the brain. These events would trigger the activation of microglial cells and promote localized damage to oligodendrocytes and the myelin sheath, ultimately compromising myelination and the integrity of neural circuits. The potential implications for research in this area and directions for future studies are discussed.

scholarly journals A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Hossam Kadry ◽  
Behnam Noorani ◽  
Luca Cucullo
Keyword(s):  
Blood Brain Barrier ◽  
Structural Integrity ◽  
Critical Role ◽  
Brain Barrier ◽  
Clinical Aspects ◽  
Advantages And Disadvantages ◽  
Blood Brain ◽  
The Brain

AbstractThe blood–brain barrier is playing a critical role in controlling the influx and efflux of biological substances essential for the brain’s metabolic activity as well as neuronal function. Thus, the functional and structural integrity of the BBB is pivotal to maintain the homeostasis of the brain microenvironment. The different cells and structures contributing to developing this barrier are summarized along with the different functions that BBB plays at the brain–blood interface. We also explained the role of shear stress in maintaining BBB integrity. Furthermore, we elaborated on the clinical aspects that correlate between BBB disruption and different neurological and pathological conditions. Finally, we discussed several biomarkers that can help to assess the BBB permeability and integrity in-vitro or in-vivo and briefly explain their advantages and disadvantages.

scholarly journals Pathology of the neurovascular unit in leukodystrophies

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Parand Zarekiani ◽  
Marjolein Breur ◽  
Nicole I. Wolf ◽  
Helga E. de Vries ◽  
Marjo S. van der Knaap ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Barrier Function ◽  
Neurovascular Unit ◽  
Underlying Disease ◽  
Aquaporin 4 ◽  
Brain Barrier ◽  
Comprehensive Overview ◽  
Blood Brain ◽  
Wide Range ◽  
The Brain

AbstractThe blood–brain barrier is a dynamic endothelial cell barrier in the brain microvasculature that separates the blood from the brain parenchyma. Specialized brain endothelial cells, astrocytes, neurons, microglia and pericytes together compose the neurovascular unit and interact to maintain blood–brain barrier function. A disturbed brain barrier function is reported in most common neurological disorders and may play a role in disease pathogenesis. However, a comprehensive overview of how the neurovascular unit is affected in a wide range of rare disorders is lacking. Our aim was to provide further insights into the neuropathology of the neurovascular unit in leukodystrophies to unravel its potential pathogenic role in these diseases. Leukodystrophies are monogenic disorders of the white matter due to defects in any of its structural components. Single leukodystrophies are exceedingly rare, and availability of human tissue is unique. Expression of selective neurovascular unit markers such as claudin-5, zona occludens 1, laminin, PDGFRβ, aquaporin-4 and α-dystroglycan was investigated in eight different leukodystrophies using immunohistochemistry. We observed tight junction rearrangements, indicative of endothelial dysfunction, in five out of eight assessed leukodystrophies of different origin and an altered aquaporin-4 distribution in all. Aquaporin-4 redistribution indicates a general astrocytic dysfunction in leukodystrophies, even in those not directly related to astrocytic pathology or without prominent reactive astrogliosis. These findings provide further evidence for dysfunction in the orchestration of the neurovascular unit in leukodystrophies and contribute to a better understanding of the underlying disease mechanism.

scholarly journals Natural Polysaccharide Carriers in Brain Delivery: Challenge and Perspective

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1183
Author(s):  
Manuela Curcio ◽  
Giuseppe Cirillo ◽  
Jourdin R. C. Rouaen ◽  
Federica Saletta ◽  
Fiore Pasquale Nicoletta ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Stimuli Responsive ◽  
Drug Bioavailability ◽  
Responsive Materials ◽  
Blood Brain ◽  
Wide Range ◽  
Materials Used ◽  
The Brain

Targeted drug delivery systems represent valuable tools to enhance the accumulation of therapeutics in the brain. Here, the presence of the blood brain barrier strongly hinders the passage of foreign substances, often limiting the effectiveness of pharmacological therapies. Among the plethora of materials used for the development of these systems, natural polysaccharides are attracting growing interest because of their biocompatibility, muco-adhesion, and chemical versatility which allow a wide range of carriers with tailored physico-chemical features to be synthetized. This review describes the state of the art in the field of targeted carriers based on natural polysaccharides over the last five years, focusing on the main targeting strategies, namely passive and active transport, stimuli-responsive materials and the administration route. In addition, in the last section, the efficacy of the reviewed carriers in each specific brain diseases is summarized and commented on in terms of enhancement of either blood brain barrier (BBB) permeation ability or drug bioavailability in the brain.

scholarly journals In silico tool for predicting and designing Blood-Brain Barrier Penetrating Peptides

2021 ◽  
Author(s):  
Vinod Kumar ◽  
Sumeet Patiyal ◽  
Anjali Dhall ◽  
Neelam Sharma ◽  
Gajendra Pal Singh Raghava
Keyword(s):  
Machine Learning ◽  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Protein Sequence ◽  
Web Server ◽  
Brain Barrier ◽  
Blood Brain ◽  
Wide Range ◽  
The Brain ◽  
Brain Barriers

Blood-brain-barrier is a major obstacle in treating brain-related disorders as it does not allow to deliver drugs in the brain. In order to facilitate delivery of drugs in brain, we developed a method for predicting blood-brain-barrier penetrating peptides. These blood-brain barriers penetrating peptides (B3PPs) can act as therapeutic as well as drug delivery agents. We trained, tested, and evaluated our models on blood-brain-barrier peptides obtained from the B3Pdb database. First, we compute a wide range of peptide features then we select relevant peptide features. Finally, we developed numerous machine learning-based models for predicting blood-brain-barrier peptides using selected features. Our model based on random forest performed best on the top 80 selected features and achieved a maximum 85.08% accuracy with 0.93 AUROC. We also developed a web server, B3pred that implements our best models. It has three major modules that allow users to; i) predict B3PPs, ii) scanning B3PPs in a protein sequence, and iii) designing B3PPs using analogs. Our web server and standalone software is freely available at https://webs.iiitd.edu.in/raghava/b3pred/.

scholarly journals The biological significance of brain barrier mechanisms: help or hindrance in drug delivery to the central nervous system?

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 313 ◽  
Author(s):  
Norman R. Saunders ◽  
Mark D. Habgood ◽  
Kjeld Møllgård ◽  
Katarzyna M. Dziegielewska
Keyword(s):  
Blood Brain Barrier ◽  
Biological Significance ◽  
The Body ◽  
Adult Brain ◽  
Brain Barrier ◽  
Cellular Transport ◽  
Internal Environment ◽  
Blood Brain ◽  
Wide Range ◽  
The Brain

Barrier mechanisms in the brain are important for its normal functioning and development. Stability of the brain’s internal environment, particularly with respect to its ionic composition, is a prerequisite for the fundamental basis of its function, namely transmission of nerve impulses. In addition, the appropriate and controlled supply of a wide range of nutrients such as glucose, amino acids, monocarboxylates, and vitamins is also essential for normal development and function. These are all cellular functions across the interfaces that separate the brain from the rest of the internal environment of the body. An essential morphological component of all but one of the barriers is the presence of specialized intercellular tight junctions between the cells comprising the interface: endothelial cells in the blood-brain barrier itself, cells of the arachnoid membrane, choroid plexus epithelial cells, and tanycytes (specialized glial cells) in the circumventricular organs. In the ependyma lining the cerebral ventricles in the adult brain, the cells are joined by gap junctions, which are not restrictive for intercellular movement of molecules. But in the developing brain, the forerunners of these cells form the neuroepithelium, which restricts exchange of all but the smallest molecules between cerebrospinal fluid and brain interstitial fluid because of the presence of strap junctions between the cells. The intercellular junctions in all these interfaces are the physical basis for their barrier properties. In the blood-brain barrier proper, this is combined with a paucity of vesicular transport that is a characteristic of other vascular beds. Without such a diffusional restrain, the cellular transport mechanisms in the barrier interfaces would be ineffective. Superimposed on these physical structures are physiological mechanisms as the cells of the interfaces contain various metabolic transporters and efflux pumps, often ATP-binding cassette (ABC) transporters, that provide an important component of the barrier functions by either preventing entry of or expelling numerous molecules including toxins, drugs, and other xenobiotics.In this review, we summarize these influx and efflux mechanisms in normal developing and adult brain, as well as indicating their likely involvement in a wide range of neuropathologies.There have been extensive attempts to overcome the barrier mechanisms that prevent the entry of many drugs of therapeutic potential into the brain. We outline those that have been tried and discuss why they may so far have been largely unsuccessful. Currently, a promising approach appears to be focal, reversible disruption of the blood-brain barrier using focused ultrasound, but more work is required to evaluate the method before it can be tried in patients. Overall, our view is that much more fundamental knowledge of barrier mechanisms and development of new experimental methods will be required before drug targeting to the brain is likely to be a successful endeavor. In addition, such studies, if applied to brain pathologies such as stroke, trauma, or multiple sclerosis, will aid in defining the contribution of brain barrier pathology to these conditions, either causative or secondary.

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