Drug and gene targeting to the brain via blood–brain barrier receptor-mediated transport systems

2005 ◽  
Vol 1277 ◽  
pp. 49-62 ◽  
Author(s):  
William M. Pardridge
Keyword(s):  
Gene Targeting ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Transport Systems ◽  
Blood Brain ◽  
The Brain

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.

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 A Reevaluation of Chitosan-Decorated Nanoparticles to Cross the Blood-Brain Barrier

Membranes ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 212 ◽  
Author(s):  
Hernán Cortés ◽  
Sergio Alcalá-Alcalá ◽  
Isaac H. Caballero-Florán ◽  
Sergio A. Bernal-Chávez ◽  
Arturo Ávalos-Fuentes ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Transport Systems ◽  
Future Directions ◽  
Blood Brain ◽  
Dynamic Interface ◽  
And Function ◽  
The Brain

The blood-brain barrier (BBB) is a sophisticated and very selective dynamic interface composed of endothelial cells expressing enzymes, transport systems, and receptors that regulate the passage of nutrients, ions, oxygen, and other essential molecules to the brain, regulating its homeostasis. Moreover, the BBB performs a vital function in protecting the brain from pathogens and other dangerous agents in the blood circulation. Despite its crucial role, this barrier represents a difficult obstacle for the treatment of brain diseases because many therapeutic agents cannot cross it. Thus, different strategies based on nanoparticles have been explored in recent years. Concerning this, chitosan-decorated nanoparticles have demonstrated enormous potential for drug delivery across the BBB and treatment of Alzheimer’s disease, Parkinson’s disease, gliomas, cerebral ischemia, and schizophrenia. Our main objective was to highlight the high potential of chitosan adsorption to improve the penetrability through the BBB of nanoformulations for diseases of CNS. Therefore, we describe the BBB structure and function, as well as the routes of chitosan for crossing it. Moreover, we define the methods of decoration of nanoparticles with chitosan and provide numerous examples of their potential utilization in a variety of brain diseases. Lastly, we discuss future directions, mentioning the need for extensive characterization of proposed nanoformulations and clinical trials for evaluation of their efficacy.

scholarly journals The blood–brain barrier

2020 ◽  
pp. S32-S34
Author(s):  
S Dingezweni
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Transport Systems ◽  
Barrier Structure ◽  
Waste Products ◽  
Blood Brain ◽  
The Central Nervous System ◽  
The Brain

The blood–brain barrier (BBB) is a dynamic barrier essential for central nervous system interstitial fluid separation from circulating blood. This dynamic separation ensures maintenance of neuronal microenvironment homeostasis against that of the everchanging in solutes and toxin concentration in circulating blood. The blood–brain barrier structure is complex, it has multiple contributors, such as specialised blood microvascular endothelium, neurons, astrocytes and pericytes. Transfer of essential nutrients to the brain and waste products from the brain to circulating blood is tightly regulated and facilitated by a large surface area and specialised transport systems. It is not only the physical characteristics of the barrier that assist in maintenance of neuronal microenvironment, biochemical substances and the high trans endothelial electrical resistance also play a major role. Circumventricular organs are those parts of the central nervous system lacking the blood–brain barrier. These are essential for optimum central nervous system interaction with circulating blood directly or using neurotransmitters. Primary or secondary central nervous system pathological states, such as infective and noninfective causes, directly or indirectly induce biochemical mediators that may disrupt and alter blood–brain barrier structure and function. Understanding of the blood–brain barrier anatomy and physiology assists in developing treatment methods to overcome degenerative and pathological states negatively affecting the central nervous system.

scholarly journals Nanocarriers for Delivery of Oligonucleotides to the CNS

2022 ◽  
Vol 23 (2) ◽  
pp. 760
Author(s):  
David Male ◽  
Radka Gromnicova
Keyword(s):  
Gene Expression ◽  
Animal Models ◽  
Blood Brain Barrier ◽  
Intrathecal Injection ◽  
Brain Barrier ◽  
Transport Systems ◽  
Animal Models Of Disease ◽  
Blood Brain ◽  
Models Of Disease ◽  
The Brain

Nanoparticles with oligonucleotides bound to the outside or incorporated into the matrix can be used for gene editing or to modulate gene expression in the CNS. These nanocarriers are usually optimised for transfection of neurons or glia. They can also facilitate transcytosis across the brain endothelium to circumvent the blood-brain barrier. This review examines the different formulations of nanocarriers and their oligonucleotide cargoes, in relation to their ability to enter the brain and modulate gene expression or disease. The size of the nanocarrier is critical in determining the rate of clearance from the plasma as well as the intracellular routes of endothelial transcytosis. The surface charge is important in determining how it interacts with the endothelium and the target cell. The structure of the oligonucleotide affects its stability and rate of degradation, while the chemical formulation of the nanocarrier primarily controls the location and rate of cargo release. Due to the major anatomical differences between humans and animal models of disease, successful gene therapy with oligonucleotides in humans has required intrathecal injection. In animal models, some progress has been made with intraventricular or intravenous injection of oligonucleotides on nanocarriers. However, getting significant amounts of nanocarriers across the blood-brain barrier in humans will likely require targeting endothelial solute carriers or vesicular transport systems.

scholarly journals Drug Transport across the Blood–Brain Barrier

2012 ◽  
Vol 32 (11) ◽  
pp. 1959-1972 ◽  
Author(s):  
William M Pardridge
Keyword(s):  
Blood Brain Barrier ◽  
Small Molecule ◽  
Drug Transport ◽  
Delivery Systems ◽  
Brain Barrier ◽  
Large Molecule ◽  
Transport Systems ◽  
Small Molecule Drugs ◽  
Blood Brain ◽  
The Brain

The blood–brain barrier (BBB) prevents the brain uptake of most pharmaceuticals. This property arises from the epithelial-like tight junctions within the brain capillary endothelium. The BBB is anatomically and functionally distinct from the blood–cerebrospinal fluid barrier at the choroid plexus. Certain small molecule drugs may cross the BBB via lipid-mediated free diffusion, providing the drug has a molecular weight <400 Da and forms <8 hydrogen bonds. These chemical properties are lacking in the majority of small molecule drugs, and all large molecule drugs. Nevertheless, drugs can be reengineered for BBB transport, based on the knowledge of the endogenous transport systems within the BBB. Small molecule drugs can be synthesized that access carrier-mediated transport (CMT) systems within the BBB. Large molecule drugs can be reengineered with molecular Trojan horse delivery systems to access receptor-mediated transport (RMT) systems within the BBB. Peptide and antisense radiopharmaceuticals are made brain-penetrating with the combined use of RMT-based delivery systems and avidin–biotin technology. Knowledge on the endogenous CMT and RMT systems expressed at the BBB enable new solutions to the problem of BBB drug transport.

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

2018 ◽  
Vol 25 (9) ◽  
pp. 1073-1089 ◽  
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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