Transport of Xenobiotics Across the Blood-Brain Barrier

Physiology ◽  
2002 ◽  
Vol 17 (6) ◽  
pp. 231-234 ◽  
Author(s):  
Bruno Hagenbuch ◽  
Bo Gao ◽  
Peter. J. Meier
Keyword(s):  
Blood Brain Barrier ◽  
Transport Proteins ◽  
Brain Barrier ◽  
Drug Transporter ◽  
Detailed Characterization ◽  
Waste Products ◽  
Blood Brain ◽  
The Brain

Distinct transport proteins regulate the movement of waste products and xenobiotics across the blood-brain barrier (BBB). Members of the drug transporter families MDR, MRP, and OATP have been identified in the BBB, and a detailed characterization of the involved proteins is now required to target drugs more efficiently to the brain.

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 Blood–Brain Barrier, Lymphatic Clearance, and Recovery: Ariadne’s Thread in Labyrinths of Hypotheses

2018 ◽  
Vol 19 (12) ◽  
pp. 3818 ◽  
Author(s):  
Oxana Semyachkina-Glushkovskaya ◽  
Dmitry Postnov ◽  
Jürgen Kurths
Keyword(s):  
Blood Brain Barrier ◽  
Lymphatic System ◽  
Metabolic Diseases ◽  
Brain Barrier ◽  
Waste Products ◽  
Brain Functions ◽  
Blood Brain ◽  
New Vision ◽  
The Brain

The peripheral lymphatic system plays a crucial role in the recovery mechanisms after many pathological changes, such as infection, trauma, vascular, or metabolic diseases. The lymphatic clearance of different tissues from waste products, viruses, bacteria, and toxic proteins significantly contributes to the correspondent recovery processes. However, understanding of the cerebral lymphatic functions is a challenging problem. The exploration of mechanisms of lymphatic communication with brain fluids as well as the role of the lymphatic system in brain drainage, clearance, and recovery is still in its infancy. Here we review novel concepts on the anatomy and physiology of the lymphatics in the brain, which warrant a substantial revision of our knowledge about the role of lymphatics in the rehabilitation of the brain functions after neural pathologies. We discuss a new vision on the connective bridge between the opening of a blood–brain barrier and activation of the meningeal lymphatic clearance. The ability to stimulate the lymph flow in the brain, is likely to play an important role in developing future innovative strategies in neurorehabilitation therapy.

scholarly journals Blood-brain barrier, lymphatic clearance and recovery: Ariadne’s thread in labyrinths of hypothesis

2018 ◽  
Author(s):  
Oxana Semyachkina-Glushkovskaya ◽  
Dmitry Postnov ◽  
Jürgen Kurths
Keyword(s):  
Blood Brain Barrier ◽  
Lymphatic System ◽  
Metabolic Diseases ◽  
Lymphatic Drainage ◽  
Brain Barrier ◽  
Waste Products ◽  
Brain Functions ◽  
Blood Brain ◽  
The Brain

The peripheral lymphatic system plays a crucial role in the recovery mechanisms after many pathological changes, such as infection, trauma, vascular, or metabolic diseases. The lymphatic clearance of different tissues from waste products, viruses, bacteria and toxic proteins significantly contributes to the correspondent recovery processes. However, understanding of the meningeal lymphatics functions is a challenging problem. The exploration of mechanisms of lymphatic communication with brain fluids as well as the role of the lymphatic system in the brain drainage, clearance and recovery are still in its infancy. Here we review novel concepts on the anatomy and physiology of the lymphatics in the brain, which warrant a substantial revision of our knowledge about the role of lymphatics in the rehabilitation of the brain functions after neural pathologies. We discuss a new vision on how to recruit the meningeal lymphatics by the opening of blood-brain barrier as a trigger mechanism of activation of the meningeal lymphatic drainage. This leads to innovative strategies in neurorehabilitation therapy.

scholarly journals On the shuttling across the blood-brain barrier via tubules formation: mechanism and cargo avidity bias

2020 ◽  
Author(s):  
Xiaohe Tian ◽  
Diana Moreira Leite ◽  
Edoardo Scarpa ◽  
Sophie Nyberg ◽  
Gavin Fullstone ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Density Lipoprotein ◽  
Brain Barrier ◽  
Receptor Interaction ◽  
High Avidity ◽  
Waste Products ◽  
Blood Brain ◽  
The Brain

The blood-brain barrier is made of polarised brain endothelial cells (BECs) phenotypically conditioned by the central nervous system (CNS). Transport across BECs is of paramount importance for nutrient uptake as well as to rid the brain of waste products. Nevertheless, currently we do not understand how large macromolecular cargo shuttles across and how BECs discriminate between the brain-bound and own nutrients. Here, we study the low-density lipoprotein receptor-related protein 1 (LRP1) an essential regulator of BEC transport, and show that it is associated with endocytic effectors, endo-lysosomal compartments as well as syndapin-2, a member of the Bin/Amphiphysin/Rvs (BAR) domain superfamily known to stabilise tubular carriers. We employed synthetic self-assembled vesicles, polymersomes, as a multivalent system with tunable avidity as a tool to investigate the mechanism of transport across BECs. We used a combination of conventional and super-resolution microscopy, both in vivo and in vitro, accompanied with biophysical modelling of transport kinetics and membrane-bound interactions. Our results demonstrate that the avidity of the ligand-receptor interaction (the overall cargo binding energy) determines the mechanism of sorting during the early stages of endocytosis and consequent trafficking. We show that high avidity cargo biases the LRP1 towards internalisation and fast degradation in BECs, while mid avidity augments the formation of syndapin-2 stabilised tubular carriers and promotes fast shuttling across BECs. Thus, we map out a very detailed mechanism where clathrin, actin, syndapin-2, dynamin and SNARE act synergistically to enable fast shuttling across BECs.

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.

Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease

2020 ◽  
Vol 26 (37) ◽  
pp. 4721-4737 ◽  
Author(s):  
Bhumika Kumar ◽  
Mukesh Pandey ◽  
Faheem H. Pottoo ◽  
Faizana Fayaz ◽  
Anjali Sharma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Side Effects ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Neural Cells ◽  
Blood Brain ◽  
The Brain

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

Brain Drug Delivery: Overcoming the Blood-brain Barrier to Treat Tauopathies

2020 ◽  
Vol 26 (13) ◽  
pp. 1448-1465 ◽  
Author(s):  
Jozef Hanes ◽  
Eva Dobakova ◽  
Petra Majerova
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Neurodegenerative Disorders ◽  
Brain Barrier ◽  
Neuronal Function ◽  
Brain Drug Delivery ◽  
Naturally Occurring ◽  
Blood Brain ◽  
Traditional Approaches ◽  
The Brain

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. Yet, these natural functions possessed by BBB represent a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics’ delivery through the BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with advanced medical techniques. Their limitations and benefits are discussed.

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