Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview (original) (raw)
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The blood-brain barrier: an overview: mechanisms, functions, treatment & Clinical implications
International Journal Of Novel Research And Development, 2023
All of the body's tissues and organs depend on blood arteries to carry oxygen and nutrients to them. The blood-brain barrier, a special property of the blood arteries that vascularize the central nervous system (CNS), enables these vessels to tightly control the transit of ions, chemicals, and cells between the blood and the brain. Correct neuronal function is enabled by the careful regulation of CNS homeostasis, which also safeguards neural tissue from toxins and infections. Alterations to these barrier qualities play a significant role in the pathophysiology and development of various neurological illnesses. The endothelial cells (ECs), which make up the blood vessel walls, have a variety of physical, transport, and metabolic characteristics that help to coordinate the physiological barrier. The unique characteristics of the Blood-Brain Barrier must be taken into account in any programme for drug discovery or delivery that seeks to target or avoid the CNS.
The blood-brain barrier/neurovascular unit in health and disease
Pharmacological reviews, 2005
The blood-brain barrier (BBB) is the regulated interface between the peripheral circulation and the central nervous system (CNS). Although originally observed by Paul Ehrlich in 1885, the nature of the BBB was debated well into the 20th century. The anatomical substrate of the BBB is the cerebral microvascular endothelium, which, together with astrocytes, pericytes, neurons, and the extracellular matrix, constitute a "neurovascular unit" that is essential for the health and function of the CNS. Tight junctions (TJ) between endothelial cells of the BBB restrict paracellular diffusion of water-soluble substances from blood to brain. The TJ is an intricate complex of transmembrane (junctional adhesion molecule-1, occludin, and claudins) and cytoplasmic (zonula occludens-1 and -2, cingulin, AF-6, and 7H6) proteins linked to the actin cytoskeleton. The expression and subcellular localization of TJ proteins are modulated by several intrinsic signaling pathways, including those i...
The blood-brain barrier in health and disease
Annals of Neurology, 2012
The blood-brain barrier (BBB) is a term used to describe a series of properties possessed by the vasculature of the central nervous system (CNS) that tightly regulate the movement of ions, molecules, and cells between the blood and the CNS. This barrier is crucial to provide the appropriate environment to allow for proper neural function, as well as protect the CNS from injury and disease. In this review, I discuss the cellular and molecular composition of the BBB and how the development and function of the BBB is regulated by interactions with the CNS microenvironment. I further discuss what is known about BBB dysfunction during CNS injury and disease, as well as methodology used to deliver drugs across the BBB to the CNS.
Blood-brain barrier transport machineries and targeted therapy of brain diseases
BioImpacts, 2016
Introduction Microcirculation of nutrients and drugs into the brain is selectively controlled by a unique biological barrier called blood-brain barrier (BBB). Such biological barrier is formed by the brain capillary endothelial cells (BCECs) whose maturation and functions is largely dependent upon intercellular interaction with brain astrocytes and pericytes. 1-3 Of the BBB cooperating cells, the astrocytes are members of the glial family, which are able to interact with neurons and other brain cells (e.g., microglia and endothelial cells) directly and/or indirectly through the exchange of soluble materials. At the BBB, the astrocytic foot process covers 99% of the abluminal surface of the capillary basement membrane, while the brain capillary pericytes share the basement membrane with BCECs (Fig. 1). The BCECs form a cooperating complex with astrocytes and pericytes (the "Neurovascular Unit") to: (a) maintain brain homeostasis, (b) selectively control the delivery of nutrients and blood-borne solutes to the brain parenchyma. 1 In addition to other modulation roles of astrocytes and pericytes on BCECs (e.g., restrictive tight junction (TJ) regulation and differentiation), they are also involved in modulating the functional expression of transport machineries required for the selective inward/ outward transportation of nutrients and drugs. 4 It is now well-documented that the capability of a
Frontiers in Cellular Neuroscience, 2019
The blood-brain barrier (BBB) helps maintain a tightly regulated microenvironment for optimal central nervous system (CNS) homeostasis and facilitates communications with the peripheral circulation. The brain endothelial cells, lining the brain's vasculature, maintain close interactions with surrounding brain cells, e.g., astrocytes, pericytes and perivascular macrophages. This function facilitates critical intercellular crosstalk, giving rise to the concept of the neurovascular unit (NVU). The steady and appropriate communication between all components of the NVU is essential for normal CNS homeostasis and function, and dysregulation of one of its constituents can result in disease. Among the different brain regions, and along the vascular tree, the cellular composition of the NVU varies. Therefore, differential cues from the immediate vascular environment can affect BBB phenotype. To support the fluctuating metabolic and functional needs of the underlying neuropil, a specialized vascular heterogeneity is required. This is achieved by variances in barrier function, expression of transporters, receptors, and adhesion molecules. This mini-review will take you on a journey through evolving concepts surrounding the BBB, the NVU and beyond. Exploring classical experiments leading to new approaches will allow us to understand that the BBB is not merely a static separation between the brain and periphery but a closely regulated and interactive entity. We will discuss shifting paradigms, and ultimately aim to address the importance of BBB endothelial heterogeneity with regard to the function of the BBB within the NVU, and touch on its implications for different neuropathologies.
Structure and function of the blood-brain barrier
Frontiers in Pharmacology, 2010
Neural signalling within the central nervous system (CNS) requires a highly controlled microenvironment. Cells at three key interfaces form barriers between the blood and the CNS: the blood-brain barrier (BBB), blood-CSF barrier and the arachnoid barrier. The BBB at the level of brain microvessel endothelium is the major site of blood-CNS exchange. The structure and function of the BBB is summarised, the physical barrier formed by the endothelial tight junctions, and the transport barrier resulting from membrane transporters and vesicular mechanisms. The roles of associated cells are outlined, especially the endfeet of astrocytic glial cells, and pericytes and microglia. The embryonic development of the BBB, and changes in pathology are described. The BBB is subject to short and long-term regulation, which may be disturbed in pathology. Any programme for drug discovery or delivery, to target or avoid the CNS, needs to consider the special features of the BBB.
Blood-Brain Barrier Permeability: From Bench to Bedside
Management of Epilepsy - Research, Results and Treatment, 2011
The concept of the blood-brain barrier (termed hematoencephalic barrier) was first introduced by Lina Stern in 1921, although the early work by Paul Ehrlich and Edwin Goldmann suggested the compartmentalization between blood and brain and a role of blood vessels in maintaining these compartments (Ehrlich, 1885; Goldmann, 1913; Vein, 2008). However, actual proof of the existence of a BBB came in the 1960s. Since then, significant progress has been made in defining the functions and properties of that barrier. The BBB is a highly specialized structural and biochemical barrier that regulates the entry of blood-borne molecules and cells into brain and preserves ionic homeostasis within the brain microenvironment (Pardridge, 2007; Rubin & Staddon, 1999; Ueno, 2007). Formed at the interface between blood and brain parenchyma, the BBB is composed of a tightly sealed monolayer of brain endothelial cells at the brain capillary surface and adjacent perivascular cells, including astrocytes and pericytes. Both astrocytic endfeet and pericyte processes wrap the abluminal capillary surface and through indirect or direct synapse-like "pegsocket" interactions provide physical support and stability to the BBB (Abbott, 2002; Armulik et al, 2010; Kim et al, 2006; Williams et al, 2001). In recent years, the concept of a BBB has been significantly extended to the concept of a neurovascular unit, which best describes the dynamic communication between brain endothelium, neurons, astrocytes, pericytes, vascular smooth muscle cells, microglia and perivascular macrophages at the interface between the blood and brain parenchyma compartments (Hawkins & Davis, 2005; Wolburg et al, 2009). A healthy brain relies on all of the cells of the neurovascular unit to function properly and communicate with each other in order for neuronal synapses and circuitries to maintain normal cognitive functions (Fig. 1). 2. Blood-brain barrier junctional complexes The structural properties of the BBB are primarily determined by the endothelial junctional complexes, consisting of tight junctions (TJ) and adherens junctions (AdJ). The interactions between brain endothelial cells provide high endothelial electrical resistance barrier, in the range of 1500-2000 Ω.cm 2 (pial vessels), as compared to 3-33 Ω.cm 2 endothelial barrier in www.intechopen.com
Blood-Brain Barrier Overview: Structural and Functional Correlation
Neural Plasticity
The blood-brain barrier (BBB) is a semipermeable and extremely selective system in the central nervous system of most vertebrates, that separates blood from the brain’s extracellular fluid. It plays a vital role in regulating the transport of necessary materials for brain function, furthermore, protecting it from foreign substances in the blood that could damage it. In this review, we searched in Google Scholar, Pubmed, Web of Science, and Saudi Digital Library for the various cells and components that support the development and function of this barrier, as well as the different pathways to transport the various molecules between blood and the brain. We also discussed the aspects that lead to BBB dysfunction and its neuropathological consequences, with the identification of some of the most important biomarkers that might be used as a biomarker to predict the BBB disturbances. This comprehensive overview of BBB will pave the way for future studies to focus on developing more specif...
Disruption of the Blood-Brain Barrier During Neuroinflammatory and Neuroinfectious Diseases
Contemporary Clinical Neuroscience
As the organ of highest metabolic demand, utilizing over 25% of total body glucose utilization via an enormous vasculature with one capillary every 73 μm, the brain evolves a barrier at the capillary and postcapillary venules to prevent toxicity during serum fluctuations in metabolites and hormones, to limit brain swelling during inflammation, and to prevent pathogen invasion. Understanding of neuroprotective barriers has since evolved to incorporate the neurovascular unit (NVU), the blood-cerebrospinal fluid (CSF) barrier, and the presence of CNS lymphatics that allow leukocyte egress. Identification of the cellular and molecular participants in BBB function at the NVU has allowed detailed analyses of mechanisms that contribute to BBB dysfunction in various disease states, which include both autoimmune and infectious etiologies. This chapter will introduce some of the cellular and molecular components that promote barrier function but may be manipulated by inflammatory mediators or pathogens during neuroinflammation or neuroinfectious diseases.