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Cells Dec 2021The construction of the blood-brain barrier (BBB), which is a natural barrier for maintaining brain homeostasis, is the result of a meticulous organisation in space and... (Review)
Review
The construction of the blood-brain barrier (BBB), which is a natural barrier for maintaining brain homeostasis, is the result of a meticulous organisation in space and time of cell-cell communication processes between the endothelial cells that carry the BBB phenotype, the brain pericytes, the glial cells (mainly the astrocytes), and the neurons. The importance of these communications for the establishment, maturation and maintenance of this unique phenotype had already been suggested in the pioneering work to identify and demonstrate the BBB. As for the history of the BBB, the evolution of analytical techniques has allowed knowledge to evolve on the cell-cell communication pathways involved, as well as on the role played by the cells constituting the neurovascular unit in the maintenance of the BBB phenotype, and more particularly the brain pericytes. This review summarises the key points of the history of the BBB, from its origin to the current knowledge of its physiology, as well as the cell-cell communication pathways identified so far during its development, maintenance, and pathophysiological alteration.
Topics: Animals; Blood-Brain Barrier; Cell Communication; Embryonic Development; Humans; Models, Biological; Phenotype
PubMed: 35011695
DOI: 10.3390/cells11010133 -
Tissue Barriers 2016The blood brain barrier (BBB) plays a critical role in the normal physiology of the central nervous system (CNS) by regulating what crosses from the periphery into the... (Review)
Review
The blood brain barrier (BBB) plays a critical role in the normal physiology of the central nervous system (CNS) by regulating what crosses from the periphery into the brain. Damage to the BBB or alterations in transport systems may mediate the pathogenesis of many CNS diseases, including HIV-associated CNS dysfunction. HIV-1 infection can result in neuropathologic changes in about one half of infected individuals and also can result in damage to the BBB. HIV-1 and the HIV-1 viral proteins, Tat and gp120, cause alterations in the integrity and function of the BBB through both paracellular and transcellular mechanisms. The current review discusses HIV and viral protein-mediated injury to the BBB with a focus on the effects on tight junction proteins, barrier permeability, and drug efflux proteins.
Topics: Animals; Blood-Brain Barrier; Capillary Permeability; HIV Infections; Humans; Tight Junction Proteins; Viral Proteins
PubMed: 27141423
DOI: 10.1080/21688370.2016.1143543 -
Methods in Molecular Biology (Clifton,... 2022The brain is endowed with highly specialized vasculature that is both structurally and functionally unique compared to vasculature supplying peripheral organs. The... (Review)
Review
The brain is endowed with highly specialized vasculature that is both structurally and functionally unique compared to vasculature supplying peripheral organs. The blood-brain barrier (BBB) is formed by endothelial cells of the cerebral vasculature and prevents extravasation of blood products into the brain to protect neural tissue and maintain a homeostatic environment. The BBB functions as part of the neurovascular unit (NVU), which is composed of neurons, astrocytes, and microglia in addition to the specialized endothelial cells, mural cells, and the basement membrane. Through coordinated intercellular signaling, these cells function as a dynamic unit to tightly regulate brain blood flow, vascular function, neuroimmune responses, and waste clearance. In this chapter, we review the functions of individual NVU components, describe neurovascular coupling as a classic example of NVU function, and discuss archetypal NVU pathophysiology during disease.
Topics: Astrocytes; Biological Transport; Blood-Brain Barrier; Brain; Endothelial Cells
PubMed: 35733036
DOI: 10.1007/978-1-0716-2289-6_1 -
Tissue Barriers Jan 2021The blood-brain barrier (BBB), a dynamic interface between blood and brain constituted mainly by endothelial cells of brain microvessels, robustly restricts the entry of... (Review)
Review
The blood-brain barrier (BBB), a dynamic interface between blood and brain constituted mainly by endothelial cells of brain microvessels, robustly restricts the entry of potentially harmful blood-sourced substances and cells into the brain, however, many therapeutically active agents concurrently cannot gain access into the brain at effective doses in the presence of an intact barrier. On the other hand, breakdown of BBB integrity may involve in the pathogenesis of various neurodegenerative diseases. Besides, certain diseases/disorders such as Alzheimer's disease, hypertension, and epilepsy are associated with varying degrees of BBB disruption. In this review, we aim to highlight the current knowledge on the cellular and molecular composition of the BBB with special emphasis on the major transport pathways across the barrier type endothelial cells. We further provide a discussion on the innovative brain drug delivery strategies in which the obstacle formed by BBB interferes with effective pharmacological treatment of neurodegenerative diseases/disorders.
Topics: Blood-Brain Barrier; Drug Delivery Systems; Humans
PubMed: 33190576
DOI: 10.1080/21688370.2020.1840913 -
Fluids and Barriers of the CNS Apr 2021The vessels of the central nervous system (CNS) have unique barrier properties. The endothelial cells (ECs) which comprise the CNS vessels contribute to the barrier via... (Review)
Review
The vessels of the central nervous system (CNS) have unique barrier properties. The endothelial cells (ECs) which comprise the CNS vessels contribute to the barrier via strong tight junctions, specific transporters, and limited endocytosis which combine to protect the brain from toxins and maintains brain homeostasis. Blood-brain barrier (BBB) leakage is a serious secondary injury in various CNS disorders like stroke, brain tumors, and neurodegenerative disorders. Currently, there are no drugs or therapeutics available to treat specifically BBB damage after a brain injury. Growing knowledge in the field of epigenetics can enhance the understanding of gene level of the BBB and has great potential for the development of novel therapeutic strategies or targets to repair a disrupted BBB. In this brief review, we summarize the epigenetic mechanisms or regulators that have a protective or disruptive role for components of BBB, along with the promising approaches to regain the integrity of BBB.
Topics: Blood-Brain Barrier; Central Nervous System Diseases; Epigenesis, Genetic; Gene Expression Regulation; Humans
PubMed: 33823899
DOI: 10.1186/s12987-021-00250-7 -
Fluids and Barriers of the CNS Jul 2020The complexity of the blood-brain barrier (BBB) and neurovascular unit (NVU) was and still is a challenge to bridge. A highly selective, restrictive and dynamic barrier,... (Review)
Review
The complexity of the blood-brain barrier (BBB) and neurovascular unit (NVU) was and still is a challenge to bridge. A highly selective, restrictive and dynamic barrier, formed at the interface of blood and brain, the BBB is a "gatekeeper" and guardian of brain homeostasis and it also acts as a "sensor" of pathological events in blood and brain. The majority of brain and cerebrovascular pathologies are associated with BBB dysfunction, where changes at the BBB can lead to or support disease development. Thus, an ultimate goal of BBB research is to develop competent and highly translational models to understand mechanisms of BBB/NVU pathology and enable discovery and development of therapeutic strategies to improve vascular health and for the efficient delivery of drugs. This review article focuses on the progress being made to model BBB injury in cerebrovascular diseases in vitro.
Topics: Astrocytes; Blood-Brain Barrier; Cerebrovascular Disorders; Endothelial Cells; Humans; In Vitro Techniques; Models, Neurological; Neurons; Tight Junctions
PubMed: 32677965
DOI: 10.1186/s12987-020-00202-7 -
Metabolic Brain Disease Aug 2020Stroke is the leading cause of disability among adults as well as the 2nd leading cause of death globally. Ischemic stroke accounts for about 85% of strokes, and... (Review)
Review
Stroke is the leading cause of disability among adults as well as the 2nd leading cause of death globally. Ischemic stroke accounts for about 85% of strokes, and currently, tissue plasminogen activator (tPA), whose therapeutic window is limited to up to 4.5 h for the appropriate population, is the only FDA approved drug in practice and medicine. After a stroke, a cascade of pathophysiological events results in the opening of the blood-brain barrier (BBB) through which further complications, disabilities, and mortality are likely to threaten the patient's health. Strikingly, tPA administration in eligible patients might cause hemorrhagic transformation and sustained damage to BBB integrity. One must, therefore, delineate upon stroke onset which cellular and molecular factors mediate BBB permeability as well as what key roles BBB rupture plays in the pathophysiology of stroke. In this review article, given our past findings of mechanisms underlying BBB opening in stroke animal models, we elucidate cellular, subcellular, and molecular factors involved in BBB permeability after ischemic stroke. The contribution of each factor to stroke severity and outcome is further discussed. Determinant factors in BBB permeability and stroke include mitochondria, miRNAs, matrix metalloproteinases (MMPs), immune cells, cytokines, chemokines, and adhesion proteins. Once these factors are interrogated and their roles in the pathophysiology of stroke are determined, novel targets for drug discovery and development can be uncovered in addition to novel therapeutic avenues for human stroke management.
Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Capillary Permeability; Humans; Ischemic Stroke
PubMed: 32297170
DOI: 10.1007/s11011-020-00573-8 -
International Journal of Nanomedicine 2014The protective properties of the blood-brain barrier (BBB) are conferred by the intricate architecture of its endothelium coupled with multiple specific transport... (Review)
Review
The protective properties of the blood-brain barrier (BBB) are conferred by the intricate architecture of its endothelium coupled with multiple specific transport systems expressed on the surface of endothelial cells (ECs) in the brain's vasculature. When the stringent control of the BBB is disrupted, such as following EC damage, substances that are safe for peripheral tissues but toxic to neurons have easier access to the central nervous system (CNS). As a consequence, CNS disorders, including degenerative diseases, can occur independently of an individual's age. Although the BBB is crucial in regulating the biochemical environment that is essential for maintaining neuronal integrity, it limits drug delivery to the CNS. This makes it difficult to deliver beneficial drugs across the BBB while preventing the passage of potential neurotoxins. Available options include transport of drugs across the ECs through traversing occludins and claudins in the tight junctions or by attaching drugs to one of the existing transport systems. Either way, access must specifically allow only the passage of a particular drug. In general, the BBB allows small molecules to enter the CNS; however, most drugs with the potential to treat neurological disorders other than infections have large structures. Several mechanisms, such as modifications of the built-in pumping-out system of drugs and utilization of nanocarriers and liposomes, are among the drug-delivery systems that have been tested; however, each has its limitations and constraints. This review comprehensively discusses the functional morphology of the BBB and the challenges that must be overcome by drug-delivery systems and elaborates on the potential targets, mechanisms, and formulations to improve drug delivery to the CNS.
Topics: Animals; Biological Transport, Active; Blood-Brain Barrier; Chemistry, Pharmaceutical; Colloids; Drug Delivery Systems; Humans; Liposomes; Nanomedicine; Nanoparticles; Nanotechnology
PubMed: 24550672
DOI: 10.2147/IJN.S52236 -
International Journal of Molecular... Aug 2021The disruption of blood-brain barrier (BBB) for multiple sclerosis (MS) pathogenesis has a double effect: early on during the onset of the immune attack and later for... (Review)
Review
The disruption of blood-brain barrier (BBB) for multiple sclerosis (MS) pathogenesis has a double effect: early on during the onset of the immune attack and later for the CNS self-sustained 'inside-out' demyelination and neurodegeneration processes. This review presents the characteristics of BBB malfunction in MS but mostly highlights current developments regarding the impairment of the neurovascular unit (NVU) and the metabolic and mitochondrial dysfunctions of the BBB's endothelial cells. The hypoxic hypothesis is largely studied and agreed upon recently in the pathologic processes in MS. Hypoxia in MS might be produced per se by the NVU malfunction or secondary to mitochondria dysfunction. We present three different but related terms that denominate the ongoing neurodegenerative process in progressive forms of MS that are indirectly related to BBB disruption: progression independent of relapses, no evidence of disease activity and smoldering demyelination or silent progression. Dimethyl fumarate (DMF), modulators of S1P receptor, cladribine and laquinimode are DMTs that are able to cross the BBB and exhibit beneficial direct effects in the CNS with very different mechanisms of action, providing hope that a combined therapy might be effective in treating MS. Detailed mechanisms of action of these DMTs are described and also illustrated in dedicated images. With increasing knowledge about the involvement of BBB in MS pathology, BBB might become a therapeutic target in MS not only to make it impenetrable against activated immune cells but also to allow molecules that have a neuroprotective effect in reaching the cell target inside the CNS.
Topics: Animals; Blood-Brain Barrier; Disease Progression; Endothelial Cells; Humans; Mitochondria; Multiple Sclerosis
PubMed: 34445097
DOI: 10.3390/ijms22168370 -
Journal of Cerebral Blood Flow and... Jan 2017The age-associated decline of the neurological and cognitive functions becomes more and more serious challenge for the developed countries with the increasing number of... (Review)
Review
The age-associated decline of the neurological and cognitive functions becomes more and more serious challenge for the developed countries with the increasing number of aged populations. The morphological and biochemical changes in the aging brain are the subjects of many extended research projects worldwide for a long time. However, the crucial role of the blood-brain barrier (BBB) impairment and disruption in the pathological processes in age-associated neurodegenerative disorders received special attention just for a few years. This article gives an overview on the major elements of the blood-brain barrier and its supporting mechanisms and also on their alterations during development, physiological aging process and age-associated neurodegenerative disorders (Alzheimer's disease, multiple sclerosis, Parkinson's disease, pharmacoresistant epilepsy). Besides the morphological alterations of the cellular elements (endothelial cells, astrocytes, pericytes, microglia, neuronal elements) of the BBB and neurovascular unit, the changes of the barrier at molecular level (tight junction proteins, adheres junction proteins, membrane transporters, basal lamina, extracellular matrix) are also summarized. The recognition of new players and initiators of the process of neurodegeneration at the level of the BBB may offer new avenues for novel therapeutic approaches for the treatment of numerous chronic neurodegenerative disorders currently without effective medication.
Topics: Aging; Blood-Brain Barrier; Humans; Neurodegenerative Diseases
PubMed: 27837191
DOI: 10.1177/0271678X16679420