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Molecular Psychiatry Jun 2022The blood-brain barrier (BBB) is vital for maintaining brain homeostasis by enabling an exquisite control of exchange of compounds between the blood and the brain... (Review)
Review
The blood-brain barrier (BBB) is vital for maintaining brain homeostasis by enabling an exquisite control of exchange of compounds between the blood and the brain parenchyma. Moreover, the BBB prevents unwanted toxins and pathogens from entering the brain. This barrier, however, breaks down with age and further disruption is a hallmark of many age-related disorders. Several drugs have been explored, thus far, to protect or restore BBB function. With the recent connection between the BBB and gut microbiota, microbial-derived metabolites have been explored for their capabilities to protect and restore BBB physiology. This review, will focus on the vital components that make up the BBB, dissect levels of disruption of the barrier, and discuss current drugs and therapeutics that maintain barrier integrity and the recent discoveries of effects microbial-derived metabolites have on BBB physiology.
Topics: Biological Transport; Blood-Brain Barrier; Brain; Homeostasis
PubMed: 35361905
DOI: 10.1038/s41380-022-01511-z -
Cells Apr 2020The blood-brain barrier (BBB) is one of the most complex and selective barriers in the human organism. Its role is to protect the brain and preserve the homeostasis of... (Review)
Review
The blood-brain barrier (BBB) is one of the most complex and selective barriers in the human organism. Its role is to protect the brain and preserve the homeostasis of the central nervous system (CNS). The central elements of this physical and physiological barrier are the endothelial cells that form a monolayer of tightly joined cells covering the brain capillaries. However, as endothelial cells regulate nutrient delivery and waste product elimination, they are very sensitive to signals sent by surrounding cells and their environment. Indeed, the neuro-vascular unit (NVU) that corresponds to the assembly of extracellular matrix, pericytes, astrocytes, oligodendrocytes, microglia and neurons have the ability to influence BBB physiology. Extracellular vesicles (EVs) play a central role in terms of communication between cells. The NVU is no exception, as each cell can produce EVs that could help in the communication between cells in short or long distances. Studies have shown that EVs are able to cross the BBB from the brain to the bloodstream as well as from the blood to the CNS. Furthermore, peripheral EVs can interact with the BBB leading to changes in the barrier's properties. This review focuses on current knowledge and potential applications regarding EVs associated with the BBB.
Topics: Animals; Biological Transport; Blood-Brain Barrier; Extracellular Vesicles; Humans; Models, Biological
PubMed: 32244730
DOI: 10.3390/cells9040851 -
Cell Stem Cell Jun 2019The blood-brain barrier (BBB) tightly regulates the entry of solutes from blood into the brain and is disrupted in several neurological diseases. Using Organ-Chip...
The blood-brain barrier (BBB) tightly regulates the entry of solutes from blood into the brain and is disrupted in several neurological diseases. Using Organ-Chip technology, we created an entirely human BBB-Chip with induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial-like cells (iBMECs), astrocytes, and neurons. The iBMECs formed a tight monolayer that expressed markers specific to brain vasculature. The BBB-Chip exhibited physiologically relevant transendothelial electrical resistance and accurately predicted blood-to-brain permeability of pharmacologics. Upon perfusing the vascular lumen with whole blood, the microengineered capillary wall protected neural cells from plasma-induced toxicity. Patient-derived iPSCs from individuals with neurological diseases predicted disease-specific lack of transporters and disruption of barrier integrity. By combining Organ-Chip technology and human iPSC-derived tissue, we have created a neurovascular unit that recapitulates complex BBB functions, provides a platform for modeling inheritable neurological disorders, and advances drug screening, as well as personalized medicine.
Topics: Astrocytes; Bioengineering; Blood-Brain Barrier; Brain; Capillary Permeability; Cell Differentiation; Cells, Cultured; Drug Evaluation, Preclinical; Endothelium, Vascular; Humans; Induced Pluripotent Stem Cells; Microfluidics; Neurons; Organ Culture Techniques; Precision Medicine
PubMed: 31173718
DOI: 10.1016/j.stem.2019.05.011 -
Journal of Cerebral Blood Flow and... Dec 2020The blood-brain barrier (BBB) is a critical regulator of CNS homeostasis. It possesses physical and biochemical characteristics (i.e. tight junction protein complexes,... (Review)
Review
The blood-brain barrier (BBB) is a critical regulator of CNS homeostasis. It possesses physical and biochemical characteristics (i.e. tight junction protein complexes, transporters) that are necessary for the BBB to perform this physiological role. Microvascular endothelial cells require support from astrocytes, pericytes, microglia, neurons, and constituents of the extracellular matrix. This intricate relationship implies the existence of a neurovascular unit (NVU). NVU cellular components can be activated in disease and contribute to dynamic remodeling of the BBB. This is especially true of microglia, the resident immune cells of the brain, which polarize into distinct proinflammatory (M1) or anti-inflammatory (M2) phenotypes. Current data indicate that M1 pro-inflammatory microglia contribute to BBB dysfunction and vascular "leak", while M2 anti-inflammatory microglia play a protective role at the BBB. Understanding biological mechanisms involved in microglia activation provides a unique opportunity to develop novel treatment approaches for neurological diseases. In this review, we highlight characteristics of M1 proinflammatory and M2 anti-inflammatory microglia and describe how these distinct phenotypes modulate BBB physiology. Additionally, we outline the role of other NVU cell types in regulating microglial activation and highlight how microglia can be targeted for treatment of disease with a focus on ischemic stroke and Alzheimer's disease.
Topics: Blood-Brain Barrier; Humans; Microglia; Oxidative Stress
PubMed: 32928017
DOI: 10.1177/0271678X20951995 -
Frontiers in Immunology 2021Blood-Brain Barrier (BBB) disruption is an important pathophysiological process of acute ischemic stroke (AIS), resulting in devastating malignant brain edema and... (Review)
Review
Blood-Brain Barrier (BBB) disruption is an important pathophysiological process of acute ischemic stroke (AIS), resulting in devastating malignant brain edema and hemorrhagic transformation. The rapid activation of immune cells plays a critical role in BBB disruption after ischemic stroke. Infiltrating blood-borne immune cells (neutrophils, monocytes, and T lymphocytes) increase BBB permeability, as they cause microvascular disorder and secrete inflammation-associated molecules. In contrast, they promote BBB repair and angiogenesis in the latter phase of ischemic stroke. The profound immunological effects of cerebral immune cells (microglia, astrocytes, and pericytes) on BBB disruption have been underestimated in ischemic stroke. Post-stroke microglia and astrocytes can adopt both an M1/A1 or M2/A2 phenotype, which influence BBB integrity differently. However, whether pericytes acquire microglia phenotype and exert immunological effects on the BBB remains controversial. Thus, better understanding the inflammatory mechanism underlying BBB disruption can lead to the identification of more promising biological targets to develop treatments that minimize the onset of life-threatening complications and to improve existing treatments in patients. However, early attempts to inhibit the infiltration of circulating immune cells into the brain by blocking adhesion molecules, that were successful in experimental stroke failed in clinical trials. Therefore, new immunoregulatory therapeutic strategies for acute ischemic stroke are desperately warranted. Herein, we highlight the role of circulating and cerebral immune cells in BBB disruption and the crosstalk between them following acute ischemic stroke. Using a robust theoretical background, we discuss potential and effective immunotherapeutic targets to regulate BBB permeability after acute ischemic stroke.
Topics: Animals; Biomarkers; Blood-Brain Barrier; Brain; Cell Communication; Disease Management; Disease Models, Animal; Disease Susceptibility; Humans; Immune System; Immunotherapy; Ischemic Stroke
PubMed: 34248961
DOI: 10.3389/fimmu.2021.678744 -
International Journal of Molecular... May 2020Traumatic brain injuries (TBIs) account for the majority of injury-related deaths in the United States with roughly two million TBIs occurring annually. Due to the... (Review)
Review
Traumatic brain injuries (TBIs) account for the majority of injury-related deaths in the United States with roughly two million TBIs occurring annually. Due to the spectrum of severity and heterogeneity in TBIs, investigation into the secondary injury is necessary in order to formulate an effective treatment. A mechanical consequence of trauma involves dysregulation of the blood-brain barrier (BBB) which contributes to secondary injury and exposure of peripheral components to the brain parenchyma. Recent studies have shed light on the mechanisms of BBB breakdown in TBI including novel intracellular signaling and cell-cell interactions within the BBB niche. The current review provides an overview of the BBB, novel detection methods for disruption, and the cellular and molecular mechanisms implicated in regulating its stability following TBI.
Topics: Animals; Aquaporins; Astrocytes; Blood-Brain Barrier; Brain Edema; Brain Injuries, Traumatic; Cytokines; Disease Models, Animal; Endothelial Cells; Humans; Inflammation
PubMed: 32397302
DOI: 10.3390/ijms21093344 -
NeuroRx : the Journal of the American... Jan 2005The blood-brain barrier (BBB) is formed by the brain capillary endothelium and excludes from the brain approximately 100% of large-molecule neurotherapeutics and more... (Review)
Review
The blood-brain barrier (BBB) is formed by the brain capillary endothelium and excludes from the brain approximately 100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs. Despite the importance of the BBB to the neurotherapeutics mission, the BBB receives insufficient attention in either academic neuroscience or industry programs. The combination of so little effort in developing solutions to the BBB problem, and the minimal BBB transport of the majority of all potential CNS drugs, leads predictably to the present situation in neurotherapeutics, which is that there are few effective treatments for the majority of CNS disorders. This situation can be reversed by an accelerated effort to develop a knowledge base in the fundamental transport properties of the BBB, and the molecular and cellular biology of the brain capillary endothelium. This provides the platform for CNS drug delivery programs, which should be developed in parallel with traditional CNS drug discovery efforts in the molecular neurosciences.
Topics: Administration, Intranasal; Animals; Blood-Brain Barrier; Carrier Proteins; Central Nervous System Agents; Drug Delivery Systems; Drug Design; Humans; Hydrogen Bonding; Molecular Weight
PubMed: 15717053
DOI: 10.1602/neurorx.2.1.3 -
International Journal of Molecular... May 2023The blood-brain barrier (BBB) is a complex network of tightly regulated cells and transport proteins that separate the circulating blood from the brain tissue [...].
The blood-brain barrier (BBB) is a complex network of tightly regulated cells and transport proteins that separate the circulating blood from the brain tissue [...].
Topics: Blood-Brain Barrier; Brain; Biological Transport; Carrier Proteins
PubMed: 37298209
DOI: 10.3390/ijms24119261 -
Journal of Cerebral Blood Flow and... Mar 2016Advancements in molecular biology have led to a greater understanding of the individual proteins responsible for generating cerebral edema. In large part, the study of... (Review)
Review
Advancements in molecular biology have led to a greater understanding of the individual proteins responsible for generating cerebral edema. In large part, the study of cerebral edema is the study of maladaptive ion transport. Following acute CNS injury, cells of the neurovascular unit, particularly brain endothelial cells and astrocytes, undergo a program of pre- and post-transcriptional changes in the activity of ion channels and transporters. These changes can result in maladaptive ion transport and the generation of abnormal osmotic forces that, ultimately, manifest as cerebral edema. This review discusses past models and current knowledge regarding the molecular and cellular pathophysiology of cerebral edema.
Topics: Animals; Aquaporins; Blood-Brain Barrier; Brain; Brain Edema; Humans; Ion Transport; Ions; Permeability; Water
PubMed: 26661240
DOI: 10.1177/0271678X15617172 -
Journal of Neuroinflammation May 2018Epilepsy, a neurological disease characterized by recurrent seizures, is often associated with a history of previous lesions in the nervous system. Impaired regulation... (Review)
Review
Epilepsy, a neurological disease characterized by recurrent seizures, is often associated with a history of previous lesions in the nervous system. Impaired regulation of the activation and resolution of inflammatory cells and molecules in the injured neuronal tissue is a critical factor to the development of epilepsy. However, it is still unclear as to how that unbalanced regulation of inflammation contributes to epilepsy. Therefore, one of the goals in epilepsy research is to identify and elucidate the interconnected inflammatory pathways in systemic and neurological disorders that may further develop epilepsy progression. In this paper, inflammatory molecules, in neurological and systemic disorders (rheumatoid arthritis, Crohn's, Type I Diabetes, etc.) that could contribute to epilepsy development, are reviewed.Understanding the neurobiology of inflammation in epileptogenesis will contribute to the development of new biomarkers for better screening of patients at risk for epilepsy and new therapeutic targets for both prophylaxis and treatment of epilepsy.
Topics: Animals; Blood-Brain Barrier; Encephalitis; Epilepsy; Humans; Inflammation; Inflammation Mediators; Neurons; Signal Transduction
PubMed: 29764485
DOI: 10.1186/s12974-018-1192-7