The blood-brain barrier in aging and neurodegeneration

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 27(6), P. 2659 - 2673

Published: March 31, 2022

Abstract The blood-brain barrier (BBB) is vital for maintaining brain homeostasis by enabling an exquisite control of exchange compounds between the blood and parenchyma. Moreover, BBB prevents unwanted toxins pathogens from entering brain. This barrier, however, breaks down with age further disruption a hallmark many age-related disorders. Several drugs have been explored, thus far, to protect or restore function. With recent connection gut microbiota, microbial-derived metabolites explored their capabilities physiology. review, will focus on components that make up BBB, dissect levels discuss current therapeutics maintain integrity discoveries effects

Language: Английский

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Structure, Function, and Regulation of the Blood-Brain Barrier Tight Junction in Central Nervous System Disorders

Frontiers in Physiology, Journal Year: 2020, Volume and Issue: 11

Published: Aug. 6, 2020

The blood-brain barrier (BBB) allows the brain to selectively import nutrients and energy critical neuronal function while simultaneously excluding neurotoxic substances from peripheral circulation. In contrast highly permeable vasculature present in most organs that reside outside of central nervous system (CNS), BBB exhibits a high transendothelial electrical resistance along with low rate transcytosis greatly restricted paracellular permeability. property permeability is controlled by tight junction protein complexes seal route between apposing microvascular endothelial cells. Although are principal contributors physical properties, they not static nature. Rather, dynamic structures where expression and/or localization individual constituent proteins can be modified response pathophysiological stressors. These stressors induce modifications involve de novo synthesis new or discrete trafficking mechanisms. Such responsiveness junctions diseases indicates these for maintenance CNS homeostasis. fulfillment this vital role, also major obstacle therapeutic drug delivery brain. There an opportunity overcome substantial optimize neuropharmacology via acquisition detailed understanding structure, function, regulation. review, we discuss physiological characteristics how properties regulate therapeutics treatment neurological diseases. Specifically, will modulation regulation both context disease states setting pharmacotherapy. particular, highlight potentially manipulated at molecular level increase levels transport

Language: Английский

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Regulation of blood–brain barrier integrity by microglia in health and disease: A therapeutic opportunity

Journal of Cerebral Blood Flow & Metabolism, Journal Year: 2020, Volume and Issue: 40(1_suppl), P. S6 - S24

Published: Sept. 14, 2020

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, constituents extracellular matrix. This intricate relationship implies existence neurovascular unit (NVU). NVU cellular components can be activated in disease contribute dynamic remodeling BBB. especially true resident immune brain, which polarize into distinct proinflammatory (M1) or anti-inflammatory (M2) phenotypes. Current data indicate M1 pro-inflammatory microglia dysfunction vascular “leak”, while M2 play protective role at Understanding biological mechanisms involved activation provides unique opportunity develop novel treatment approaches neurological diseases. In review, we highlight describe how these phenotypes modulate physiology. Additionally, outline other cell types regulating microglial targeted with focus on ischemic stroke Alzheimer’s disease.

Language: Английский

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Pathophysiology of Blood–Brain Barrier Permeability Throughout the Different Stages of Ischemic Stroke and Its Implication on Hemorrhagic Transformation and Recovery

Frontiers in Neurology, Journal Year: 2020, Volume and Issue: 11

Published: Dec. 9, 2020

The blood-brain barrier (BBB) is a dynamic interface responsible for maintaining the central nervous system homeostasis. Its unique characteristics allow protecting brain from unwanted compounds, but its impairment involved in vast number of pathological conditions. Disruption BBB and increase permeability are key development several neurological diseases have been extensively studied stroke. Ischemic stroke most prevalent type characterized by myriad events triggered an arterial occlusion that can eventually lead to fatal outcomes such as hemorrhagic transformation (HT). seems follow multiphasic pattern throughout different stages associated with distinct biological substrates. In hyperacute stage, sudden hypoxia damages BBB, leading cytotoxic edema increased permeability; acute neuroinflammatory response aggravates injury, higher consequent risk HT be motivated reperfusion therapy; subacute stage (1-3 weeks), repair mechanisms take place, especially neoangiogenesis. Immature vessels show leaky this has improved clinical recovery. chronic (>6 restoration factors leads start decreasing permeability. Nonetheless, will persist some degree weeks after injury. Understanding behind dysregulation pathophysiology could potentially help guide care decisions new therapeutic targets; however, effective translation into practice still lacking. review, we address physiological through ischemic their role

Language: Английский

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The relationship between inflammation and neurocognitive dysfunction in obstructive sleep apnea syndrome

Journal of Neuroinflammation, Journal Year: 2020, Volume and Issue: 17(1)

Published: Aug. 1, 2020

Obstructive sleep apnea syndrome (OSAS), a state of disorder, is characterized by repetitive apnea, chronic hypoxia, oxygen desaturation, and hypercapnia. Previous studies have revealed that intermittent hypoxia (IH) conditions in OSAS patients elicited neuron injury (especially the hippocampus cortex), leading to cognitive dysfunction, significant extraordinary complication patients. The repeated courses airway collapse obstruction resulted arousal during sleep, IH excessive daytime sleepiness (EDS) subsequently contributing development inflammation. IH-mediated inflammation could further trigger various types dysfunction. Many researchers found that, besides continuous positive pressure (CPAP) treatment surgery, anti-inflammatory substances might alleviate IH-induced neurocognitive Clarifying role impairment crucial for potentially valuable therapies future research related domain. objective this article was critically review relationship between deficits OSAS.

Language: Английский

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Microthrombus‐Targeting Micelles for Neurovascular Remodeling and Enhanced Microcirculatory Perfusion in Acute Ischemic Stroke

Advanced Materials, Journal Year: 2019, Volume and Issue: 31(21)

Published: April 8, 2019

Reperfusion injury exists as the major obstacle to full recovery of neuron functions after ischemic stroke onset and clinical thrombolytic therapies. Complex cellular cascades including oxidative stress, neuroinflammation, brain vascular impairment occur within neurovascular units, leading microthrombus formation ultimate death. In this work, a multitarget micelle system is developed simultaneously modulate various cell types involved in these events. Briefly, rapamycin encapsulated self-assembled micelles that are consisted reactive oxygen species (ROS)-responsive fibrin-binding polymers achieve retention controlled drug release lesion. Neuron survival reinforced by combination facilitated ROS elimination antistress signaling pathway interference under ischemia conditions. vivo results demonstrate an overall remodeling unit through polarized M2 microglia repair blood-brain barrier preservation, enhanced neuroprotection blood perfusion. This strategy gives proof concept units can serve integrated target for treatment with nanomedicines.

Language: Английский

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Systemic inflammation after stroke: implications for post‐stroke comorbidities

EMBO Molecular Medicine, Journal Year: 2022, Volume and Issue: 14(9)

Published: Aug. 15, 2022

Language: Английский

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Factors influencing the blood-brain barrier permeability

Brain Research, Journal Year: 2022, Volume and Issue: 1788, P. 147937 - 147937

Published: May 11, 2022

The blood-brain barrier (BBB) is a dynamic structure that protects the brain from harmful blood-borne, endogenous and exogenous substances maintains homeostatic microenvironment. All constituent cell types play indispensable roles in BBB's integrity, other structural BBB components, such as tight junction proteins, adherens junctions, junctional can control permeability. Regarding need to exchange nutrients toxic materials, solute carriers, ATP-binding case families, ion transporter, well transcytosis regulate influx efflux transport, while difference localisation expression contribute functional differences transport properties. Numerous chemical mediators factors non-physicochemical have been identified alter permeability by mediating components function, because of close relationship with inflammation. In this review, we highlight recently gained mechanistic insights into maintenance disruption BBB. A better understanding influencing could supporting promising potential therapeutic targets for protecting delivery central nervous system drugs via interventions under pathological conditions.

Language: Английский

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Vascular Endothelial Cells: Heterogeneity and Targeting Approaches

Cells, Journal Year: 2021, Volume and Issue: 10(10), P. 2712 - 2712

Published: Oct. 10, 2021

Forming the inner layer of vascular system, endothelial cells (ECs) facilitate a multitude crucial physiological processes throughout body. Vascular ECs enable vessel wall passage nutrients and diffusion oxygen from blood into adjacent cellular structures. regulate tone coagulation as well adhesion transmigration circulating cells. The EC functions is reflected by tremendous diversity. can form extremely tight barriers, thereby restricting xenobiotics or immune cell invasion, whereas, in other organ systems, fenestrated (e.g., glomeruli kidney), discontinuous liver sinusoids) less dense to allow for rapid molecular exchange. not only differ between organs they also change along tree specialized subpopulations be found within capillaries single organ. Molecular tools that selective targeting are helpful experimentally dissect role distinct populations, improve imaging pave way novel treatment options diseases. This review provides an overview diversity highlights most successful methods subpopulations.

Language: Английский

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Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cells, Journal Year: 2021, Volume and Issue: 10(6), P. 1548 - 1548

Published: June 19, 2021

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around globe. The development therapeutic strategies for CNS conditions has suffered due to poor understanding underlying pathologies that manifest them. Understanding common etiological origins at cellular molecular level is essential enhance efficacious targeted treatment options. Over years, neuroinflammation been posited as link between multiple neurological, neurodegenerative neuropsychiatric disorders. Processes precipitate neuroinflammatory including genetics, infections, physical injury psychosocial factors, like stress trauma, closely dysregulation in kynurenine pathway (KP) tryptophan metabolism possible pathophysiological factor 'fuel fire' diseases. In this study, we aim review emerging evidence provide mechanistic insights different disorders, KP. We thorough overview branches KP pertinent disease pathology have implications selected strategies.

Language: Английский

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