scholarly journals Triggers and Effectors of Oxidative Stress at Blood-Brain Barrier Level: Relevance for Brain Ageing and Neurodegeneration

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Ana-Maria Enciu ◽  
Mihaela Gherghiceanu ◽  
Bogdan O. Popescu
Keyword(s):  
Oxidative Stress ◽  
Protein Expression ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Wide Spectrum ◽  
Cell Signalling ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Blood Brain ◽  
Brain Ageing

As fundamental research advances, it is becoming increasingly clear that a clinically expressed disease implies a mixture of intertwining molecular disturbances. Oxidative stress is one of such pathogenic pathways involved in virtually all central nervous system pathologies, infectious, inflammatory, or degenerative in nature. Since brain homeostasis largely depends on integrity of blood-brain barrier (BBB), many studies focused lately on BBB alteration in a wide spectrum of brain diseases. The proper two-way molecular transfer through BBB depends on several factors, including the functional status of its tight junction (TJ) complexes of proteins sealing neighbour endothelial cells. Although there is abundant experimental work showing that oxidative stress associates BBB permeability alteration, less is known about its implications, at molecular level, in TJ protein expression or TJ-related cell signalling. In this paper, oxidative stress is presented as a common pathway for different brain pathogenic mechanisms which lead to BBB dysregulation. We revise here oxidative-induced molecular mechanisms of BBB disruption and TJ protein expression alteration, in relation to ageing and neurodegeneration.

scholarly journals Interleukin-1β-induced barrier dysfunction is signaled through PKC-θ in human brain microvascular endothelium

2012 ◽  
Vol 302 (10) ◽  
pp. C1513-C1522 ◽  
Author(s):  
Robert R. Rigor ◽  
Richard S. Beard ◽  
Olesya P. Litovka ◽  
Sarah Y. Yuan
Keyword(s):  
Human Brain ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Barrier Dysfunction ◽  
Microvascular Endothelium ◽  
Blood Brain ◽  
Pkc Isoforms ◽  
Junction Protein

Blood-brain barrier dysfunction is a serious consequence of inflammatory brain diseases, cerebral infections, and trauma. The proinflammatory cytokine interleukin (IL)-1β is central to neuroinflammation and contributes to brain microvascular leakage and edema formation. Although it is well known that IL-1β exposure directly induces hyperpermeability in brain microvascular endothelium, the molecular mechanisms mediating this response are not completely understood. In the present study, we found that exposure of the human brain microvascular endothelium to IL-1β triggered activation of novel PKC isoforms δ, μ, and θ, followed by decreased transendothelial electrical resistance (TER). The IL-1β-induced decrease in TER was prevented by small hairpin RNA silencing of PKC-θ or by treatment with the isoform-selective PKC inhibitor Gö6976 but not by PKC inhibitors that are selective for all PKC isoforms other than PKC-θ. Decreased TER coincided with increased phosphorylation of regulatory myosin light chain and with increased proapoptotic signaling indicated by decreased uptake of mitotracker red in response to IL-1β treatment. However, neither of these observed effects were prevented by Gö6976 treatment, indicating lack of causality with respect to decreased TER. Instead, our data indicated that the mechanism of decreased TER involves PKC-θ-dependent phosphorylation of the tight junction protein zona occludens (ZO)-1. Because IL-1β is a central inflammatory mediator, our interpretation is that inhibition of PKC-θ or inhibition of ZO-1 phosphorylation could be viable strategies for preventing blood-brain barrier dysfunction under a variety of neuroinflammatory conditions.

scholarly journals Targeting Transcription Factor Nrf2 (Nuclear Factor Erythroid 2-Related Factor 2) for the Intervention of Vascular Cognitive Impairment and Dementia

2020 ◽  
Author(s):  
Tuo Yang ◽  
Feng Zhang
Keyword(s):  
Oxidative Stress ◽  
Cognitive Impairment ◽  
White Matter ◽  
Blood Brain Barrier ◽  
Vascular Cognitive Impairment ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Related Factor ◽  
Nuclear Factor ◽  
Blood Brain

Vascular cognitive impairment and dementia (VCID) is an age-related, mild to severe mental disability due to a broad panel of cerebrovascular disorders. Its pathobiology involves neurovascular dysfunction, blood-brain barrier disruption, white matter damage, microRNAs, oxidative stress, neuroinflammation, and gut microbiota alterations, etc. Nrf2 (Nuclear factor erythroid 2-related factor 2) is the master regulator of redox status and controls the transcription of a panel of antioxidative and anti-inflammatory genes. By interacting with NF-κB (nuclear factor-κB), Nrf2 also fine-tunes the cellular oxidative and inflammatory balance. Aging is associated with Nrf2 dysfunction, and increasing evidence has proved the role of Nrf2 in mitigating the VCID process. Based on VCID pathobiologies and Nrf2 studies from VCID and other brain diseases, we point out several hypothetical Nrf2 targets for VCID management, including restoration of endothelial function and neurovascular coupling, preservation of blood-brain barrier integrity, reduction of amyloidopathy, promoting white matter integrity, and mitigating oxidative stress and neuroinflammation. Collectively, the Nrf2 pathway could be a promising direction for future VCID research. Targeting Nrf2 would shed light on VCID managing strategies.

Abstract 657: Inhibition Of MMPs In Hypertensive Cerebropathy Protects Blood-Brain Barrier In Dahl-Salt Sensitive Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Joanthan C Vacek ◽  
Pushpakumar Sathnur ◽  
Naira Metreveli ◽  
Sourav Kundu ◽  
Suresh C Tyagi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Protein Expression ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Tight Junction Proteins ◽  
Lewis Rats ◽  
Blood Brain ◽  
Junction Proteins

Hypertensive cerebropathy is a pathological condition associated with cerebral edema and breakdown of the blood-brain barrier (BBB). Previous studies have shown that increased activity of matrix metalloproteinases (MMPs) leads to alteration in the extracellular matrix (ECM) which is associated with impairment of the neurovasculature, resulting in destruction of the BBB. However, the molecular pathways leading to this condition remains obscure. In this study, we hypothesize that pharmacological inhibition of MMPs modulates BBB disruption by decreasing MMP activity and thus ameliorating hypertensive cerebropathy. Methods: We used Dahl-salt sensitive (Dahl-SS) and Lewis rats which were fed a high salt diet. The groups were 1) Dahl-SS, 2) Dahl-SS+GM6001 (non-specific MMP inhibitor), 3) Lewis, and 4) Lewis+GM6001. GM6001 was given at 0.5mg/mL by intra-peritoneal injection on alternate days for 3 weeks. Blood pressure was measured by tail-cuff. The brain tissues were analyzed for oxidative stress, matrix metalloproteinase-9 (MMP-9) activity and tight junction proteins by Western blot and Zymography. Immunohistochemistry was used to determine the collogen/elastion ratio. Results: Mean arterial blood pressure was 169.10 ± 0.57 mm Hg in hypertensive Dahl-SS rats compared to 134.12 ± 1.2 mm Hg in Dahl-SS+GM6001 rats. The mean arterial pressures in Lewis and Lewis+GM6001 groups were 96.66 ± 0.54 and 87.69 ± 2.9 mm Hg respectively. There was an up-regulation in p47 (oxidative stress) and nitrotyrosine protein expression but down-regulation in super oxide dismutase-1(SOD-1) and tight junction proteins levels (zonula-occluden-1 and occludin) in hypertensive Dahl-SS and Lewis rats compared to GM6001 treated rats. MMP-9 protein expression as well activity was increased in hypertensive Dahl-SS and Lewis rats compared to GM6001 treated rats. Brain section stained for collagen and elastin showed an increase in collagen level in hypertensive Dahl-SS and Lewis rats compared to GM6001 treated rats, whereas the elastin level decreased in hypertensive Dahl-SS and Lewis rats compared to GM6001 treated rats. Conclusion: Our results suggest that in hypertensive Dahl-SS rats, pharmacological inhibition of MMPs attenuates high blood pressure and prevents disruption of blood brain barrier.

scholarly journals Expression of Endothelial NOX5 Alters the Integrity of the Blood-Brain Barrier and Causes Loss of Memory in Aging Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1311
Author(s):  
Adriana Cortés ◽  
Maite Solas ◽  
Álvaro Pejenaute ◽  
Miguel A. Abellanas ◽  
Marcos Garcia-Lacarte ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Cognitive Status ◽  
Brain Barrier ◽  
Morris Water Maze Test ◽  
Arterial Blood ◽  
Blood Brain ◽  
Nadph Oxidase 5

Blood-Brain barrier (BBB) disruption is a hallmark of central nervous system (CNS) dysfunction, and oxidative stress is one of the molecular mechanisms that may underlie this process. NADPH oxidases (NOX) are involved in oxidative stress-mediated vascular dysfunction and participate in the pathophysiology of its target organs. The NADPH oxidase 5 (NOX5) isoform is absent in rodents, and although little is known about the role it may play in disrupting the BBB, it has recently been implicated in experimental stroke. Our aim was to investigate the role of NADPH oxidase 5 (NOX5) in promoting vascular alterations and to identify its impact on the cognitive status of aged mice. No differences were detected in the arterial blood pressure or body weight between knock-in mice expressing endothelial NOX5 and the control mice. The Morris water maze test showed memory impairments in the aged knock-in mice expressing NOX5 compared with their control littermates. For assessing the BBB integrity, we studied the protein expression of two tight junction (TJ) proteins: Zonula occludens-1 (ZO-1) and occludin. Compared to the control animals, Aged NOX5 mice exhibited reduced levels of both proteins, demonstrating an alteration of the BBB integrity. Our data indicate that vascular NOX5 may favor behavioral changes with aging through oxidative stress-mediated BBB breakdown.

scholarly journals Loud music and the specific sound stress open the blood-brain barrier: new fundamental, biomedical, and social aspects

2018 ◽  
Author(s):  
O. Semyachkina-Glushkovskaya ◽  
V. Chekhonin ◽  
D. Bragin ◽  
O. Bragina ◽  
E. Vodovozova ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Social Aspects ◽  
Brain Delivery ◽  
Brain Drug Delivery ◽  
Blood Brain ◽  
Loud Music ◽  
New Research

AbstractThe blood-brain barrier (BBB) poses a significant challenge for drug brain delivery. The limitation of our knowledge about the nature of BBB explains the slow progress in the therapy of brain diseases and absence of methods for drug brain delivery in the clinical practice.Here we show that BBB opens for low/high weight molecules and nanocarriers after exposure of loud music/sound of 90 dB and 100 dB (regardless its frequency) as being easily produced by MP3/MP4 players, kitchen appliances, loudspeakers at concerts. The role of sound, sound-induced stress and molecular mechanisms behind is discussed in the framework of BBB opening as an informative platform for a novel fundamental knowledge about the nature of BBB and for the development of a non-invasive brain drug delivery technology.Social aspects of music/sound-induced opening of BBB provide completely new information about noise and healthy life conditions that will stimulate new research in this field.

Blood-brain barrier-supported neurogenesis in healthy and diseased brain

2017 ◽  
Vol 28 (4) ◽  
pp. 397-415 ◽  
Author(s):  
Elena A. Pozhilenkova ◽  
Olga L. Lopatina ◽  
Yulia K. Komleva ◽  
Vladimir V. Salmin ◽  
Alla B. Salmina
Keyword(s):  
Blood Brain Barrier ◽  
Wide Spectrum ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Local Conditions ◽  
Blood Brain ◽  
Stem And Progenitor Cells ◽  
Activity Dependent

AbstractAdult neurogenesis is one of the most important mechanisms contributing to brain development, learning, and memory. Alterations in neurogenesis underlie a wide spectrum of brain diseases. Neurogenesis takes place in highly specialized neurogenic niches. The concept of neurogenic niches is becoming widely accepted due to growing evidence of the important role of the microenvironment established in the close vicinity to stem cells in order to provide adequate control of cell proliferation, differentiation, and apoptosis. Neurogenic niches represent the platform for tight integration of neurogenesis and angiogenesis supported by specific properties of cerebral microvessel endothelial cells contributing to establishment of partially compromised blood-brain barrier (BBB) for the adjustment of local conditions to the current metabolic needs of stem and progenitor cells. Here, we review up-to-date data on microvascular dynamics in activity-dependent neurogenesis, specific properties of BBB in neurogenic niches, endothelial-driven mechanisms of clonogenic activity, and future perspectives for reconstructing the neurogenic niches in vitro.

scholarly journals Blood–brain barrier disruption and ventricular enlargement are the earliest neuropathological changes in rats with repeated sub-concussive impacts over 2 weeks

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bailey Hiles-Murison ◽  
Andrew P. Lavender ◽  
Mark J. Hackett ◽  
Joshua J. Armstrong ◽  
Michael Nesbit ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Brain Barrier ◽  
Hippocampal Formation ◽  
Brain Barrier ◽  
Lateral Ventricles ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption ◽  
Underlying Mechanisms

AbstractRepeated sub-concussive impact (e.g. soccer ball heading), a significantly lighter form of mild traumatic brain injury, is increasingly suggested to cumulatively alter brain structure and compromise neurobehavioural function in the long-term. However, the underlying mechanisms whereby repeated long-term sub-concussion induces cerebral structural and neurobehavioural changes are currently unknown. Here, we utilised an established rat model to investigate the effects of repeated sub-concussion on size of lateral ventricles, cerebrovascular blood–brain barrier (BBB) integrity, neuroinflammation, oxidative stress, and biochemical distribution. Following repeated sub-concussion 3 days per week for 2 weeks, the rats showed significantly enlarged lateral ventricles compared with the rats receiving sham-only procedure. The sub-concussive rats also presented significant BBB dysfunction in the cerebral cortex and hippocampal formation, whilst neuromotor function assessed by beamwalk and rotarod tests were comparable to the sham rats. Immunofluorescent and spectroscopic microscopy analyses revealed no significant changes in neuroinflammation, oxidative stress, lipid distribution or protein aggregation, within the hippocampus and cortex. These data collectively indicate that repeated sub-concussion for 2 weeks induce significant ventriculomegaly and BBB disruption, preceding neuromotor deficits.

scholarly journals Can Natural Products Exert Neuroprotection without Crossing the Blood–Brain Barrier?

2021 ◽  
Vol 22 (7) ◽  
pp. 3356
Author(s):  
Manon Leclerc ◽  
Stéphanie Dudonné ◽  
Frédéric Calon
Keyword(s):  
Natural Products ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Omega 3 ◽  
Indirect Pathway ◽  
Brain Functions ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Peripheral Metabolism

The scope of evidence on the neuroprotective impact of natural products has been greatly extended in recent years. However, a key question that remains to be answered is whether natural products act directly on targets located in the central nervous system (CNS), or whether they act indirectly through other mechanisms in the periphery. While molecules utilized for brain diseases are typically bestowed with a capacity to cross the blood–brain barrier, it has been recently uncovered that peripheral metabolism impacts brain functions, including cognition. The gut–microbiota–brain axis is receiving increasing attention as another indirect pathway for orally administered compounds to act on the CNS. In this review, we will briefly explore these possibilities focusing on two classes of natural products: omega-3 polyunsaturated fatty acids (n-3 PUFAs) from marine sources and polyphenols from plants. The former will be used as an example of a natural product with relatively high brain bioavailability but with tightly regulated transport and metabolism, and the latter as an example of natural compounds with low brain bioavailability, yet with a growing amount of preclinical and clinical evidence of efficacy. In conclusion, it is proposed that bioavailability data should be sought early in the development of natural products to help identifying relevant mechanisms and potential impact on prevalent CNS disorders, such as Alzheimer’s disease.

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