Nonthermal GSM RF and ELF EMF effects upon rat BBB permeability

Background: Alzheimer’s disease (AD), an irreversible complex neurodegenerative disorder, is most common type of dementia, with progressive loss of cholinergic neurons. Based on the multi- factorial etiology of Alzheimer’s disease, novel ligands strategy appears as up-coming approach for the development of newer molecules against AD. This study is envisaged to investigate anti-Alzheimer’s potential of 10 synthesized compounds. The screening of compounds (1-10) was carried out using in silico techniques. Methods: For in silico screening of physicochemical properties of compounds molinspiration property engine v.2018.03, Swiss ADME online web-server and pkCSM ADME were used. For pharmacodynamic prediction PASS software while toxicity profile of compounds were analyzed through ProTox-II online software. Simultaneously, molecular docking analysis was performed on mouse AChE enzyme (PDB ID:2JGE, obtained from RSCB PDB) using Auto Dock Tools 1.5.6. Results: Based on in silico studies, compound 9 and 10 have been found to have better drug likeness, LD50 value, and better anti-Alzheimer’s, nootropic activities. However, these compounds had poor blood brain barrier (BBB) permeability. Compound 4 and 9 were predicted with better docking score for AChE enzyme. Conclusion: The outcome of in silico studies have suggested, out of various substitutions at different positions of pyridoxine-carbamate, compound 9 have shown promising drug likeness, with better safety and efficacy profile for anti-Alzheimer’s activity. However, BBB permeability appears as one the major limitation of all these compounds. Further studies are required to confirm its biological activities.

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Dual Roles of Astrocyte-Derived Factors in Regulation of Blood-Brain Barrier Function after Brain Damage

International Journal of Molecular Sciences ◽

10.3390/ijms20030571 ◽

2019 ◽

Vol 20 (3) ◽

pp. 571 ◽

Cited By ~ 32

Author(s):

Shotaro Michinaga ◽

Yutaka Koyama

Keyword(s):

Brain Damage ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Blood Brain ◽

Secondary Damage ◽

The Central Nervous System ◽

Bbb Permeability ◽

Novel Therapeutic Strategies ◽

Glial Derived Neurotrophic Factor ◽

Endothelial Growth Factors

The blood-brain barrier (BBB) is a major functional barrier in the central nervous system (CNS), and inhibits the extravasation of intravascular contents and transports various essential nutrients between the blood and the brain. After brain damage by traumatic brain injury, cerebral ischemia and several other CNS disorders, the functions of the BBB are disrupted, resulting in severe secondary damage including brain edema and inflammatory injury. Therefore, BBB protection and recovery are considered novel therapeutic strategies for reducing brain damage. Emerging evidence suggests key roles of astrocyte-derived factors in BBB disruption and recovery after brain damage. The astrocyte-derived vascular permeability factors include vascular endothelial growth factors, matrix metalloproteinases, nitric oxide, glutamate and endothelin-1, which enhance BBB permeability leading to BBB disruption. By contrast, the astrocyte-derived protective factors include angiopoietin-1, sonic hedgehog, glial-derived neurotrophic factor, retinoic acid and insulin-like growth factor-1 and apolipoprotein E which attenuate BBB permeability resulting in recovery of BBB function. In this review, the roles of these astrocyte-derived factors in BBB function are summarized, and their significance as therapeutic targets for BBB protection and recovery after brain damage are discussed.

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Improved Antiglioblastoma Activity and BBB Permeability by Conjugation of Paclitaxel to a Cell‐Penetrative MMP‐2‐Cleavable Peptide

Advanced Science ◽

10.1002/advs.202001960 ◽

2020 ◽

pp. 2001960

Author(s):

Dan Hua ◽

Lida Tang ◽

Weiting Wang ◽

Shengan Tang ◽

Lin Yu ◽

...

Keyword(s):

A Cell ◽

Bbb Permeability ◽

Cleavable Peptide

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Pseudogene ACTBP2 increases blood–brain barrier permeability by promoting KHDRBS2 transcription through recruitment of KMT2D/WDR5 in Aβ1–42 microenvironment

Cell Death Discovery ◽

10.1038/s41420-021-00531-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Qianshuo Liu ◽

Xiaobai Liu ◽

Defeng Zhao ◽

Xuelei Ruan ◽

Rui Su ◽

...

Keyword(s):

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Rna Binding ◽

Vital Role ◽

Brain Barrier ◽

Blood Brain ◽

Bbb Permeability ◽

Novel Target ◽

And Function

AbstractThe blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48 h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.

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Blood-brain barrier transport of neuropeptides: analysis with a metabolically stable dermorphin analogue

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1994.267.1.e124 ◽

1994 ◽

Vol 267 (1) ◽

pp. E124-E131 ◽

Cited By ~ 6

Author(s):

A. Samii ◽

U. Bickel ◽

U. Stroth ◽

W. M. Pardridge

Keyword(s):

Carotid Artery ◽

Internal Carotid Artery ◽

Intravenous Injection ◽

Internal Carotid ◽

Lipid Solubility ◽

Permeability Surface ◽

Bbb Permeability ◽

The Brain ◽

Artery Perfusion ◽

Internal Carotid Artery Perfusion

To avoid the confounding effect of metabolic degradation, the stable mu-opioid peptide agonist [D-Arg2,Lys4]-dermorphin analogue (DALDA) was used to quantitate blood-brain barrier (BBB) permeability by intravenous injection and internal carotid artery perfusion techniques. With intravenous injection, the BBB permeability-surface area products for [3H]DALDA (0.84 +/- 0.13 microliters.min-1.g-1) and [14C]sucrose (0.39 +/- 0.05 microliters.min-1.g-1) correlated with the lipid solubility of the two molecules: the 1-octanol-Ringer partition coefficient for DALDA was approximately 2 log orders greater than that for sucrose. The brain delivery of [3H]DALDA at 30 min after intravenous administration was 0.019 +/- 0.002% of the injected dose per gram, and analgesia was induced with a 5-mg/kg dose administered systemically. In contrast to the result after intravenous injection, the BBB permeability-surface area product for DALDA estimated with the internal carotid artery perfusion technique was manyfold greater. This was due to nonspecific absorption of the peptide into the cerebral microvasculature, which precluded use of the capillary depletion technique to study transcytosis through the BBB after internal carotid artery perfusion. The present studies show that the brain delivery of a metabolically stable peptide, such as DALDA, is comparable to that for sucrose, correlates with lipid solubility, and is mediated by a nonsaturable mechanism, probably free diffusion.

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Early Appearance of Activated Matrix Metalloproteinase-9 after Focal Cerebral Ischemia in Mice: A Possible Role in Blood—Brain Barrier Dysfunction

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199909000-00010 ◽

1999 ◽

Vol 19 (9) ◽

pp. 1020-1028 ◽

Cited By ~ 301

Author(s):

Yvan Gasche ◽

Miki Fujimura ◽

Yuiko Morita-Fujimura ◽

Jean-Christophe Copin ◽

Makoto Kawase ◽

...

Keyword(s):

Cerebral Ischemia ◽

Blood Brain Barrier ◽

Focal Cerebral Ischemia ◽

Vasogenic Edema ◽

Tissue Inhibitor Of Metalloproteinase ◽

Brain Barrier ◽

Critical Event ◽

Secondary Brain Injury ◽

Blood Brain ◽

Bbb Permeability

During cerebral ischemia blood–brain barrier (BBB) disruption is a critical event leading to vasogenic edema and secondary brain injury. Gelatinases A and B are matrix metalloproteinases (MMP) able to open the BBB. The current study analyzes by zymography the early gelatinases expression and activation during permanent ischemia in mice (n = 15). ProMMP-9 expression was significantly ( P < 0.001) increased in ischemic regions compared with corresponding contralateral regions after 2 hours of ischemia (mean 694.7 arbitrary units [AU], SD ± 238.4 versus mean 107.6 AU, SD ± 15.6) and remained elevated until 24 hours (mean 745,7 AU, SD ± 157.4). Moreover, activated MMP-9 was observed 4 hours after the initiation of ischemia. At the same time as the appearance of activated MMP-9, we detected by the Evan's blue extravasation method a clear increase of BBB permeability, Tissue inhibitor of metalloproteinase-1 was not modified during permanent ischemia at any time. The ProMMP-2 was significantly ( P < 0.05) increased only after 24 hours of permanent ischemia (mean 213.2 AU, SD ± 60.6 versus mean 94.6 AU, SD ± 13.3), and no activated form was observed. The appearance of activated MMP-9 after 4 hours of ischemia in correlation with BBB permeability alterations suggests that MMP-9 may play an active role in early vasogenic edema development after stroke.

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Glycocalyx degradation leads to blood–brain barrier dysfunction and brain edema after asphyxia cardiac arrest in rats

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17726062 ◽

2017 ◽

Vol 38 (11) ◽

pp. 1979-1992 ◽

Cited By ~ 19

Author(s):

Jiajia Zhu ◽

Xing Li ◽

Jia Yin ◽

Yafang Hu ◽

Yong Gu ◽

...

Keyword(s):

Cardiac Arrest ◽

Survival Rate ◽

Brain Edema ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Neurologic Outcome ◽

Endothelial Glycocalyx ◽

Inflammatory Factors ◽

Blood Brain ◽

Bbb Permeability

The role of glycocalyx in blood–brain barrier (BBB) integrity and brain damage is poorly understood. Our study aimed to investigate the impacts of endothelial glycocalyx on BBB function in a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Male Sprague-Dawley rats subjected to 8-min asphyxia CA/CPR. Compared to controls, glycocalyx was mildly injured by CA, severely disrupted by hyaluronidase (HAase) with CA, and mitigated by hydrocortisone (HC) with CA. More importantly, the disruption of glycocalyx caused by HAase treatment was associated with higher BBB permeability and aggravated brain edema at 24 h after return of spontaneous circulation, as well as lower survival rate and poorer neurologic outcome at seventh day. Reversely, less degradation of glycocalyx by HC treatment was accompanied by higher seven-day survival rate and better neurologic outcome. Mechanistically, HAase treatment further increased CA/CPR-induced activation of glia cells and expression of inflammatory factors, whereas HC decreased them in the brain cortex and hippocampus. Glycocalyx degradation results in BBB leakage, brain edema, and deteriorates neurologic outcome after asphyxia CA/CPR in rats. Preservation of glycocalyx by HC could improve neurologic outcome and reduce BBB permeability, apparently through reduced gene transcription-protein synthesis and inflammation.

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Effect of vascular endothelial growth factor (VEGF) on blood‐brain barrier (BBB) permeability of pial arteries vs. parenchymal arterioles

The FASEB Journal ◽

10.1096/fasebj.20.4.a706 ◽

2006 ◽

Vol 20 (4) ◽

Author(s):

Rachael M. Hannah ◽

Lisa Vitullo ◽

Marilyn Jcipolla

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Vascular Endothelial ◽

Pial Arteries ◽

Blood Brain ◽

Bbb Permeability ◽

Endothelial Growth Factor

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Direct Current Stimulation Disrupts Endothelial Glycocalyx and Tight Junctions of the Blood-Brain Barrier in vitro

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.731028 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yifan Xia ◽

Yunfei Li ◽

Wasem Khalid ◽

Marom Bikson ◽

Bingmei M. Fu

Keyword(s):

Endothelial Cells ◽

Tight Junction ◽

Tight Junctions ◽

Blood Brain Barrier ◽

Direct Current ◽

Endothelial Glycocalyx ◽

Microvascular Endothelial Cells ◽

Bbb Permeability

Transcranial direct current stimulation (tDCS) is a non-invasive physical therapy to treat many psychiatric disorders and to enhance memory and cognition in healthy individuals. Our recent studies showed that tDCS with the proper dosage and duration can transiently enhance the permeability (P) of the blood-brain barrier (BBB) in rat brain to various sized solutes. Based on the in vivo permeability data, a transport model for the paracellular pathway of the BBB also predicted that tDCS can transiently disrupt the endothelial glycocalyx (EG) and the tight junction between endothelial cells. To confirm these predictions and to investigate the structural mechanisms by which tDCS modulates P of the BBB, we directly quantified the EG and tight junctions of in vitro BBB models after DCS treatment. Human cerebral microvascular endothelial cells (hCMECs) and mouse brain microvascular endothelial cells (bEnd3) were cultured on the Transwell filter with 3 μm pores to generate in vitro BBBs. After confluence, 0.1–1 mA/cm2 DCS was applied for 5 and 10 min. TEER and P to dextran-70k of the in vitro BBB were measured, HS (heparan sulfate) and hyaluronic acid (HA) of EG was immuno-stained and quantified, as well as the tight junction ZO-1. We found disrupted EG and ZO-1 when P to dextran-70k was increased and TEER was decreased by the DCS. To further investigate the cellular signaling mechanism of DCS on the BBB permeability, we pretreated the in vitro BBB with a nitric oxide synthase (NOS) inhibitor, L-NMMA. L-NMMA diminished the effect of DCS on the BBB permeability by protecting the EG and reinforcing tight junctions. These in vitro results conform to the in vivo observations and confirm the model prediction that DCS can disrupt the EG and tight junction of the BBB. Nevertheless, the in vivo effects of DCS are transient which backup its safety in the clinical application. In conclusion, our current study directly elucidates the structural and signaling mechanisms by which DCS modulates the BBB permeability.

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Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness

International Journal of Molecular Sciences ◽

10.3390/ijms22168546 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8546

Author(s):

Francisco J. Carrera Arias ◽

Kristina Aenlle ◽

Maria Abreu ◽

Mary A. Holschbach ◽

Lindsay T. Michalovicz ◽

...

Keyword(s):

Signaling Pathways ◽

Human Subjects ◽

Treatment Strategies ◽

Gulf War ◽

Clinical Samples ◽

Stable States ◽

Response Dynamics ◽

Gulf War Illness ◽

Bbb Permeability ◽

The Brain

Gulf War Illness (GWI) is a persistent chronic neuroinflammatory illness exacerbated by external stressors and characterized by fatigue, musculoskeletal pain, cognitive, and neurological problems linked to underlying immunological dysfunction for which there is no known treatment. As the immune system and the brain communicate through several signaling pathways, including the hypothalamic–pituitary–adrenal (HPA) axis, it underlies many of the behavioral and physiological responses to stressors via blood-borne mediators, such as cytokines, chemokines, and hormones. Signaling by these molecules is mediated by the semipermeable blood–brain barrier (BBB) made up of a monocellular layer forming an integral part of the neuroimmune axis. BBB permeability can be altered and even diminished by both external factors (e.g., chemical agents) and internal conditions (e.g., acute or chronic stress, or cross-signaling from the hypothalamic–pituitary–gonadal (HPG) axis). Such a complex network of regulatory interactions that possess feed-forward and feedback connections can have multiple response dynamics that may include several stable homeostatic states beyond normal health. Here we compare immune and hormone measures in the blood of human clinical samples and mouse models of Gulf War Illness (GWI) subtyped by exposure to traumatic stress for subtyping this complex illness. We do this via constructing a detailed logic model of HPA–HPG–Immune regulatory behavior that also considers signaling pathways across the BBB to neuronal–glial interactions within the brain. We apply conditional interactions to model the effects of changes in BBB permeability. Several stable states are identified in the system beyond typical health. Following alignment of the human and mouse blood profiles in the context of the model, mouse brain sample measures were used to infer the neuroinflammatory state in human GWI and perform treatment simulations using a genetic algorithm to optimize the Monte Carlo simulations of the putative treatment strategies aimed at returning the ill system back to health. We identify several ideal multi-intervention strategies and potential drug candidates that may be used to treat chronic neuroinflammation in GWI.

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