scholarly journals SARS-CoV-2 S1 Protein Induces Endolysosome Dysfunction and Neuritic Dystrophy

2021 ◽  
Vol 15 ◽  
Author(s):  
Gaurav Datta ◽  
Nicole M. Miller ◽  
Peter W. Halcrow ◽  
Nabab Khan ◽  
Timothy Colwell ◽  
...  
Keyword(s):  
Human Brain ◽  
Blood Brain Barrier ◽  
Neurological Disorders ◽  
Cortical Neurons ◽  
Neuronal Injury ◽  
Brain Barrier ◽  
Brain Cells ◽  
Blood Brain ◽  
High Incidence ◽  
Neuritic Dystrophy

SARS-CoV-2 is the viral cause of the COVID-19 pandemic. Increasingly, significant neurological disorders have been associated with COVID-19. However, the pathogenesis of these neurological disorders remains unclear especially because only low or undetectable levels of SARS-CoV-2 have been reported in human brain specimens. Because SARS-CoV-2 S1 protein can be released from viral membranes, can cross the blood-brain barrier, and is present in brain cells including neurons, we tested the hypothesis that SARS-CoV-2 S1 protein can directly induce neuronal injury. Incubation of primary human cortical neurons with SARS-CoV-2 S1 protein resulted in accumulation of the S1 protein in endolysosomes as well as endolysosome de-acidification. Further, SARS-CoV-2 S1 protein induced aberrant endolysosome morphology and neuritic varicosities. Our findings suggest that SARS-CoV-2 S1 protein directly induces neuritic dystrophy, which could contribute to the high incidence of neurological disorders associated with COVID-19.

scholarly journals Second-generation tricyclic pyrimido-pyrrolo-oxazine mTOR inhibitor with predicted blood–brain barrier permeability

2021 ◽  
Author(s):  
Chiara Borsari ◽  
Erhan Keles ◽  
Andrea Treyer ◽  
Martina De Pascale ◽  
Paul Hebeisen ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Neurological Disorders ◽  
Second Generation ◽  
Mtor Inhibitor ◽  
Kinase Inhibitor ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability

Here we present the first pyrimido-pyrrolo-oxazine-based mTOR kinase inhibitor (11) predicted to penetrate the blood brain barrier (BBB). Thus, 11 has a potential in treatments of neurological disorders.

scholarly journals A microfluidic model of human brain (μHuB) for assessment of blood brain barrier

2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Tyler D. Brown ◽  
Maksymilian Nowak ◽  
Alexandra V. Bayles ◽  
Balabhaskar Prabhakarpandian ◽  
Pankaj Karande ◽  
...  
Keyword(s):  
Human Brain ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Proof-of-Concept Study of Drug Brain Permeability Between in Vivo Human Brain and an in Vitro iPSCs-Human Blood-Brain Barrier Model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Gwenaëlle Le Roux ◽  
Rafika Jarray ◽  
Anne-Cécile Guyot ◽  
Serena Pavoni ◽  
Narciso Costa ◽  
...  
Keyword(s):  
Human Brain ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Apparent Permeability ◽  
Clinical Drug Development ◽  
Blood Brain

Abstract The development of effective central nervous system (CNS) drugs has been hampered by the lack of robust strategies to mimic the blood-brain barrier (BBB) and cerebrovascular impairments in vitro. Recent technological advancements in BBB modeling using induced pluripotent stem cells (iPSCs) allowed to overcome some of these obstacles, nonetheless the pertinence for their use in drug permeation study remains to be established. This mandatory information requires a cross comparison of in vitro and in vivo pharmacokinetic data in the same species to avoid failure in late clinical drug development. Here, we measured the BBB permeabilities of 8 clinical positron emission tomography (PET) radioligands with known pharmacokinetic parameters in human brain in vivo with a newly developed in vitro iPSC-based human BBB (iPSC-hBBB) model. Our findings showed a good correlation between in vitro and in vivo drug brain permeability (R2 = 0.83; P = 0.008) which contrasted with the limited correlation between in vitro apparent permeability for a set of 18 CNS/non-CNS compounds using the in vitro iPSCs-hBBB model and drug physicochemical properties. Our data suggest that the iPSC-hBBB model can be integrated in a flow scheme of CNS drug screening and potentially used to study species differences in BBB permeation.

scholarly journals Human Brain Endothelial CXCR2 is Inflammation-Inducible and Mediates CXCL5- and CXCL8-Triggered Paraendothelial Barrier Breakdown

2019 ◽  
Vol 20 (3) ◽  
pp. 602 ◽  
Author(s):  
Axel Haarmann ◽  
Michael Schuhmann ◽  
Christine Silwedel ◽  
Camelia-Maria Monoranu ◽  
Guido Stoll ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Tight Junction ◽  
Human Brain ◽  
Blood Brain Barrier ◽  
Barrier Function ◽  
Morphological Changes ◽  
Brain Barrier ◽  
Microvascular Endothelial Cell ◽  
Inflammatory Conditions ◽  
Blood Brain

Chemokines (C-X-C) motif ligand (CXCL) 5 and 8 are overexpressed in patients with multiple sclerosis, where CXCL5 serum levels were shown to correlate with blood–brain barrier dysfunction as evidenced by gadolinium-enhanced magnetic resonance imaging. Here, we studied the potential role of CXCL5/CXCL8 receptor 2 (CXCR2) as a regulator of paraendothelial brain barrier function, using the well-characterized human cerebral microvascular endothelial cell line hCMEC/D3. Low basal CXCR2 mRNA and protein expression levels in hCMEC/D3 were found to strongly increase under inflammatory conditions. Correspondingly, immunohistochemistry of brain biopsies from two patients with active multiple sclerosis revealed upregulation of endothelial CXCR2 compared to healthy control tissue. Recombinant CXCL5 or CXCL8 rapidly and transiently activated Akt/protein kinase B in hCMEC/D3. This was followed by a redistribution of tight junction-associated protein zonula occludens-1 (ZO-1) and by the formation of actin stress fibers. Functionally, these morphological changes corresponded to a decrease of paracellular barrier function, as measured by a real-time electrical impedance-sensing system. Importantly, preincubation with the selective CXCR2 antagonist SB332235 partially prevented chemokine-induced disturbance of both tight junction morphology and function. We conclude that human brain endothelial CXCR2 may contribute to blood–brain barrier disturbance under inflammatory conditions with increased CXCL5 and CXCL8 expression, where CXCR2 may also represent a novel pharmacological target for blood–brain barrier stabilization.

scholarly journals Human brain microvascular endothelial cell pairs model tissue-level blood–brain barrier function

2020 ◽  
Vol 12 (3) ◽  
pp. 64-79
Author(s):  
Blakely B O’Connor ◽  
Thomas Grevesse ◽  
John F Zimmerman ◽  
Herdeline Ann M Ardoña ◽  
Jorge A Jimenez ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Human Brain ◽  
Blood Brain Barrier ◽  
Barrier Function ◽  
Cytoskeletal Proteins ◽  
Fiber Formation ◽  
Brain Barrier ◽  
Actin Stress Fiber ◽  
Barrier Permeability ◽  
Blood Brain

Abstract The blood–brain barrier plays a critical role in delivering oxygen and nutrients to the brain while preventing the transport of neurotoxins. Predicting the ability of potential therapeutics and neurotoxicants to modulate brain barrier function remains a challenge due to limited spatial resolution and geometric constraints offered by existing in vitro models. Using soft lithography to control the shape of microvascular tissues, we predicted blood–brain barrier permeability states based on structural changes in human brain endothelial cells. We quantified morphological differences in nuclear, junction, and cytoskeletal proteins that influence, or indicate, barrier permeability. We established a correlation between brain endothelial cell pair structure and permeability by treating cell pairs and tissues with known cytoskeleton-modulating agents, including a Rho activator, a Rho inhibitor, and a cyclic adenosine monophosphate analog. Using this approach, we found that high-permeability cell pairs showed nuclear elongation, loss of junction proteins, and increased actin stress fiber formation, which were indicative of increased contractility. We measured traction forces generated by high- and low-permeability pairs, finding that higher stress at the intercellular junction contributes to barrier leakiness. We further tested the applicability of this platform to predict modulations in brain endothelial permeability by exposing cell pairs to engineered nanomaterials, including gold, silver–silica, and cerium oxide nanoparticles, thereby uncovering new insights into the mechanism of nanoparticle-mediated barrier disruption. Overall, we confirm the utility of this platform to assess the multiscale impact of pharmacological agents or environmental toxicants on blood–brain barrier integrity.

scholarly journals Pharmacological targeting of the PDGF-CC signaling pathway for blood–brain barrier restoration in neurological disorders

2016 ◽  
Vol 167 ◽  
pp. 108-119 ◽  
Author(s):  
Sebastian A. Lewandowski ◽  
Linda Fredriksson ◽  
Daniel A. Lawrence ◽  
Ulf Eriksson
Keyword(s):  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Neurological Disorders ◽  
Brain Barrier ◽  
Blood Brain
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