Browsing by Author "Fisher, David W."

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    Are claudin-5 tight-junction proteins in the blood-brain barrier porous?
    (Wolters Kluwer Health, 2020) Fisher, David W.; Mentor, Shireen
    The capillaries of the brain are particularly special, as they are not simply conduits for blood, but are primarily responsible to ensure that the neurons function in a strictly regulated homeostatic interstitium. Brain endothelial cells (BECs) express a plethora of ion channels on its luminal and abluminal surfaces, namely: potassium (K+ ) channels (i.e., Kir2 and Kv1), chloride (Cl–)/bicarbonate (HCO3–) channels, as well as a number of ion-solute exchangers (Redzic et al., 2011). These channels essentially prioritize vectorial transendothelial transport, especially for the regulation of K+ flux across the blood-brain barrier (BBB) (Redzic et al., 2011). The differences between the K+ concentration of the brain interstitium and plasma is only 2 mM to 4 mM, but the maintenance of this ionic concentration difference provides a constancy for the neuronal resting membrane potential, their associated firing thresholds and the preservation of a constant level of neuronal excitability.
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    Permeation challenges of drugs for treatment of neurological tuberculosis and HIV and the application of magneto-electric nanoparticle drug delivery systems
    (MDPI, 2021) Fisher, David W.; Tchoula Tchokonte, Moise B.; Dube, Admire; Mhambi, Sinaye
    The anatomical structure of the brain at the blood-brain barrier (BBB) creates a limitation for the movement of drugs into the central nervous system (CNS). Drug delivery facilitated by magneto-electric nanoparticles (MENs) is a relatively new non-invasive approach for the delivery of drugs into the CNS. These nanoparticles (NPs) can create localized transient changes in the permeability of the cells of the BBB by inducing electroporation. MENs can be applied to deliver antiretrovirals and antibiotics towards the treatment of human immunodeficiency virus (HIV) and tuberculosis (TB) infections in the CNS. This review focuses on the drug permeation challenges and reviews the application of MENs for drug delivery for these diseases. We conclude that MENs are promising systems for effective CNS drug delivery and treatment for these diseases, however, further preclinical and clinical studies are required to achieve translation of this approach to the clinic. © 2021 by the authors. Licensee MDPI, Basel, Switzerland
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    The synergistic and neuroprotective effects of alcohol–antioxidant treatment on blood–brain barrier endothelial cells
    (Wiley-Blackwell, 2020) Fisher, David W.; Thomas, Kelly Angelique; Abdul-Rasool, Sahar
    Background: Alcohol (EtOH) is reported to adversely affect one of the most crucial roles of the blood–brain barrier (BBB), the regulation of its permeability, thereby compromising the stability of the homeostatic environment of the brain. The central component of the BBB, endothelial cells (ECs), regulates BBB transcellular transport, while their paracellular pathways are made virtually impermeable by molecular structures called tight junctions (TJs). These TJs are composed of proteins, such as claudin-5, a protein involved in the regulation of paracellular permeability and of key interest in this study. Methods and Results: The working hypothesis of this study postulated that the high levels of antioxidants (AOs) in the fermented Aspalathus linearis (Rooibos; Rf) tincture may protect the ECs of the BBB against oxidative stress induced by EtOH exposure. Cells were exposed for 24 hours to selected concentrations of EtOH (25 and 100 mM), Rf (containing an antioxidant equivalence of 1.9 nM Aspalathin), and cotreatments of EtOH and Rf. Cell viability, live cell number, and toxicity were analyzed using the trypan blue exclusion assay. RT-qPCR was implemented to quantify claudin-5 transcription. In addition, permeability (Transepithelial Electrical Resistance) of bEnd5 monolayers was measured. The experimental timeline for the above-mentioned parameters was 24 and 48 hours. Conclusions: Our study showed that simultaneous exposure of Rf and EtOH was able to negate the effects of EtOH on cell viability and cell proliferation, but was not able to reverse or reduce the effects of EtOH on claudin-5 transcription and paracellular permeability. Furthermore, a novel finding in this study suggests that very low concentrations of AOs in tinctures such as Rooibos tea could profoundly alter the redox status of brain ECs.