Cytoskeletal remodeling and gap junction translocation mediates blood–brain barrier disruption by non-invasive low-voltage pulsed electric fields Journal Article


Authors: Rajagopalan, N. R.; Vista, W. R.; Fujimori, M.; Vroomen, L. G. P. H.; Jiménez, J. M.; Khadka, N.; Bikson, M.; Srimathveeravalli, G.
Article Title: Cytoskeletal remodeling and gap junction translocation mediates blood–brain barrier disruption by non-invasive low-voltage pulsed electric fields
Abstract: High-voltage pulsed electric fields (HV-PEF) delivered with invasive needle electrodes for electroporation applications is known to induce off-target blood–brain barrier (BBB) disruption. In this study, we sought to determine the feasibility of minimally invasive PEF application to produce BBB disruption in rat brain and identify the putative mechanisms mediating the effect. We observed dose-dependent presence of Evans Blue (EB) dye in rat brain when PEF were delivered with a skull mounted electrode used for neurostimulation application. Maximum region of dye uptake was observed while using 1500 V, 100 pulses, 100 μs and 10 Hz. Results of computational models suggested that the region of BBB disruption was occurring at thresholds of 63 V/cm or higher; well below intensity levels for electroporation. In vitro experiments recapitulating this effect with human umbilical vein endothelial cells (HUVEC) demonstrated cellular alterations that underlie BBB manifests at low-voltage high-pulse conditions without affecting cell viability or proliferation. Morphological changes in HUVECs due to PEF were accompanied by disruption of actin cytoskeleton, loss of tight junction protein—ZO-1 and VE-Cadherin at cell junctions and partial translocation into the cytoplasm. Uptake of propidium iodide (PI) in PEF treated conditions is less than 1% and 2.5% of total number of cells in high voltage (HV) and low-voltage (LV) groups, respectively, implying that BBB disruption to be independent of electroporation under these conditions. 3-D microfabricated blood vessel permeability was found to increase significantly following PEF treatment and confirmed with correlative cytoskeletal changes and loss of tight junction proteins. Finally, we show that the rat brain model can be scaled to human brains with a similar effect on BBB disruption characterized by electric field strength (EFS) threshold and using a combination of two bilateral HD electrode configurations. © 2023, The Author(s) under exclusive licence to Biomedical Engineering Society.
Keywords: controlled study; human cell; nonhuman; proteins; animal; metabolism; animals; animal tissue; animal experiment; physiology; endothelium cell; endothelial cells; blood; feasibility study; brain; rat; blood brain barrier; blood-brain barrier; cell membranes; electroporation; rats; computer model; biological transport; drug delivery system; blood vessels; nerve stimulation; drug delivery; transport at the cellular level; electrodes; gap junction; gap junctions; targeted drug delivery; umbilical vein endothelial cell; cytoskeletal; controlled drug delivery; nanofabrication; electric fields; low voltages; humans; human; male; article; biological response; pulsed electric field; biological response to electroporation; blood–brain barrier (bbb) disruption; low-voltage pulsed electric field; blood–brain barrier disruption; rats brain; high voltage pulsed electric field
Journal Title: Annals of Biomedical Engineering
Volume: 52
Issue: 1
ISSN: 0090-6964
Publisher: Springer  
Date Published: 2024-01-01
Start Page: 89
End Page: 102
Language: English
DOI: 10.1007/s10439-023-03211-3
PUBMED: 37115366
PROVIDER: scopus
DOI/URL:
Notes: Article -- Source: Scopus
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  1. William-Ray Vista
    7 Vista