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dc.contributor.authorPalomino, S.M.
dc.contributor.authorLevine, A.A.
dc.contributor.authorWahl, J.
dc.contributor.authorLiktor-Busa, E.
dc.contributor.authorStreicher, J.M.
dc.contributor.authorLargent-Milnes, T.M.
dc.date.accessioned2022-10-24T23:51:14Z
dc.date.available2022-10-24T23:51:14Z
dc.date.issued2022
dc.identifier.citationPalomino, S. M., Levine, A. A., Wahl, J., Liktor-Busa, E., Streicher, J. M., & Largent-Milnes, T. M. (2022). Inhibition of HSP90 Preserves Blood–Brain Barrier Integrity after Cortical Spreading Depression. Pharmaceutics, 14(8).
dc.identifier.issn1999-4923
dc.identifier.doi10.3390/pharmaceutics14081665
dc.identifier.urihttp://hdl.handle.net/10150/666475
dc.description.abstractCortical spreading depression (CSD) is a pathophysiological mechanism underlying headache disorders, including migraine. Blood–brain barrier (BBB) permeability is increased during CSD. Recent papers have suggested that heat shock proteins (HSP) contribute to the integrity of the blood–brain barrier. In this study, the possible role of HSP90 in CSD-associated blood–brain barrier leak at the endothelial cell was investigated using an in vitro model, for the blood–endothelial barrier (BEB), and an in vivo model with an intact BBB. We measured barrier integrity using trans endothelial electric resistance (TEER) across a monolayer of rodent brain endothelial cells (bEnd.3), a sucrose uptake assay, and in situ brain perfusion using female Sprague Dawley rats. CSD was induced by application of 60 mM KCl for 5 min in in vitro experiments or cortical injection of KCl (1 M, 0.5 µL) through a dural cannula in vivo. HSP90 was selectively blocked by 17-AAG. Our data showed that preincubation with 17-AAG (1 µM) prevented the reduction of TEER values caused by the KCl pulse on the monolayer of bEnd.3 cells. The elevated uptake of 14C-sucrose across the same endothelial monolayer induced by the KCl pulse was significantly reduced after preincubation with HSP90 inhibitor. Pre-exposure to 17-AAG significantly mitigated the transient BBB leak after CSD induced by cortical KCl injection as determined by in situ brain perfusion in female rats. Our results demonstrated that inhibition of HSP90 with the selective agent 17-AAG reduced CSD-associated BEB/BBB paracellular leak. Overall, this novel observation supports HSP90 inhibition mitigates KCl-induced BBB permeability and suggests the development of new therapeutic approaches targeting HSP90 in headache disorders. © 2022 by the authors.
dc.language.isoen
dc.publisherMDPI
dc.rightsCopyright © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subject17-AAG
dc.subjectblood–brain barrier
dc.subjectblood–endothelial barrier
dc.subjectcortical spreading depression
dc.subjectheat shock protein 90
dc.subjectin situ brain perfusion
dc.titleInhibition of HSP90 Preserves Blood–Brain Barrier Integrity after Cortical Spreading Depression
dc.typeArticle
dc.typetext
dc.contributor.departmentDepartment of Pharmacology, University of Arizona
dc.identifier.journalPharmaceutics
dc.description.noteOpen access journal
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
dc.eprint.versionFinal published version
dc.source.journaltitlePharmaceutics
refterms.dateFOA2022-10-24T23:51:14Z


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Copyright © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Except where otherwise noted, this item's license is described as Copyright © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).