{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T05:04:08Z","timestamp":1788498248591,"version":"build-2803163510"},"reference-count":76,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T00:00:00Z","timestamp":1627257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1-NS102337"],"award-info":[{"award-number":["RO1-NS102337"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Iron and other transition metals, such as copper and manganese, are essential for supporting brain function, yet over-accumulation is cytotoxic. This over-accumulation of metals, particularly iron, is common to several neurological disorders; these include Alzheimer\u2019s disease, Parkinson\u2019s disease, Friedrich\u2019s ataxia and other disorders presenting with neurodegeneration and associated brain iron accumulation. The management of iron flux by the blood-brain barrier provides the first line of defense against the over-accumulation of iron in normal physiology and in these pathological conditions. In this study, we determined that the iron chelator PBT434, which is currently being developed for treatment of Parkinson\u2019s disease and multiple system atrophy, modulates the uptake of iron by human brain microvascular endothelial cells (hBMVEC) by chelation of extracellular Fe<jats:sup>2+<\/jats:sup>. Treatment of hBMVEC with PBT434 results in an increase in the abundance of the transcripts for transferrin receptor (TfR) and ceruloplasmin (Cp). Western blot and ELISA analyses reveal a corresponding increase in the proteins as well. Within the cell, PBT434 increases the detectable level of chelatable, labile Fe<jats:sup>2+<\/jats:sup>; data indicate that this Fe<jats:sup>2+<\/jats:sup>is released from ferritin. In addition, PBT434 potentiates iron efflux likely due to the increase in cytosolic ferrous iron, the substrate for the iron exporter, ferroportin. PBT434 equilibrates rapidly and bi-directionally across an hBMVEC blood-brain barrier. These results indicate that the PBT434-iron complex is not substrate for hBMVEC uptake and thus support a model in which PBT434 would chelate interstitial iron and inhibit re-uptake of iron by endothelial cells of the blood-brain barrier, as well as inhibit its uptake by the other cells of the neurovascular unit. Overall, this presents a novel and promising mechanism for therapeutic iron chelation.<\/jats:p>","DOI":"10.1371\/journal.pone.0254794","type":"journal-article","created":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T17:27:08Z","timestamp":1627320428000},"page":"e0254794","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":22,"title":["The iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9128-0199","authenticated-orcid":true,"given":"Danielle K.","family":"Bailey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Whitney","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel 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