The iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells.

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's disease, Parkinson's...

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Autores principales:	Danielle K Bailey, Whitney Clark, Daniel J Kosman
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8a2ce6d16ed64ce897df7e728b055785
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spelling	oai:doaj.org-article:8a2ce6d16ed64ce897df7e728b0557852021-12-02T20:04:50ZThe iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells.1932-620310.1371/journal.pone.0254794https://doaj.org/article/8a2ce6d16ed64ce897df7e728b0557852021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0254794https://doaj.org/toc/1932-6203Iron 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's disease, Parkinson's disease, Friedrich's 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's disease and multiple system atrophy, modulates the uptake of iron by human brain microvascular endothelial cells (hBMVEC) by chelation of extracellular Fe2+. 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 Fe2+; data indicate that this Fe2+ 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.Danielle K BaileyWhitney ClarkDaniel J KosmanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0254794 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Danielle K Bailey Whitney Clark Daniel J Kosman The iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells.
description	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's disease, Parkinson's disease, Friedrich's 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's disease and multiple system atrophy, modulates the uptake of iron by human brain microvascular endothelial cells (hBMVEC) by chelation of extracellular Fe2+. 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 Fe2+; data indicate that this Fe2+ 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.
format	article
author	Danielle K Bailey Whitney Clark Daniel J Kosman
author_facet	Danielle K Bailey Whitney Clark Daniel J Kosman
author_sort	Danielle K Bailey
title	The iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells.
title_short	The iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells.
title_full	The iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells.
title_fullStr	The iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells.
title_full_unstemmed	The iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells.
title_sort	iron chelator, pbt434, modulates transcellular iron trafficking in brain microvascular endothelial cells.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/8a2ce6d16ed64ce897df7e728b055785
work_keys_str_mv	AT daniellekbailey theironchelatorpbt434modulatestranscellularirontraffickinginbrainmicrovascularendothelialcells AT whitneyclark theironchelatorpbt434modulatestranscellularirontraffickinginbrainmicrovascularendothelialcells AT danieljkosman theironchelatorpbt434modulatestranscellularirontraffickinginbrainmicrovascularendothelialcells AT daniellekbailey ironchelatorpbt434modulatestranscellularirontraffickinginbrainmicrovascularendothelialcells AT whitneyclark ironchelatorpbt434modulatestranscellularirontraffickinginbrainmicrovascularendothelialcells AT danieljkosman ironchelatorpbt434modulatestranscellularirontraffickinginbrainmicrovascularendothelialcells
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The iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells.

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