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Lookup NU author(s): Dr Joanna Elson, Dr Ilse Pienaar
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
While the etiology of non-familial Parkinson’s disease (PD) remains unclear, there is evidence that increased levels of tissue iron may be a contributing factor. Moreover, exposure to some environmental toxicants is considered an additional risk factor. Therefore, brain-targeted iron chelators are of interest as antidotes for poisoning with dopaminergic toxicants, and as potential treatment of PD. We therefore designed a series of small molecules with high affinity for ferric iron and containing structural elements to allow their transport to the brain via the neutral amino acid transporter, LAT1 (SLC7A5). Five candidate molecules were synthesized and initially characterized for protection from ferroptosis in human neurons. The promising hydroxypyridinone SK4 was characterized further. Selective iron chelation within the physiological range of pH values and uptake by LAT1 were confirmed. Concentrations of 10-20 µM blocked neurite loss and cell demise triggered by the parkinsonian neurotoxicants, methyl-phenyl-pyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) in human dopaminergic neuronal cultures (LUHMES cells). SK4 derivatives that either lacked LAT1 affinity or had reduced iron chelation potency showed altered activity in our assay panel, as expected. Thus, an iron chelator was developed that revealed neuroprotective properties, as assessed in several models. The data strongly supports the role of iron in dopaminergic neurotoxicity and suggests further exploration of the proposed design strategy for improving brain iron chelation.
Author(s): Gutbier S, Kyriakou S, Schildknecht s, Uckert AK, Brüll k, Lewis F, Dickens D, Pearson L, Elson JL, Michel S, Hubscher-Bruder V, Brandel J, Tetard T, Leist M, Pienaar IS
Publication type: Article
Publication status: Published
Journal: Archives of Toxicology
Year: 2020
Volume: 94
Pages: 3105-3123
Print publication date: 01/09/2020
Online publication date: 30/06/2020
Acceptance date: 24/06/2020
Date deposited: 25/06/2020
ISSN (print): 0340-5761
ISSN (electronic): 1432-0738
Publisher: Springer
URL: https://doi.org/10.1007/s00204-020-02826-y
DOI: 10.1007/s00204-020-02826-y
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