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Borchard, S. ; Raschke, S.* ; Zak, K.M. ; Eberhagen, C. ; Einer, C. ; Weber, E. ; Müller, S.M.* ; Michalke, B. ; Lichtmannegger, J. ; Wieser, A. ; Rieder, T.* ; Popowicz, G.M. ; Adamski, J. ; Klingenspor, M.* ; Coles, A.H.* ; Viana, R.* ; Vendelbo, M.H.* ; Sandahl, T.D.* ; Schwerdtle, T.* ; Plitz, T.* ; Zischka, H.

Bis-choline tetrathiomolybdate prevents copper-induced blood-brain barrier damage.

Life Sci. All. 5:e202101164 (2022)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
In Wilson disease, excessive copper accumulates in patients' livers and may, upon serum leakage, severely affect the brain according to current viewpoints. Present remedies aim at avoiding copper toxicity by chelation, for example, by D-penicillamine (DPA) or bis-choline tetrathiomolybdate (ALXN1840), the latter with a very high copper affinity. Hence, ALXN1840 may potentially avoid neurological deterioration that frequently occurs upon DPA treatment. As the etiology of such worsening is unclear, we reasoned that copper loosely bound to albumin, that is, mimicking a potential liver copper leakage into blood, may damage cells that constitute the blood-brain barrier, which was found to be the case in an in vitro model using primary porcine brain capillary endothelial cells. Such blood-brain barrier damage was avoided by ALXN1840, plausibly due to firm protein embedding of the chelator bound copper, but not by DPA. Mitochondrial protection was observed, a prerequisite for blood-brain barrier integrity. Thus, high-affinity copper chelators may minimize such deterioration in the treatment of neurologic Wilson disease.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Relative Exchangeable Copper; Wilson Disease Gene; Ammonium Tetrathiomolybdate; D-penicillamine; Rat Model; Serum; Zinc; Ceruloplasmin; Binding; Metal
ISSN (print) / ISBN 2575-1077
e-ISSN 2575-1077
Journal Life Science Alliance
Quellenangaben Volume: 5, Issue: 3, Pages: , Article Number: e202101164 Supplement: ,
Publisher EMBO Press
Publishing Place Heidelberg
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Toxicology and Pharmacology (TOXI)
Institute of Structural Biology (STB)
Research Unit Analytical BioGeoChemistry (BGC)
Institute of Radiation Medicine (IRM)
Institute of Experimental Genetics (IEG)
Grants Wilson Therapeutics AB/Alexion AstraZeneca Rare Disease
Morbus Wilson e.V.