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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
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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
Keywords Relative Exchangeable Copper; Wilson Disease Gene; Ammonium Tetrathiomolybdate; D-penicillamine; Rat Model; Serum; Zinc; Ceruloplasmin; Binding; Metal
Language english
Publication Year 2022
Prepublished in Year 2021
HGF-reported in Year 2021
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
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Toxicology and Pharmacology (TOX)
Institute of Structural Biology (STB)
Research Unit BioGeoChemistry and Analytics (BGC)
Institute of Radiation Medicine (IRM)
Institute of Experimental Genetics (IEG)
POF-Topic(s) 30203 - Molecular Targets and Therapies
30202 - Environmental Health
30201 - Metabolic Health
Research field(s) Enabling and Novel Technologies
Environmental Sciences
Radiation Sciences
Genetics and Epidemiology
PSP Element(s) G-505200-003
G-503000-001
G-505200-001
G-505293-001
G-504800-002
G-501391-001
G-500600-001
Grants Wilson Therapeutics AB/Alexion AstraZeneca Rare Disease
Morbus Wilson e.V.
DOI 10.26508/lsa.202101164
WOS ID WOS:000727807500002
Scopus ID 85122124702
PubMed ID 34857647
Erfassungsdatum 2021-12-07
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