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

Autor:	Borchard S; Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany., Raschke S; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.; TraceAge-Deutsche Forschungsgemeinschaft Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (Forschungsgruppe 2558), Berlin-Potsdam-Jena-Wuppertal, Germany., Zak KM; Institute of Structural Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany., Eberhagen C; Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany., Einer C; Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany., Weber E; Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany., Müller SM; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany., Michalke B; Research Unit Analytical BioGeoChemistry, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany., Lichtmannegger J; Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany., Wieser A; Institute of Radiation Medicine, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany., Rieder T; Technical University Munich, School of Medicine, Institute of Toxicology and Environmental Hygiene, Munich, Germany., Popowicz GM; Institute of Structural Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany., Adamski J; Research Unit Molecular Endocrinology and Metabolism, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.; Lehrstuhl für Experimentelle Genetik, Technical University Munich, Freising-Weihenstephan, Germany.; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Klingenspor M; Chair of Molecular Nutritional Medicine, Technical University of Munich, School of Life Sciences Weihenstephan, Freising, Germany.; Else-Kröner Fresenius Center for Nutritional Medicine, Technical University of Munich, Freising, Germany., Coles AH; Alexion AstraZeneca Rare Disease, Boston, MA, USA., Viana R; Alexion AstraZeneca Rare Disease, Boston, MA, USA., Vendelbo MH; Department of Nuclear Medicine and Positron Emission Tomography Centre, Aarhus University Hospital, Aarhus, Denmark.; Department of Biomedicine, Aarhus University, Aarhus C, Denmark., Sandahl TD; Medical Department Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark., Schwerdtle T; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.; TraceAge-Deutsche Forschungsgemeinschaft Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (Forschungsgruppe 2558), Berlin-Potsdam-Jena-Wuppertal, Germany., Plitz T; Wilson Therapeutics AB, Stockholm, Sweden., Zischka H; Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany zischka@helmholtz-muenchen.de.; Technical University Munich, School of Medicine, Institute of Toxicology and Environmental Hygiene, Munich, Germany.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2021 Dec 02; Vol. 5 (3). Date of Electronic Publication: 2021 Dec 02 (Print Publication: 2022).
DOI:	10.26508/lsa.202101164
Abstrakt:	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. (© 2021 Borchard et al.)
Databáze:	MEDLINE
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