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

Life Sci Alliance. 2021 Dec 2;5(3):e202101164. doi: 10.26508/lsa.202101164. Print 2022 Mar.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport
  • Biomarkers
  • Blood-Brain Barrier / diagnostic imaging
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology*
  • Brain / diagnostic imaging
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Cell Survival
  • Chelating Agents / pharmacology
  • Copper / adverse effects
  • Copper / chemistry
  • Copper / metabolism*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Humans
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Models, Molecular
  • Molybdenum / pharmacology*
  • Penicillamine / pharmacology*
  • Positron-Emission Tomography
  • Protein Binding
  • Rats
  • Serum Albumin / chemistry
  • Serum Albumin / metabolism
  • Structure-Activity Relationship


  • Biomarkers
  • Chelating Agents
  • Serum Albumin
  • Copper
  • Molybdenum
  • tetrathiomolybdate
  • Penicillamine