title: Bis(thiosemicarbazone) copper complexes: mechanism of intracellular accumulation.
abstract: The molecular basis of Alzheimer's disease has not been clearly established, but disruption of brain metal ion homeostasis, particularly copper and zinc, might be closely involved in the pathogenesis of this disease and its characteristic β-amyloid neuropathological features. The use of complexes of copper with bis(thiosemicarbazones) ([Cu(btsc)]) has been proposed for the treatment of Alzheimer's disease. Their mode of action could involve modulation of the concentration of copper or zinc, and it has been suggested that the compounds can modulate the production of β-amyloid peptide at the neuron level. Furthermore, it has been reported that [Cu(btsc)] complexes can be reduced inside the cells. However, to our knowledge the intracellular reduction of these compounds has never been demonstrated. Thus, the goal of our study was to increase understanding of the mechanism of intracellular accumulation of [Cu(btsc)] complexes. Our results reveal that the intracellular concentration of copper inside the cells is very high and that these compounds are not P-glycoprotein substrates. This protein is a key element of the low permeability properties of the blood-brain barrier. Furthermore, no intracellular reduction of cupric ions was detected. Finally, once inside the cells, the complexes undergo aggregation, strongly suggesting that aggregation of complexes is the driving force responsible for their intracellular accumulation.
authors.affiliation: Université Paris 13, Sorbonne Paris Cité, Laboratoire CSPBAT, CNRS (UMR 7244), UFR-SMBH, 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lambert
authors.forename: Heloisa
authors.initials: H
authors.lastname: Beraldo
authors.forename: Nicole
authors.initials: N
authors.lastname: Lievre
authors.forename: Arlette
authors.initials: A
authors.lastname: Garnier-Suillerot
authors.forename: Pierre
authors.initials: P
authors.lastname: Dorlet
authors.forename: Milena
authors.initials: M
authors.lastname: Salerno
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D003300:Copper / Q000737:chemistry*; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D006037:Glyoxal / Q000737:chemistry; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D020014:K562 Cells; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism*; D012664:Semicarbazones / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009942:Organometallic Compounds; D012664:Semicarbazones; D014867:Water; D006037:Glyoxal; D003300:Copper; D004121:Dimethyl Sulfoxide