title: Cuprizone neurotoxicity, copper deficiency and neurodegeneration.
abstract: Cuprizone is used to obtain demyelination in mice. Cuprizone-treated mice show symptoms similar to several neurodegenerative disorders such as severe status spongiosus. Although it has a simple chemical formula, its neurotoxic mechanism is still unknown. In this work, we examined both physico-chemical properties and biological effects of cuprizone. Our results indicate that cuprizone has very complicated and misunderstood solution chemistry. Moreover, we show here the inability of cuprizone to cross neither the intestinal epithelial barrier nor the neuronal cell membrane, as well its high tolerability by cultured neurons. If added to mice diet, cuprizone does not accumulate in liver or in brain. Therefore, its neurotoxic effect is explainable only in terms of its capability to chelate copper, leading to chronic copper deficiency.
authors.affiliation: Department of Biology, University of Padova, via U. Bassi 58/B, 35121 Padova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Benetti
authors.forename: Marcello
authors.initials: M
authors.lastname: Ventura
authors.forename: Benedetta
authors.initials: B
authors.lastname: Salmini
authors.forename: Stefano
authors.initials: S
authors.lastname: Ceola
authors.forename: Donatella
authors.initials: D
authors.lastname: Carbonera
authors.forename: Stefano
authors.initials: S
authors.lastname: Mammi
authors.forename: Andrea
authors.initials: A
authors.lastname: Zitolo
authors.forename: Paola
authors.initials: P
authors.lastname: D'Angelo
authors.forename: Emanuela
authors.initials: E
authors.lastname: Urso
authors.forename: Michele
authors.initials: M
authors.lastname: Maffia
authors.forename: Benedetto
authors.initials: B
authors.lastname: Salvato
authors.forename: Enzo
authors.initials: E
authors.lastname: Spisni
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002570:Ceruloplasmin / Q000187:drug effects; D055598:Chemical Phenomena; D003300:Copper / Q000172:deficiency* / Q000378:metabolism; D003471:Cuprizone / Q000737:chemistry / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008099:Liver / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000633:toxicity*; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism; D009447:Neuroblastoma; D020258:Neurotoxicity Syndromes / Q000150:complications / Q000209:etiology / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D013054:Spectrophotometry, Atomic / Q000379:methods
chemical_list: D008996:Monoamine Oxidase Inhibitors; D003471:Cuprizone; D003300:Copper; D010088:Oxidoreductases; D002570:Ceruloplasmin