Cuprizone neurotoxicity, copper deficiency and neurodegeneration.
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.
Benetti
Federico
F
Department of Biology, University of Padova, via U. Bassi 58/B, 35121 Padova, Italy.
Ventura
Marcello
M
Salmini
Benedetta
B
Ceola
Stefano
S
Carbonera
Donatella
D
Mammi
Stefano
S
Zitolo
Andrea
A
D'Angelo
Paola
P
Urso
Emanuela
E
Maffia
Michele
M
Salvato
Benedetto
B
Spisni
Enzo
E
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
D008996:Monoamine Oxidase Inhibitors; D003471:Cuprizone; D003300:Copper; D010088:Oxidoreductases; D002570:Ceruloplasmin