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 neurotoxicity mechanism is still unknown. In this work, we examined both physical-chemical properties and biological effects of cuprizone. Our results indicate that cuprizone has very complicated and misunderstood solution chemistry. Moreover, we show the cuprizone inability 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 brains. Therefore, its neurotoxicity is explainable only in terms of its capacity to chelate copper, leading to chronic copper deficiency.