Effect of copper and disulfiram combination therapy on the macular mouse, a model of Menkes disease.

Menkes disease (MD) is a genetic neurodegenerative disorder characterized by copper deficiency due to a defect in ATP7A. Standard treatment involves parenteral copper-histidine administration. However, the treatment is ineffective if initiated after two months of age, because the administered copper accumulates in the blood-brain barrier and is not transported to neurons. To resolve this issue, we investigated the effects of a combination therapy comprising copper and disulfiram, a lipophilic chelator, in the macular mouse, an animal model of MD. Seven-day-old macular mice treated subcutaneously with 50 μg of CuCl(2) on postnatal day 4 were used. The mice were given a subcutaneous injection of CuCl(2) (10 μg) with oral administration of disulfiram (0.3mg/g body weight) twice a week until eight weeks of age, and then sacrificed. Copper concentrations in the cerebellum, liver, and serum of treated macular mice were significantly higher than those of control macular mice, which received only copper. Mice treated with the combination therapy exhibited higher cytochrome c oxidase activity in the brain. The ratios of noradrenaline and adrenaline to dopamine in the brain were also increased by the treatment, suggesting that dopamine β-hydroxylase activity was improved by the combination therapy. Liver and renal functions were almost normal, although renal copper concentration was higher in treated macular mice than in controls. These results suggest that disulfiram facilitates the passage of copper across the blood-brain barrier and that copper-disulfiram combination therapy may be an effective treatment for MD patients.