Disulfiram decreases copper accumulation in the kidney of Menkes disease model mice as evaluated by PET imaging

Objectives Menkes disease (MD) is a genetic disease leading copper deficiency. It causes multisystemic disorders with severe neurodegeneration. Subcutaneous copper injection is standard treatment for MD but has limited clinical efficacy. Furthermore, long-term copper injection is known to cause copper accumulation in the kidney and potentially degrades renal function. Previously, we demonstrated that lipophilic chelator (disulfiram) was effective to deliver injected-copper into the brain for MD. Therefore, we investigated how injected-copper distributes into the kidney with or without chelator in MD by using microPET.

Methods C3H/He mice were used as wild type and macular mice were used as MD model. Mice were pretreated with two types of chelator (disulfiram as lipophilic chelator or D-penicillamine as hydrophilic chelator) for 30 minutes before copper injection. 64CuCl2 were injected intravenously and continuous PET imaging was performed for 4 hours. Then mice were sacrificed and γ- counting and autoradiography of the kidneys were performed.

Results In wild type mice, injected-copper was dominantly accumulated in the liver. On the other hand, in macular mice, the copper was preferentially taken up by the kidney. Disulfiram pretreatment reduced the aberrant copper accumulation in the kidney and increased copper accumulation in the liver in MD model mice. D-penicillamine pretreatment enhanced copper excretion in urine and decreased kidney accumulation.

Conclusions Our study demonstrated that 1) in MD, injected-copper aberrantly accumulated into the kidney, 2) disulfiram pretreatment corrected the copper biodistribution pattern as seen in wild type mice, 3) D-penicillamine had strong effect on urinary excretion of copper in MD. MicroPET imaging was useful to understand pathophysiology of MD and evaluate the effect of novel treatments for MD.