Disulfiram enhanced delivery of orally administered copper into the central nervous system in Menkes disease mouse model

• Published in: Journal of inherited metabolic disease Vol. 41; no. 6; pp. 1285 - 1291
• Main Authors: Hoshina, Takao, Nozaki, Satoshi, Hamazaki, Takashi, Kudo, Satoshi, Nakatani, Yuka, Kodama, Hiroko, Shintaku, Haruo, Watanabe, Yasuyoshi
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.12.2018; Blackwell Publishing Ltd
• Subjects: Animals; Autoradiography; Biochemistry; Blood-Brain Barrier - metabolism; Central nervous system; Cerebral cortex; Children; Copper; Copper - metabolism; Copper - pharmacology; Disease Models, Animal; Disulfiram; Disulfiram - therapeutic use; Drug Carriers; Hereditary diseases; Human Genetics; Internal Medicine; Intestine; Lipophilic; Liver; Male; Medicine; Medicine & Public Health; Menkes Kinky Hair Syndrome - blood; Menkes Kinky Hair Syndrome - drug therapy; Menkes Kinky Hair Syndrome - metabolism; Menkes syndrome; Metabolic Diseases; Mice; Mice, Inbred C3H; Nervous system; Neurodegeneration; Oral administration; Original Article; Parenchyma; Pediatrics; Protein transport; Radioactivity
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1007/s10545-018-0239-3

Introduction Menkes disease (MD) is an X-linked recessive disorder caused by dysfunction of a copper-transporting protein, leading to severe neurodegeneration in early childhood. We investigated whether a lipophilic copper chelator, disulfiram, could enhance copper absorption from the intestine and transport copper across the blood–brain barrier in MD model mice. Methods Wild type and MD model mice were pretreated with disulfiram for 30 min before oral administration of 64 CuCl 2 . Each organ was sequentially analyzed for radioactivity with γ counting. Copper uptake into the brain parenchyma was assessed by ex vivo autoradiography. Results In wild type mice, orally administered copper was initially detected in the intestine within 2 h, reaching a maximum level in the liver (19.6 ± 3.8 percentage injected dose per gram [%ID/g]) at 6 h. In MD model mice, the copper reached the maximum level in the liver (5.3 ± 1.5 %ID/g) at 4 h, which was lower than that of wild type mice (19.0 ± 7.4 %ID/g) ( P  < 0.05). Pretreatment of disulfiram in MD model mice increased the copper level in the brain (0.59 ± 0.28 %ID/g) at 24 h compared with MD model mice without disulfiram (0.07 ± 0.05 %ID/g) ( P  < 0.05). Ex vivo autoradiography revealed that high levels of copper uptake was observed in the cerebral cortex upon disulfiram pretreatment. Conclusion Our data demonstrated that disulfiram enhanced the delivery of orally administered copper into the central nervous system in MD model mice. The administration of disulfiram will enable patients to avoid unpleasant subcutaneous copper injection in the future.