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Disulfiram enhanced delivery of orally administered copper into the central nervous system in Menkes disease mouse model
Author(s) -
Hoshina Takao,
Nozaki Satoshi,
Hamazaki Takashi,
Kudo Satoshi,
Nakatani Yuka,
Kodama Hiroko,
Shintaku Haruo,
Watanabe Yasuyoshi
Publication year - 2018
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-018-0239-3
Subject(s) - disulfiram , menkes disease , pharmacology , in vivo , central nervous system , ex vivo , copper , oral administration , chemistry , atp7a , pharmacokinetics , endocrinology , medicine , biochemistry , atpase , biology , in vitro , copper metabolism , microbiology and biotechnology , organic chemistry , enzyme
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.