Abstract
Background
Menkes disease is a copper metabolism disorder caused by mutations in ATP7A, a copper-transporting P-type ATPase. In this study, oral copper supplementation via glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) (CuGTSM), a lipophilic copper complex, was investigated in male hemizygous macular (MoMl/y) mice, a mouse model of Menkes disease.
Methods
CuGTSM was administered by oral gavage on postnatal days 5, 8, 11, 17, 23, and 32. The copper levels in the organs and serum, copper-dependent enzyme activities in the brain, and ceruloplasmin (Cp) activity in the serum were measured at 15 days and 3 and 8 months of age. Histological analysis of the intestines and the rotarod test were also performed.
Results
CuGTSM treatment extended the lifespan of MoMl/y mice and partly restored the copper concentrations and cytochrome oxidase and DBH activities in the brain; however, the rotarod test showed impaired motor performance. The treatment also increased copper concentrations and Cp activity in the serum. In suckling MoMl/y mice, CuGTSM treatment transiently induced diarrhea accompanied by copper accumulation and altered villus morphology in the ileum.
Conclusion
Oral administration of CuGTSM extended the lifespan of MoMl/y mice. Oral administration is attractive, but pharmaceutical studies are needed to reduce the adverse enteral effects.
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Acknowledgements
We thank Yukari Takase, Yuko Hino, Tomoyo Yamanobe, Kumiko Kurosaki, Yoko Chiba, Kumi Itoh, Tomoko Hiroki, and Masashi Funakoshi for providing technical assistance. We also acknowledge the support of the Animal Pathology Platform at the Biomedical Research Core of Tohoku University Graduate School of Medicine. This research was supported by a Grant-in-Aid for Scientific Research to Mitsutoshi Munakata from The Ministry of Education, Culture, Sports, Science and Technology of Japan (16K09959).
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Munakata, M., Kodama, H., Tani, N. et al. Menkes disease: Oral administration of glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) rescues the macular mouse. Pediatr Res 84, 770–777 (2018). https://doi.org/10.1038/s41390-018-0116-7
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DOI: https://doi.org/10.1038/s41390-018-0116-7
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