Menkes disease: Oral administration of glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) rescues the macular mouse.
Menkes disease: Oral administration of glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) rescues the macular mouse.
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门克斯病：口服乙二醛-双(N(4)-甲硫基氨基脲)-铜(II)可挽救黄斑小鼠。
DOI：
10.1038/s41390-018-0116-7
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Kure Shigeo
中科院分区：
文献类型：
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作者：
Munakata Mitsutoshi;Kodama Hiroko;Tani Norihiko;Kimura Kazuhiro;Takahashi Hideyo;Maruyama Kazuo;Sakamoto Yoshimasa;Kure Shigeo
背景门克斯病是一种由 ATP7A（一种铜转运 P 型 ATP 酶）突变引起的铜代谢紊乱。在本研究中，在雄性半合子黄斑 (MoMl/y) 小鼠（门克斯病小鼠模型）中研究了通过乙二醛-双(N(4)-甲硫缩氨基脲)-铜(II) (CuGTSM)（一种亲脂性铜复合物）口服铜补充剂。方法在出生后第 5 天通过口服强饲法给予 CuGTSM， 8、11、17、23和32。在15天、3个月和8个月时测量器官和血清中的铜水平、大脑中的铜依赖性酶活性以及血清中的铜蓝蛋白(Cp)活性。还进行了肠道组织学分析和转棒试验。结果CuGTSM治疗延长了MoMl/y小鼠的寿命，并部分恢复了大脑中的铜浓度、细胞色素氧化酶和DBH活性；然而，转棒测试显示运动性能受损。该治疗还增加了血清中的铜浓度和 Cp 活性。在哺乳MoMl/y小鼠中，CuGTSM治疗短暂地引起腹泻，并伴有铜积累和回肠绒毛形态改变。结论口服CuGTSM延长了MoMl/y小鼠的寿命。口服给药很有吸引力，但需要进行药物研究以减少不良肠内反应。
BackgroundMenkes 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.MethodsCuGTSM 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.ResultsCuGTSM treatment extended the lifespan of MoMl/ymice 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/ymice, CuGTSM treatment transiently induced diarrhea accompanied by copper accumulation and altered villus morphology in the ileum.ConclusionOral administration of CuGTSM extended the lifespan of MoMl/ymice. Oral administration is attractive, but pharmaceutical studies are needed to reduce the adverse enteral effects.