Copper Metabolism in the Macular Mutant Mouse: An Animal Model of Menkes’s Kinky-Hair Disease

Shiraishi, Noriyuki; Aono, Kaname; Taguchi, Takafumi

doi:10.1159/000242849

Cited by 17 publications

(7 citation statements)

References 25 publications

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“…In this study, the copper concentration and CCO activity in brain tissue of macular mice without treatment (MC) were found to be significantly lower than those of control mice (CC), while the copper concentration in the kidney and intestine of MC was significantly higher than that of CC mice. These results are similar to previously reported findings Shiraishi et al 1988;Yoshimura et al 1990).…”

Section: Discussionsupporting

confidence: 93%

Effect of copper and diethyldithiocarbamate combination therapy on the macular mouse, an animal model of Menkes disease

Kodama

Sato

et al. 2005

J of Inher Metab Disea

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Menkes disease (MD) is a neurodegenerative disorder characterized by a copper deficiency in the brain. It is caused by the defective intestinal absorption of copper resulting from a deficiency of a copper-transporting ATPase, ATP7A. This gives rise to an accumulation of copper in the intestine. The copper deficiency in the brain of MD patients cannot be improved by copper injections, because the administered copper accumulates at the blood-brain barrier and is not transported across to the neurons. To resolve this problem, we investigated the effect of a combination therapy of copper and sodium diethyldithiocarbamate (DEDTC), a lypophilic chelator, in an animal model of MD, the macular mouse. Four-week-old macular mice treated with 50 mug of CuCl2 on the 7th day after birth were used. Experimental mice were given a subcutaneous injection of CuCl2 (4 microg) and an intraperitoneal injection of DEDTC (0.2 mg/g body weight) twice a week for 4 weeks and then sacrificed. Copper concentrations and cytochrome-c oxidase activity in the brains of treated mice were higher than those of control macular mice, which received only copper or saline. The ratios of brain noradrenaline to dopamine and of adrenaline to dopamine were also increased by the treatment, suggesting that the activity of dopamine beta-hydroxylase, a copper-dependent enzyme, was improved by the treatment. Liver and renal function tests showed no abnormalities in the treated mice, although copper concentrations in the kidneys of treated mice were higher than those of control macular mice. These results suggest that DEDTC facilitates the passage of copper across the blood-brain barrier and that the combination therapy of copper and DEDTC may be an effective treatment for the neurological disturbances suffered by patients with MD.

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Section: Discussionsupporting

confidence: 93%

Effect of copper and diethyldithiocarbamate combination therapy on the macular mouse, an animal model of Menkes disease

Kodama

Sato

et al. 2005

J of Inher Metab Disea

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“…Another important aspect of parenteral copper administration is that copper treatment is sometimes associated with excess copper accumulation in the kidneys, leading to renal dysfunction in patients and macular mice with MD (6,15). Previous reports demonstrated that copper administration lengthened the life-span of MD model mice but that copper accumulation to toxic levels in the kidneys led to severe renal damage (16,17).…”

mentioning

confidence: 99%

PET Imaging Analysis with ⁶⁴Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

Nomura

Nozaki²,

Hamazaki

et al. 2014

J Nucl Med

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Menkes disease (MD), an X-linked recessive disorder of copper metabolism caused by mutations in the copper-transporting ATP7A gene, results in growth failure and severe neurodegeneration in early childhood. Subcutaneous copper-histidine injection is the standard treatment for MD, but it has limited clinical efficacy. Furthermore, long-term copper injection causes excess copper accumulation in the kidneys, resulting in renal dysfunction. To attempt to resolve this issue, we used PET imaging with 64 Cu to investigate the effects of disulfiram on copper biodistribution in living mice serving as an animal model for MD (MD model mice). Methods: Macular mice were used as MD model mice, and C3H/He mice were used as wild-type mice. Mice were pretreated with 2 types of chelators (disulfiram, a lipophilic chelator, and D-penicillamine, a hydrophilic chelator) 30 min before 64 CuCl 2 injection. After 64 CuCl 2 injection, emission scans covering the whole body were performed for 4 h. After the PET scans, the brain and kidneys were analyzed for radioactivity with γ counting and autoradiography. Results: After copper injection alone, marked accumulation of radioactivity ( 64 Cu) in the liver was demonstrated in wild-type mice, whereas in MD model mice, copper was preferentially accumulated in the kidneys (25.56 ± 3.01 percentage injected dose per gram [%ID/g]) and was detected to a lesser extent in the liver (13.83 ± 0.26 %ID/g) and brain (0.96 ± 0.08 %ID/g). Copper injection with disulfiram reduced excess copper accumulation in the kidneys (14.54 ± 2.68 %ID/g) and increased copper transport into the liver (29.42 ± 0.98 %ID/g) and brain (5.12 ± 0.95 %ID/g) of MD model mice. Copper injection with D-penicillamine enhanced urinary copper excretion and reduced copper accumulation in most organs in both mouse groups. Autoradiography demonstrated that disulfiram pretreatment induced copper transport into the brain parenchyma and reduced copper accumulation in the renal medulla. Conclusion: PET studies with 64 Cu revealed that disulfiram had significant effects on the copper biodistribution of MD. Disulfiram increased copper transport into the brain and reduced copper uptake in the kidneys of MD model mice. The application of 64 Cu PET for the treatment of MD and other copperrelated disorders may be useful in clinical settings.

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“…Recently, we have reported that the Cu content in kidney and intestine from the 7-day-old mutant were extremely high compared to normal, and there were marked elevations in renal metallothionein-(MT)-Cu contents and marked reductions in hepatic MT-Cu contents [9,10]. These results were very similar to those in brindled mice [11 -14].…”

Section: Introductionmentioning

confidence: 58%

“…Tissue Cu and Zn concentrations were measured by an atomic-absorption spectrophotometer (Hitachi 180-80). Pooled tissues removed from 5-14 mice were used for the metal determination as described previously [10]. Values are expressed means ± SD pg metal/g wet weight.…”

Section: Methodsmentioning

confidence: 99%

Metallothionein Messenger RNA Levels in the Macular Mutant Mouse: An Animal Model of Menkes’ Kinky-Hair Disease

Shiraishi

Taguchi

Kinebuchi³

1991

Neonatology

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Levels of metallothionein-1 (MT-1) messenger RNA (mRNA) in various tissues from normal and macular mutant mice at different stages of development (17 days of gestation, 1-, 3-, 7- and 14-day-old) were determined by Northern blot analysis. Renal MT-1 mRNA levels in mutant mice were slightly elevated at 3 stages compared to normal mice, with the exception of mutant fetus and 3-day-old mutant mice. Intestinal MT-1 mRNA levels in mutant mice were elevated at 3 stages compared to normal mice with the exception of mutant fetus and 3-day-old mutant mice. Hepatic MT-1 mRNA levels in mutant fetus and 1-day-old mutant mice were approximately the same compared to normal mice. In 3- and 7-day-old mutant mice, hepatic MT-1 mRNA levels were depressed and in 14-day-old mutant mice, they were increased compared to normal mice. Brain MT-1 mRNA could not be detected in normal and mutant mice at the 4 stages with the exception of 14-day-old mice. MT-1 mRNA in 14-day-old mice was detected and the level of that in mutant mice was slightly elevated compared to normal mice. After injection of Cu, MT-1 mRNA levels in kidney, liver and intestine were determined. The injection of Cu increased the level of MT-1 mRNA in the tissues of normal and mutant mice compared to control (saline-injected) mice. Significant differences in MT-1 mRNA levels in the tissues of both Cu-injected mice were not observed.

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Copper Metabolism in the Macular Mutant Mouse: An Animal Model of Menkes’s Kinky-Hair Disease

Cited by 17 publications

References 25 publications

Effect of copper and diethyldithiocarbamate combination therapy on the macular mouse, an animal model of Menkes disease

Effect of copper and diethyldithiocarbamate combination therapy on the macular mouse, an animal model of Menkes disease

PET Imaging Analysis with ⁶⁴Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

Metallothionein Messenger RNA Levels in the Macular Mutant Mouse: An Animal Model of Menkes’ Kinky-Hair Disease

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Copper Metabolism in the Macular Mutant Mouse: An Animal Model of Menkes’s Kinky-Hair Disease

Cited by 17 publications

References 25 publications

Effect of copper and diethyldithiocarbamate combination therapy on the macular mouse, an animal model of Menkes disease

Effect of copper and diethyldithiocarbamate combination therapy on the macular mouse, an animal model of Menkes disease

PET Imaging Analysis with 64Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

Metallothionein Messenger RNA Levels in the Macular Mutant Mouse: An Animal Model of Menkes’ Kinky-Hair Disease

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PET Imaging Analysis with ⁶⁴Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model