The effect of copper supplementation on the concentration of copper in the brain of the brindled mouse

Wenk, Gary L.; Suzuki, Kinuko

doi:10.1042/bj2050485

Cited by 19 publications

(10 citation statements)

References 24 publications

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“…For macular mice, well-established as an MD model, the present study confirmed that copper accumulation after systemic copper injection without a chelator shifted to the kidneys rather than the liver and brain, as in wild-type mice; these findings are consistent with previous findings for MD patients and MD model mice (2,12). Copper deficiency in the brain due to copper transport dysfunction at the BBB causes severe neurodegeneration in MD (8); therefore, it is important to develop an effective strategy for improving copper transport into the brain on the basis of copper dynamics in living systems.…”

Section: Discussionsupporting

confidence: 81%

“…To correct systemic copper deficiencies in MD, subcutaneous copper-histidine injection is the standard treatment (10)(11)(12), but its efficacy depends on the age-related maturation of the blood-brain barrier (BBB) or residual copper transport by a partially functional gene (12)(13)(14). When copper treatment is initiated in the neonatal period or early infancy, when the BBB is immature, the injected copper is delivered to the neurons and, thus, is an effective treatment for neurologic disorders (11,14).…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 81%

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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“…The brindled mutant is most like classical MD, and much of the knowledge of the human condition was derived from studies in these mice, which die of neurological damage at about 14 or 15 days after birth [Danks, 1995]. A single large dose of copper-histidine injected on day 7 cures these mice, but the same treatment on day 10 is ineffective [Mann et al, 1979;Wenk and Suzuki, 1982]. The blotchy mouse shows mainly connective tissue abnormalities, with no apparent brain involvement.…”

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confidence: 98%

Early treatment of Menkes disease with parenteral Cooper-Histidine: Long-term follow-up of four treated patients

Danks²,

et al. 1998

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We report on the long-term clinical course of 4 boys with Menkes disease, treated from early infancy with parenteral copper-histidine, with follow-up over 10-20 years. Three of the 4 had male relatives with a severe clinical course compatible with classical Menkes disease. As a consequence of early treatment, our patients have normal or near-normal intellectual development, but have developed many of the more severe somatic abnormalities of the related disorder, occipital horn syndrome, including severe orthostatic hypotension in 2. In addition, 1 boy developed a previously unreported anomaly, namely, massive splenomegaly and hypersplenism as a consequence of a splenic artery aneurysm. Previously reported molecular studies in 2 of these patients had shown gene defects which would have predicted a truncated and probably nonfunctional gene product. Despite the favorable effects on the neurological symptoms, parenteral copper treatment for Menkes disease should still be regarded as experimental. The development of more effective treatments must await a more precise delineation of the role which the Menkes protein plays in intracellular copper trafficking.

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“…Consequently, there is an abnormal copper distribution in various tissues, with increased copper accumulation in some organs (e.g. kid ney and intestinal mucosa), but decreased copper accu mulation in the brain [1,2], A mutation which arises spontaneously in the C57BL inbred mouse strain has provided an animal model of this clinical disorder [3][4][5]. The brindled mottled (Mobr) mutant mouse, referred to as the brindled mouse, can either be a hemizygous male or heterozygous female.…”

Section: Introductionmentioning

confidence: 99%

The Female Brindled Mouse as a Model of Menkes' Disease: The Relationship of Fur Pattern to Behavioral and Neurochemical Abnormalities

Martin¹,

Irino²,

Suzuki³

et al. 1991

Dev Neurosci

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The brindled mottled mutant mouse, a model of Menkes'' disease, has alterations in copper homeostasis which cause, among other sequelae, neuronal degeneration in selected areas of brain. This work examined the neurochemical changes at postnatal days (PND) 15, 30 and 60 in females heterozygous for the sex-linked brindled mutation. These data were compared to behavioral alterations and to fur coat color at these same time points. The brindled heterozygotic females had lower concentrations of norepinephrine (NE) in the cingulate cortex, and higher levels of dopamine or dopamine metabolites in the cingulate cortex, thalamus and hypothalamus across all ages, although the difference was greatest at PND 15. The brindled females were much less active than their normal littermates at PND 15, but the differences were no longer evident at PND 30 and 60. Mottling of the fur is believed to result from low tyrosinase activity caused by abnormalities in copper metabolism. The fur pattern and behavior of the brindled mice were highly correlated with NE levels in the cingulate cortex and thalamus. These data show that female brindled mice have neurochemical abnormalities similar to (if less severe than) the male hemizygotes, that these abnormalities are regionally specific, are most apparent prior to 30 days of age, and are linked to behavioral deficits. These data also show that the extent of such deficits can be predicted by a quantitative analysis of the fur pattern of these females.

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The effect of copper supplementation on the concentration of copper in the brain of the brindled mouse

Cited by 19 publications

References 24 publications

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

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

Early treatment of Menkes disease with parenteral Cooper-Histidine: Long-term follow-up of four treated patients

The Female Brindled Mouse as a Model of Menkes' Disease: The Relationship of Fur Pattern to Behavioral and Neurochemical Abnormalities

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The effect of copper supplementation on the concentration of copper in the brain of the brindled mouse

Cited by 19 publications

References 24 publications

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

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

Early treatment of Menkes disease with parenteral Cooper-Histidine: Long-term follow-up of four treated patients

The Female Brindled Mouse as a Model of Menkes' Disease: The Relationship of Fur Pattern to Behavioral and Neurochemical Abnormalities

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

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