Copper-trafficking efficacy of copper-pyruvaldehyde bis(N4-methylthiosemicarbazone) on the macular mouse, an animal model of Menkes disease

Munakata, Mitsutoshi; Kodama, Hiroko; Fujisawa, Chie; Hiroki, Tomoko; Kimura, Kazuhiko; Watanabe, Mika; Nishikawa, Masazumi; Tsuchiya, Shigeru

doi:10.1038/pr.2012.85

Cited by 8 publications

(7 citation statements)

References 31 publications

(36 reference statements)

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“…We found that both strains, under the chosen assay conditions, grew normally in the presence of copper up to a concentration of at least 300 M (data not shown). Although macrophages can challenge bacteria with a copper concentration of up to 400 M (24), we chose to screen at a copper concentration of 50 M, which is about twice the copper concentration present in human blood (25,26). We reasoned that a slightly higher copper concentration in the assay may increase its sensitivity, thereby aiding in the detection of weaker synergistic interactions between copper and compounds which could be useful for subsequent structure-activity relationship analysis.…”

Section: Resultsmentioning

confidence: 99%

Copper Complexation Screen Reveals Compounds with Potent Antibiotic Properties against Methicillin-Resistant Staphylococcus aureus

Haeili

Moore

Davis

et al. 2014

Antimicrob Agents Chemother

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on MRSA. Our data indicate that the activity of the GTSM-copper complex goes beyond the general antibacterial effects of accumulated copper ions and suggest that, in contrast to prevailing opinion, copper complexes can indeed exhibit species-and target-specific activities. Based on experimental evidence, we propose that copper ions impose structural changes upon binding to the otherwise inactive GTSM ligand and transfer antibacterial properties to the chelate. In turn, GTSM determines target specificity and utilizes a redox-sensitive release mechanism through which copper ions are deployed at or in close proximity to a putative target. According to our proof-of-concept screen, copper activation is not a rare event and even extends to already established drugs. Thus, copper-activated compounds could define a novel class of anti-MRSA agents that amplify copper-dependent innate immune functions of the host. To this end, we provide a blueprint for a high-throughput drug screening campaign which considers the antibacterial properties of copper ions at the host-pathogen interface.

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Section: Resultsmentioning

confidence: 99%

Copper Complexation Screen Reveals Compounds with Potent Antibiotic Properties against Methicillin-Resistant Staphylococcus aureus

Haeili

Moore

Davis

et al. 2014

Antimicrob Agents Chemother

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“…In previous studies, copper supplementation with CuDMDTC or CuPTSM caused lower copper accumulation in the kidneys of a mouse model of Menkes disease compared to supplementation with CuCl 2 . 6,11 The reduced renal copper accumulation is a possible benefit of these lipophilic copper complexes.…”

Section: Discussionmentioning

confidence: 99%

“…[8][9][10] Pyruvaldehyde-bis(N(4)-methylthiosemicarbazonato)-copper(II) (CuPTSM), a neutral and lipophilic CuBTSC, was partially effective for a Menkes disease mouse model, although the utility of the compound was highly restricted by poor water solubility. 11 Recently, oral gavage of glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) (CuGTSM) was shown to increase copper levels in the brain and ameliorate brain dysfunction in Alzheimer's disease mouse models. 8 Therefore, oral gavage of CuGTSM may have therapeutic effects in Menkes disease without the burden of prolonged injections of copper.…”

Section: Introductionmentioning

confidence: 99%

Menkes disease: Oral administration of glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) rescues the macular mouse

et al. 2018

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“…NPY decrease glutamate release and results obtained by Richichi and co-workers indicated that both acute and chronic seizures can be reduced by increasing NPY expression in the hippocampus (Richichi et al, 2004 ; Bousquet-Moore et al, 2010 ). Macular and brindled mutants also exhibit reduced cerebral cytochrom c oxidase activity (Donsante et al, 2011 ; Munakata et al, 2012 ).…”

Section: Lessons From the Mottled Micementioning

confidence: 99%

“…Interestingly, reduced Cu accumulation in the kidney has also been achieved using the highly lipophilic organic Cu-complex, Cu-pyruvaldehyde bis(N 4 -methylthiosemicarbazone; Cu-PTSM). In the cells, Cu-PTSM is irreversibly reduced and cleaved to liberate Cu ions which can be incorporated into the intracellular Cu pools (Fujibayashi et al, 1993 ; Munakata et al, 2012 ). In macular mutants treated with Cu-PTSM, the renal Cu content was half of the Cu content in CuCl 2 -treated mutants.…”

Section: Lessons From the Mottled Micementioning

confidence: 99%

Mottled Mice and Non-Mammalian Models of Menkes Disease

Lenartowicz

Krzeptowski

Lipiński

et al. 2015

Front. Mol. Neurosci.

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Menkes disease is a multi-systemic copper metabolism disorder caused by mutations in the X-linked ATP7A gene and characterized by progressive neurodegeneration and severe connective tissue defects. The ATP7A protein is a copper (Cu)-transporting ATPase expressed in all tissues and plays a critical role in the maintenance of copper homeostasis in cells of the whole body. ATP7A participates in copper absorption in the small intestine and in copper transport to the central nervous system (CNS) across the blood-brain-barrier (BBB) and blood–cerebrospinal fluid barrier (BCSFB). Cu is essential for synaptogenesis and axonal development. In cells, ATP7A participates in the incorporation of copper into Cu-dependent enzymes during the course of its maturation in the secretory pathway. There is a high degree of homology (>80%) between the human ATP7A and murine Atp7a genes. Mice with mutations in the Atp7a gene, called mottled mutants, are well-established and excellent models of Menkes disease. Mottled mutants closely recapitulate the Menkes phenotype and are invaluable for studying Cu-metabolism. They provide useful models for exploring and testing new forms of therapy in Menkes disease. Recently, non-mammalian models of Menkes disease, Drosophila melanogaster and Danio rerio mutants were used in experiments which would be technically difficult to carry out in mammals.

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Copper-trafficking efficacy of copper-pyruvaldehyde bis(N4-methylthiosemicarbazone) on the macular mouse, an animal model of Menkes disease

Cited by 8 publications

References 31 publications

Copper Complexation Screen Reveals Compounds with Potent Antibiotic Properties against Methicillin-Resistant Staphylococcus aureus

Copper Complexation Screen Reveals Compounds with Potent Antibiotic Properties against Methicillin-Resistant Staphylococcus aureus

Menkes disease: Oral administration of glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) rescues the macular mouse

Mottled Mice and Non-Mammalian Models of Menkes Disease

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