Cuprizone neurotoxicity, copper deficiency and neurodegeneration

Benetti, Federico; Ventura, Marcello; Salmini, Benedetta; Ceola, Stefano; Carbonera, Donatella; Mammi, Stefano; Zitolo, Andrea; D’Angelo, P.; Urso, Emanuela; Maffia, Michele; Salvato, Benedetto; Spisni, Enzo

doi:10.1016/j.neuro.2010.05.008

Cited by 60 publications

(41 citation statements)

References 46 publications

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“…The exact mechanisms of general cuprizone toxicity are not fully understood so far. However, the neurotoxic effect of cuprizone is believed to be in part attributed to its capability of chelating copper, ultimately leading to chronic copper deficiency with subsequent inhibition of copper-dependent enzymes (Benetti et al 2010). Moreover, activity of monoamino oxidase B, an iron-dependent enzyme, has been detected in PAS-positive granules of SAMP8 mice (Nakamura et al 1995).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Periodic Acid-Schiff-Positive Granular Deposits in the Hippocampus of SJL/J Mice

et al. 2015

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Periodic acid-Schiff (PAS)-positive granular deposits in the hippocampus have been reported previously in certain inbred mouse strains such as C57BL/6 and the senescent-accelerated mouse prone-8. Here, we report for the first time that similar PAS-positive granules age dependently occur in SJL/J mice, a mouse strain, for instance, used for central nervous system disease research. Moreover, similar granules stained intensely positive with a polyclonal antibody directed against p75 neurotrophin receptor (p75 NTR ). Granular deposits were absent in young mice and developed with aging in CA1 and CA2 regions of the hippocampus. Interestingly, granules significantly diminished in SJL/J mice previously treated with cuprizone, a copper chelator, which is a useful model for toxic demyelination. The presented data support the idea that granules might be the result of an imbalance of redox-active metals and/or a dysregulation of complementary mechanisms that regulate their homeostasis in astrocyte-neuron coupling, respectively. It remains to be determined whether the unsuspected immunoreactivity for p75 NTR represents a false-positive reaction or whether p75 NTR is crucially involved in the pathogenesis of age-related hippocampal granular deposits in mice.

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Section: Discussionmentioning

confidence: 99%

Characterization of Periodic Acid-Schiff-Positive Granular Deposits in the Hippocampus of SJL/J Mice

et al. 2015

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“…One study demonstrated that oligomers of CPZ-Cu 2+ precipitated in the gut, and this was proposed to result in a widespread deficiency of copper throughout the body, including the brain. 10 In contrast, chemical studies of the binding of CPZ to copper showed that upon copper binding, a 2CPZ-Cu 3+ species was formed and an extended feeding of low concentrations of CPZ resulted in increased levels of copper in the brain. 5 Recently, copper, iron, and manganese levels were measured in the brain after CPZ treatment for 6 weeks.…”

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confidence: 99%

Cuprizone Intoxication Induces Cell Intrinsic Alterations in Oligodendrocyte Metabolism Independent of Copper Chelation

Taraboletti

Walker

Avila³

et al. 2017

Biochemistry

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Cuprizone intoxication is a common animal model used to test myelin regenerative therapies for the treatment of diseases such as multiple sclerosis. Mice fed this copper chelator develop reversible, region-specific oligodendrocyte loss and demyelination. While the cellular changes influencing the demyelinating process have been explored in this model, there is no consensus about the biochemical mechanisms of toxicity in oligodendrocytes and about whether this damage arises from the chelation of copper in vivo. Here we have identified an oligodendroglial cell line that displays sensitivity to cuprizone toxicity and performed global metabolomic profiling to determine biochemical pathways altered by this treatment. We link these changes with alterations in brain metabolism in mice fed cuprizone for 2 and 6 weeks. We find that cuprizone induces widespread changes in one-carbon and amino acid metabolism as well as alterations in small molecules that are important for energy generation. We used mass spectrometry to examine chemical interactions that are important for copper chelation and toxicity. Our results indicate that cuprizone induces global perturbations in cellular metabolism that may be independent of its copper chelating ability and potentially related to its interactions with pyridoxal 5′-phosphate, a coenzyme essential for amino acid metabolism.

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“…A deficiency of copper has been proved to be related to microglial activation in the cerebral cortex and thalamus. Proinflammatory molecules such as radical oxygen species and cytokines which are secreted by activated microglia can ultimately damage oligodendrocytes and growth retardation [30]. Also myelination is a copper dependent process in CNS [29] and myelin is lost in the neuropathies of copper deficiency [31].…”

Section: Discussionmentioning

confidence: 99%

A Research on the Level of Zinc and Copper in the Hair of Students with Lower IQ

Meghrazi

Sabet²,

Kheradmand

et al. 2017

Zahedan J Res Med Sci

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Background: The measurement of trace elements in human body has proved to be of great use in the evaluation of human health and the diagnosis of various diseases. No light, however, has been shed on these elements where they concern the human intelligence. Objectives:The goal is to make a comparison between the students with a lower IQ and those having an ordinary IQ in terms of the amount of zinc and copper as two trace elements. Methods: This is a case-control study and the subjects as the patients were chosen from mentally retarded students having no particular diseases. The sample size for the patient and control was 30 for each. The hair samples of the experimental group and the ordinary students (the control group) were digested with concentrated HNO3 after being washed with water and acetone. After being digested, the values of zinc and copper in the samples were measured with atomic absorption spectroscopy. The obtained data were analyzed using SPSS-15 via two independent sample tests of significance tests.

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Cuprizone neurotoxicity, copper deficiency and neurodegeneration

Cited by 60 publications

References 46 publications

Characterization of Periodic Acid-Schiff-Positive Granular Deposits in the Hippocampus of SJL/J Mice

Characterization of Periodic Acid-Schiff-Positive Granular Deposits in the Hippocampus of SJL/J Mice

Cuprizone Intoxication Induces Cell Intrinsic Alterations in Oligodendrocyte Metabolism Independent of Copper Chelation

A Research on the Level of Zinc and Copper in the Hair of Students with Lower IQ

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