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Cuprizone-induced Demyelination in Mouse Brain is not due to Depletion of Copper

The cuprizone (CPZ) model allows the study of the biochemical processes underlying nonautoimmune-mediated demyelination, remyelination, and chronic white matter disease progression. CPZ is a copper (Cu) chelator that chiefly causes oligodendrocyte apoptosis in the corpus callosum and cerebellum when...

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Autores principales: Morgan, Megan L., Teo, Wulin, Hernandez, Yda, Brideau, Craig, Cummins, Karen, Kuipers, Hedwich F., Stys, Peter K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9483969/
https://www.ncbi.nlm.nih.gov/pubmed/36114624
http://dx.doi.org/10.1177/17590914221126367
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author Morgan, Megan L.
Teo, Wulin
Hernandez, Yda
Brideau, Craig
Cummins, Karen
Kuipers, Hedwich F.
Stys, Peter K.
author_facet Morgan, Megan L.
Teo, Wulin
Hernandez, Yda
Brideau, Craig
Cummins, Karen
Kuipers, Hedwich F.
Stys, Peter K.
author_sort Morgan, Megan L.
collection PubMed
description The cuprizone (CPZ) model allows the study of the biochemical processes underlying nonautoimmune-mediated demyelination, remyelination, and chronic white matter disease progression. CPZ is a copper (Cu) chelator that chiefly causes oligodendrocyte apoptosis in the corpus callosum and cerebellum when administered in the mouse diet. While disruption of Cu homeostasis is known to cause neurodegeneration (as is observed in Wilson’s and Menkes disease), no consensus exists to date as to CPZ’s mechanism of action. We sought to determine whether CPZ-induced pathology is due to Cu depletion as is generally believed. Cu supplementation in chow, in stoichiometric excess to the added CPZ, did not reduce CPZ-induced demyelination in C57Bl/6 mice. Moreover, equivalent doses of other known Cu chelators neocuproine and D-penicillamine (D-Pen) failed to induce central nervous system (CNS) demyelination. Since administration of D-Pen in the treatment of Wilson’s disease can induce hypocupremia, we next sought to recreate penicillamine-induced Cu deficiency to compare with purported CPZ-induced Cu deficiency. The resulting clinical phenotype and histopathology were unlike that of CPZ. D-Pen-treated mice exhibited digit paralysis, tail flaccidity, subcutaneous hemorrhaging, and optic and sciatic neuropathy, all of which were prevented with Cu supplementation. No demyelination of the corpus callosum or cerebellum was observed, even with D-Pen doses tenfold higher than CPZ. Intriguingly, addition of D-Pen to the CPZ diet paradoxically prevented demyelination in a dose-dependent manner. SUMMARY STATEMENT: The demyelinating effects of CPZ are not due to Cu deficiency but are instead consistent with acute toxicity of a CPZ + Cu complex.
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spelling pubmed-94839692022-09-20 Cuprizone-induced Demyelination in Mouse Brain is not due to Depletion of Copper Morgan, Megan L. Teo, Wulin Hernandez, Yda Brideau, Craig Cummins, Karen Kuipers, Hedwich F. Stys, Peter K. ASN Neuro Original Papers The cuprizone (CPZ) model allows the study of the biochemical processes underlying nonautoimmune-mediated demyelination, remyelination, and chronic white matter disease progression. CPZ is a copper (Cu) chelator that chiefly causes oligodendrocyte apoptosis in the corpus callosum and cerebellum when administered in the mouse diet. While disruption of Cu homeostasis is known to cause neurodegeneration (as is observed in Wilson’s and Menkes disease), no consensus exists to date as to CPZ’s mechanism of action. We sought to determine whether CPZ-induced pathology is due to Cu depletion as is generally believed. Cu supplementation in chow, in stoichiometric excess to the added CPZ, did not reduce CPZ-induced demyelination in C57Bl/6 mice. Moreover, equivalent doses of other known Cu chelators neocuproine and D-penicillamine (D-Pen) failed to induce central nervous system (CNS) demyelination. Since administration of D-Pen in the treatment of Wilson’s disease can induce hypocupremia, we next sought to recreate penicillamine-induced Cu deficiency to compare with purported CPZ-induced Cu deficiency. The resulting clinical phenotype and histopathology were unlike that of CPZ. D-Pen-treated mice exhibited digit paralysis, tail flaccidity, subcutaneous hemorrhaging, and optic and sciatic neuropathy, all of which were prevented with Cu supplementation. No demyelination of the corpus callosum or cerebellum was observed, even with D-Pen doses tenfold higher than CPZ. Intriguingly, addition of D-Pen to the CPZ diet paradoxically prevented demyelination in a dose-dependent manner. SUMMARY STATEMENT: The demyelinating effects of CPZ are not due to Cu deficiency but are instead consistent with acute toxicity of a CPZ + Cu complex. SAGE Publications 2022-09-16 /pmc/articles/PMC9483969/ /pubmed/36114624 http://dx.doi.org/10.1177/17590914221126367 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Papers
Morgan, Megan L.
Teo, Wulin
Hernandez, Yda
Brideau, Craig
Cummins, Karen
Kuipers, Hedwich F.
Stys, Peter K.
Cuprizone-induced Demyelination in Mouse Brain is not due to Depletion of Copper
title Cuprizone-induced Demyelination in Mouse Brain is not due to Depletion of Copper
title_full Cuprizone-induced Demyelination in Mouse Brain is not due to Depletion of Copper
title_fullStr Cuprizone-induced Demyelination in Mouse Brain is not due to Depletion of Copper
title_full_unstemmed Cuprizone-induced Demyelination in Mouse Brain is not due to Depletion of Copper
title_short Cuprizone-induced Demyelination in Mouse Brain is not due to Depletion of Copper
title_sort cuprizone-induced demyelination in mouse brain is not due to depletion of copper
topic Original Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9483969/
https://www.ncbi.nlm.nih.gov/pubmed/36114624
http://dx.doi.org/10.1177/17590914221126367
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