title: Cuprizone Intoxication Induces Cell Intrinsic Alterations in Oligodendrocyte Metabolism Independent of Copper Chelation.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Akron , Akron, Ohio 44325, United States.
authors.forename: Alexandra
authors.identifier: 0000-0002-8779-483X
authors.initials: A
authors.lastname: Taraboletti
authors.affiliation: Department of Chemistry, Indiana University Northwest , Gary, Indiana 46408, United States.
authors.forename: Tia
authors.initials: T
authors.lastname: Walker
authors.affiliation: Renovo Neural, Inc. , Cleveland, Ohio 44106, United States.
authors.forename: Robin
authors.initials: R
authors.lastname: Avila
authors.affiliation: Department of Chemistry, University of Akron , Akron, Ohio 44325, United States.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Joel
authors.initials: J
authors.lastname: Caporoso
authors.affiliation: Department of Chemistry, University of Akron , Akron, Ohio 44325, United States.
authors.forename: Erendra
authors.initials: E
authors.lastname: Manandhar
authors.affiliation: Department of Chemistry, College of Wooster , Wooster, Ohio 44691, United States.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Leeper
authors.affiliation: Department of Chemistry, University of Akron , Akron, Ohio 44325, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Modarelli
authors.affiliation: Renovo Neural, Inc. , Cleveland, Ohio 44106, United States.
authors.forename: Satish
authors.initials: S
authors.lastname: Medicetty
authors.affiliation: Department of Chemistry, University of Akron , Akron, Ohio 44325, United States.|Department of Biology, University of Akron , Akron, Ohio 44325, United States.
authors.forename: Leah P
authors.initials: LP
authors.lastname: Shriver
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry; D002460:Cell Line; D002614:Chelating Agents / Q000378:metabolism / Q000633:toxicity*; D003300:Copper / Q000378:metabolism; D003471:Cuprizone / Q000378:metabolism / Q000633:toxicity*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004734:Energy Metabolism; D008297:Male; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011732:Pyridoxal Phosphate / Q000378:metabolism
chemical_list: D000596:Amino Acids; D002614:Chelating Agents; D003471:Cuprizone; D011732:Pyridoxal Phosphate; D003300:Copper