Cuprizone Administration Alters the Iron Metabolism in the Mouse Model of Multiple Sclerosis

Abstract

Cuprizone (CZ) is a widely used copper chelating agent to develop non-autoimmune animal model of multiple sclerosis, characterized by demyelination of the corpus callosum (CC) and other brain regions. The exact mechanisms of CZ action are still arguable, but it seems that the only affected cells are the mature oligodendrocytes, possibly via metabolic disturbances caused by copper deficiency. During the pathogenesis of multiple sclerosis, high amount of deposited iron can be found throughout the demyelinated areas of the brain in the form of extracellular iron deposits and intracellularly accumulated iron in microglia. In the present study, we used the accepted experimental model of 0.2% CZ-containing diet with standard iron concentration to induce demyelination in the brain of C57BL/6 mice. Our aim was to examine the changes of iron homeostasis in the CC and as a part of the systemic iron regulation, in the liver. Our data showed that CZ treatment changed the iron metabolism of both tissues; however, it had more impact on the liver. Besides the alterations in the expressions of iron storage and import proteins, we detected reduced serum iron concentration and iron stores in the liver, together with elevated hepcidin levels and feasible disturbances in the Fe-S cluster biosynthesis. Our results revealed that the CZ-containing diet influences the systemic iron metabolism in mice, particularly the iron homeostasis of the liver. This inadequate systemic iron regulation may affect the iron homeostasis of the brain, eventually indicating a relationship among CZ treatment, iron metabolism, and neurodegeneration.

Quantitative Imaging of White and Gray Matter Remyelination in the Cuprizone Demyelination Model Using the Macromolecular Proton Fraction

“…Abnormal iron deposition in the subcortical gray matter anatomic structures is a known pathological feature of MS [15,64,65]. A growing body of evidence suggests that an altered iron metabolism is closely associated with myelin pathology in both human MS disease and animal demyelination models [66,67,68,69]. Sensitivity to tissue relaxation properties is a known problem in alternative approaches for myelin imaging, such as multi-component relaxation methods [70,71,72] and MTR, while MPF mapping overcomes this limitation [12,15].…”

Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis

“…Cuprizone (CPZ) is synthesised by combining cyclohexanone and oxaldihydrazone [38]. While the mechanism of its toxic actions remain ill-defined, copper chelation [39] and dis-homeostasis of iron, zinc, sodium and manganese have been reported [40,41,42,43,44]. Such ion imbalance leads to endoplasmic reticulum stress, reduced mitochondrial ATP synthesis, and increased production of reactive oxygen and nitrogen species (reviewed in [2]).…”

Relationship of Iron Metabolism and Short-Term Cuprizone Treatment of C57BL/6 Mice

“…In our previous works, we examined the effect of CZ on iron metabolism regulation both locally in the brain and systemically via the hormone hepcidin produced by the liver [49]. The reason for these experiments was that there is evidence that the metabolisms of the two ions (iron and copper) are closely related [54,55].…”

“…Our previous experiments revealed that cuprizone as a copper chelating agent affected the iron metabolism in brain and liver tissues following four-week long cuprizone treatment [49]. To determine the early effect of CZ treatment on iron homeostasis regulation, cytosolic and mitochondrial iron storage, as well as some lipid metabolism genes we investigated the expression of respective iron homeostasis and lipid metabolism genes of the corpus callosum (CC) and the liver after short-term (two and eight days) CZ administration.…”