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

Abstract

One of the models to investigate the distinct mechanisms contributing to neurodegeneration in multiple sclerosis is based on cuprizone (CZ) intoxication. CZ is toxic to mature oligodendrocytes and produces demyelination within the central nervous system but does not cause direct neuronal damage. The CZ model is suitable for better understanding the molecular mechanism of de- and remyelination processes of oligodendrocytes. CZ is a copper chelating agent and it also affects the iron metabolism in brain and liver tissues. 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 CZ administration. In the present study C57BL/6 male mice aged four weeks were fed with standard rodent food premixed with 0.2 w/w% CZ for two or eight days. The major findings of our experiments are that short-term CZ treatment causes significant changes in iron metabolism regulation as well as in the expression of myelin and lipid synthesis-related genes, even before apparent demyelination occurs. Both in the CC and the liver the iron uptake, utilization and storage are modified, though not always the same way or to the same extent in the two organs. Understanding the role of iron in short-term and long-term CZ intoxication could provide a partial explanation of the discrepant signs of acute and chronic MS. These could contribute to understanding the development of multiple sclerosis and might provide a possible drug target.

Can MRI measure myelin? Systematic review, qualitative assessment, and meta-analysis of studies validating microstructural imaging with myelin histology

“…Conditions such as MS, or animal models such as Cuprizone-fed and Shiverer mice, are often used in validation studies, because of their known effect on myelin, but they also affect iron metabolism, due to iron’s role in myelin maintenance (e.g. Hametner, Wimmer, Haider, Pfeifenbring, Brück, Lassmann, 2013 , Pandur, Pap, Varga, Jánosa, Komoly, Fórizs, Sipos, 2019 , Sergeant, Vesvres, Devès, Guillou, 2005 ) and axons, since myelin and axonal health are tightly coupled ( Stassart et al., 2018 ).…”

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].…”

Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination

“…Iron homeostasis is dysregulated in the liver and brain of mice fed with cuprizone, as several iron metabolism enzymes like hepcidin, transferrin receptor 1 and 2, ferritin heavy chain, and mitochondrial iron transport proteins are dysregulated in the corpus callosum compared to control animals [ 284 , 285 ]. Dysregulation of these enzymes alters the intracellular iron pool, which can lead to ferroptosis [ 286 ].…”