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.
Highlights
Multiple sclerosis (MS) is a disease of the central nervous system (CNS), causing inflammation and demyelination both in the grey and the white matter [1,2]
The demyelination process due to CZ administration can be followed by monitoring the mRNA levels of IL-6 cytokine and growth/differentiation factor 15 (GDF15), a transcription factor expressed by oligodendrocytes in corpus callosum (CC) [12]
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
Summary
Multiple sclerosis (MS) is a disease of the central nervous system (CNS), causing inflammation and demyelination both in the grey and the white matter [1,2]. Several models have been developed to investigate the distinct mechanisms contributing to neurodegeneration in MS [3]. There are two effects attributed to CZ, the disturbance of copper homeostasis and the induction of copper chelate [7,8], but the exact mechanism of action of CZ is not fully understood. It is controversial whether in CZ treatment CZ can be reabsorbed from the duodenum and pass through the plasma membranes of neuronal cells [9]. Astrocyte-microglia interactions with oligodendrocytes contribute to CZ-mediated de- and remyelination [14]
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