Abnormal iron accumulation is involved in the pathogenesis of the demyelinating dmy rat but not in the hypomyelinating mv rat

In the central nervous system (CNS), iron is enriched in oligodendrocytes, the myelin forming cells. The importance of iron in CNS myelination has been demonstrated by studies using rodent models, in which iron deficiency is associated with hypomyelination. Besides iron deficiency, an abnormal iron accumulation is thought to be involved in the pathogenesis of demyelination in multiple sclerosis, an autoimmune demyelinating disease in humans. To determine the importance of iron metabolism in myelin diseases, we investigated iron metabolism using two different myelin mutant dmy (demyelination model) and mv (hypomyelination model) rats. Our results demonstrated an abnormal iron deposition, and significant upregulation of antioxidant enzyme heme oxygenase-1 (HO-1) and iron storage protein ferritin in the dmy rat, but not in the mv rat. The expression of iron transporter transferrin mRNA was significantly decreased in the mv but not dmy rat, which may reflect a part of functional abnormalities of oligodendrocytes in the mv rat. Iron accumulation and increased expression of ferritin in the dmy rat were mainly found in astrocytes, suggesting a protective role of astrocytes in iron-mediated cytotoxicity. HO-1 was predominantly induced in oligodendrocytes during the early stage of demyelination in the dmy rat, suggesting that iron-mediated oxidative stress is most likely involved in the pathogenesis of demyelination in the dmy rat.