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Prof. Hans Lassman - Iron metabolism in normal appearing brain matter in MS patients
Prof. Hans Lassman, Centre for Brain Research, Medical University of Vienna, Austria, is interviewed on the importance of iron in Multiple Sclerosis (MS), and in particular its relevance in relation to oxidative stress.
Iron is a potential source for oxygen radicals in the brain. However, iron also has many functions, also in the brain, e.g. as cofactor for many neuronal enzymes and those involved in myelination. Iron is present in all cells, at different levels. The brain is accumulating iron with age, storing it mainly in oligodendrocytes and myelin. Here it is bound to ferritin, that also detoxifies the iron. With MS, both myelin and oligodendrocytes are being destroyed, releasing the ferritin into the extracellular space where the protein is degraded and the iron is liberated. The non-toxic (trivalent) form can in an inflammatory environment be converted to the toxic (divalent) form of iron, potentially amplifying the risks for oxidative injury. Iron metabolism in normal appearing brain matter in MS patients In a recent study, Lassman and colleagues investigated iron metabolism in normal appearing brain matter in MS patients (comparing to control) and in active MS leasions. They were able to confirm earlier data in healthy brains showing iron is accumulating with age, predominantly residing in oligodendrocytes and myelin. Strikingly, also in normal appearing brain of MS patients iron is lost from oligodendrocytes and the general iron levels are lower than in control brain. The idea is that chronic inflammation in MS is changing iron metabolism. In agreement with this hypothesis is the finding that iron export proteins are upregulated in oligodendrocytes from normal appearing MS brain. The loss of iron may not so much affect mature myelin, but it can affect the re-myelination process, as iron has an important role in this process. How to work further, from this hypothesis? Animal models can not be used, as rodents have only minimal iron accumulation in the brain. Clinical applications may be sought in the use of iron chelators to capture the free-radical iron in older patients with aggressive new lesions – as the blood-brain barrier (BBB) is wide open in these instances, a chelator may have some effect for the short term. With an intact BBB chelators applied in the periphery will be ineffective and harmful, as it will deplete necessary iron. Prof. Lassman sees greatest potential in targeting downstream pathways of oxidative injury, as such molecules will be easier to target than iron itself. The great challenges in this respect are to design drugs that will reach the brain in patient with an intact BBB, and to design clinical trials targeting primary/secondary progressive MS.