Iron released from oligodendrocytes during
demyelination or derived from haemoglobin breakdown products is believed to amplify oxidative tissue injury in
multiple sclerosis (MS). However, the pathophysiological significance of
iron-containing haemoglobin breakdown products themselves is rarely considered in the context of MS and their cellular specificity and mode of action remain unclear. Using myelinating cell cultures, we now report the cytotoxic potential of
hemin (
ferriprotoporphyrin IX chloride), a major degradation product of haemoglobin, is 25-fold greater than equimolar concentrations of free
iron in myelinating cultures; a model that reproduces the complex multicellular environment of the CNS. At low micro molar concentrations (3.3 - 10 μM) we observed
hemin preferentially binds to myelin and axons to initiate a complex detrimental response that results in targeted
demyelination and axonal loss but spares neuronal cell bodies, astrocytes and the majority of oligodendroglia.
Demyelination and axonal loss in this context are executed by a combination of mechanisms that include
iron-dependent peroxidation by
reactive oxygen species (ROS) and ferroptosis. These effects are microglial-independent, do not require any initiating inflammatory insult and represent a direct effect that compromises the structural integrity of myelinated axons in the CNS. Our data identify
hemin-mediated
demyelination and axonal loss as a novel mechanism by which intracerebral degradation of haemoglobin may contribute to lesion development in MS.