More from Dr. Lassman and his team in Vienna.
In contrast to these previous studies, we show here that DNA and lipid oxidation is associated with ongoing demyelination and neurodegeneration in active multiple sclerosis lesions. Furthermore, we show for the first time that acute cell injury and cell death of oligodendrocytes, axons and neurons in multiple sclerosis is linked to profound cytoplasmic and nuclear oxidative damage. The reason for the different results between our current and previous studies is not entirely clear. The most likely explanation comes from our observation that oxidized DNA and lipids were mainly present in a small zone of active multiple sclerosis lesions, which represents that previously described as the area of initial demyelination (Marik et al., 2007) or the ‘prephagocytic’ lesion (Barnett and Prineas, 2004; Henderson et al., 2009). Such lesions or lesion areas may not have been included in earlier studies. It has been shown previously that oxidized phospholipids and MDA epitopes are present in apoptotic cells as well as in apoptotic bodies ingested by macrophages (Chang et al., 1999). Apoptotic oligodendrocytes are predominantly seen in multiple sclerosis lesions in areas of initial (prephagocytic) demyelination (Barnett and Prineas, 2004; Marik et al., 2007). Furthermore, apoptotic cell death through oxidative mechanisms may exert proinflammatory and immunogenic actions (Chang et al., 2004), which in part may explain the progressive increase in inflammation with lesion maturation in multiple sclerosis (Marik et al., 2007; Henderson et al., 2009).
In summary, our study provides evidence for an important role of oxidative damage in the pathogenesis of demyelination and neurodegeneration in multiple sclerosis lesions, which may act in addition to, or in cooperation with nitric oxide radicals, as described previously (Bagasra et al., 1995; Zeis et al., 2009). It further shows—for the first time—that the analysis of oxidized lipid epitopes in multiple sclerosis lesions allows identification of acute damage of oligodendrocytes, axons and neurons at different stages of lesion formation. Our data also suggest that oxidative damage is in part related to inflammation, that it affects different cellular components of the CNS, but that myelin, oligodendrocytes, neurons and axons may be more sensitive to oxidative damage than astrocytes.