Oxidative damage in multiple sclerosis lesions

Abstract

Multiple sclerosis is a chronic inflammatory disease of the central nervous system, associated with demyelination and neurodegeneration. The mechanisms of tissue injury are currently poorly understood, but recent data suggest that mitochondrial injury may play an important role in this process. Since mitochondrial injury can be triggered by reactive oxygen and nitric oxide species, we analysed by immunocytochemistry the presence and cellular location of oxidized lipids and oxidized DNA in lesions and in normal-appearing white matter of 30 patients with multiple sclerosis and 24 control patients without neurological disease or brain lesions. As reported before in biochemical studies, oxidized lipids and DNA were highly enriched in active multiple sclerosis plaques, predominantly in areas that are defined as initial or ‘prephagocytic’ lesions. Oxidized DNA was mainly seen in oligodendrocyte nuclei, which in part showed signs of apoptosis. In addition, a small number of reactive astrocytes revealed nuclear expression of 8-hydroxy-d-guanosine. Similarly, lipid peroxidation-derived structures (malondialdehyde and oxidized phospholipid epitopes) were seen in the cytoplasm of oligodendrocytes and some astrocytes. In addition, oxidized phospholipids were massively accumulated in a fraction of axonal spheroids with disturbed fast axonal transport as well as in neurons within grey matter lesions. Neurons stained for oxidized phospholipids frequently revealed signs of degeneration with fragmentation of their dendritic processes. The extent of lipid and DNA oxidation correlated significantly with inflammation, determined by the number of CD3 positive T cells and human leucocyte antigen-D expressing macrophages and microglia in the lesions. Our data suggest profound oxidative injury of oligodendrocytes and neurons to be associated with active demyelination and axonal or neuronal injury in multiple sclerosis.

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

“…Oxidized lipids and DNA are highly enriched in MS plaques (36) and have been associated with oxidative injury of oligodendrocytes and active demyelination as well as axonal or neuronal injury. It is noteworthy that antioxidant therapy in patients with MS has shown benefits in some studies but not in others, with one study showing no effect in the secondary progressive MS subtype but another showing a positive effect on patients with milder disease (37,38).…”

The molecular basis of neurodegeneration in multiple sclerosis

“…In line with this interpretation is a study, which analyzed nitrotyrosine in well defined active lesions, where it was found to be present in oligodendrocytes [115]. We have recently addressed this question in more detail by analyzing a large sample of well defined lesion stages from patients with fulminant acute as well as chronic MS [40]. In this material profound immunoreactivity for oxidized DNA and lipids was found in active and slowly expanding lesions, where it was predominantly present in the areas of initial tissue injury.…”

“…While clinical disease is highly variable between patients with relapsing MS, the clinical course of the disease is surprisingly uniform in patients who have entered the progressive phase. Furthermore, onset of steady disease progression, both in patients with primary or secondary progressive disease, occurs around the same age (age [40][41][42][43][44][45][46][47][48][49][50], irrespective of previous disease severity or course [21,22].…”

“…In fact, anti-inflammatory or immunomodulatory treatments are effective in the relapsing stage, but the benefit is lost when the patients have entered the progressive phase [20]. Despite the lower extent of inflammation in the progressive stage of the disease oxidative damage within the active or slowly expanding lesions in patients with progressive disease is quite similar as in lesions of patients, who died at early stages of the disease [40]. These data suggest that inflammation may become less prominent in driving tissue injury in the progressive stage and that additional possibly age-related mechanisms may amplify neurodegeneration in this phase of the disease.…”

Glutathione in multiple sclerosis: More than just an antioxidant?

“…7 This suggests that in response to oxidative and inflammatory damage, the main protective cellular antioxidant mechanisms, namely those regulated by Nrf2, are activated early in lesion formation; however, enhanced levels of endogenous antioxidants are detected concomitantly with several oxidative stress markers, indicating that the endogenous antioxidant response is not sufficient to restore the delicate redox-balance and prevent oxidative damage. 6,7 Glutathione metabolism in the CNS…”