Does Nrf2 help nerves to survive?

Does Nrf2 help nerves to survive? Dimethyl fumarate (DMF) has recently been approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) after showing beneficial effects on clinical and radiologic endpoints in 2 phase 3 clinical trials. 1,2 While DMF's mode of action is not completely understood, experimental data suggest that putative neuroprotective properties may be mediated by the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. 3,4 Specifically, DMF leads to translocation of Nrf2 to the nucleus, thereby enhancing the expression of antioxidant enzymes and promoting neuroprotection in cell culture models. 4 In line with this, DMF improved the clinical course and preservation of myelin, axons, and neu-rons in an animal model of MS. These effects were lost in Nrf2-deficient mice, suggesting a central role for Nrf2 in mediating neuroprotection. 3 In this issue of Neurology ® Neuroimmunology & Neuroinflammation, Metz et al. 5 report on a patient with RRMS who after more than 1 year of DMF treatment underwent brain biopsy for a large unusual left occipital lesion. Histopathologic workup of this lesion revealed a more than 6-fold higher number of Nrf2-positive nuclei than control lesions from patients with MS not treated with DMF. The most prominent nuclear Nrf2 signal was observed in astro-cytes, whereas other cell types such as oligodendro-cytes and lymphocytes displayed a predominantly cytoplasmic staining. Metz et al. could also analyze biopsied lesions from 3 patients with psoriasis who had developed progressive multifocal leukoencepha-lopathy (PML) as a rare complication of ongoing fumarate treatment. Lesions from 2 of those 3 patients likewise exhibited higher numbers of Nrf2-positive nuclei than control PML lesions. Although based on only a few cases, these data provide circumstantial evidence that DMF treatment may induce nuclear translocation of Nrf2 in CNS cells in vivo, thus potentially preventing oxida-tive damage of neurons and glial cells in vivo. Nevertheless, the findings of Metz et al. are derived from single biopsies and therefore do not permit us to draw conclusions on the temporal dynamics of Nrf2 expression. Another note of caution is that the MS lesion was biopsied 8 weeks after the last DMF dosage, raising the question as to whether levels of DMF would have been sufficiently high to exert biological functions at that time. Although the results of Metz et al. therefore do not formally prove Nrf2 nuclear translocation in patients treated with fumarate, they are consistent with previous observations in cell culture experiments and …