Activation of the astrocytic Nrf2/ARE system ameliorates the formation of demyelinating lesions in a multiple sclerosis animal model

Abstract

Oxidative stress critically contributes to the pathogenesis of a variety of neurodegenerative diseases such as multiple sclerosis. Astrocytes are the main regulators of oxidative homeostasis in the brain and dysregulation of these cells likely contributes to the accumulation of oxidative damage. The nuclear factor erythroid 2-related factor 2 (Nrf2) is the main transcriptional regulator of the anti-oxidant stress defense. In this study, we elucidate the effects of astrocytic Nrf2-activation on brain-intrinsic inflammation and lesion development. Cells deficient for the Nrf2 repressor kelch-like ECH-associated protein 1 (Keap1) are characterized by hyperactivation of Nrf2-signaling. Therefore, wild type mice and mice with a GFAP-specific Keap1-deletion were fed with 0.25% cuprizone for 1 or 3 weeks. Cuprizone intoxication induced pronounced oligodendrocyte loss, demyelination and reactive gliosis in wild type animals. In contrast, astrocyte-specific Nrf2-activation was sufficient to prevent oligodendrocyte loss and demyelination, to ameliorate brain intrinsic inflammation and to counteract axonal damage. Our results highlight the potential of the Nrf2/ARE system for the treatment of neuroinflammation in general and of multiple sclerosis in particular. © GLIA 2016;64:2219-2230.

Functional antagonism of sphingosine‐1‐phosphate receptor 1 prevents cuprizone‐induced demyelination

“…7), in line with a recent study that demonstrated that ablation of Erk2 in the CNS reduced the levels of immune mediators, gliosis and demyelination in the cuprizone model (Okazaki et al 2016). Consistent with the critical role of astrocytes in toxin induced demyelination, forced over-activation of astrocytic Nrf2, a main transcriptional regulator for the anti-oxidative defense system, through GFAP-specific deletion of the Nrf2 repressor Keap1 , ameliorates the cuprizone-induced loss of oligodendrocytes and inflammation (Draheim et al 2016). While the loss of S1pr1 in astrocytes diminished the therapeutic efficacy of FTY720 during EAE (Choi et al 2011) and FTY720 suppresses pathogenic astrocyte activation and chronic disease progression (Rothhammer et al 2017), further investigation of cell-type specific targeting of S1pr1 is required to definitively delineate the exact role of S1PR1 signaling in the context of demyelination and neurodegeneration.…”

(−)-Epicatechin, a Natural Flavonoid Compound, Protects Astrocytes Against Hemoglobin Toxicity via Nrf2 and AP-1 Signaling Pathways

“…Interestingly, a new study has shown that astrocytes with mutant SOD1 increase P-glycoprotein in endothelial cells in vitro [44]. Moreover, astrocytic Nrf2 activation helps to prevent oligodendrocyte loss and demyelination in an animal model of multiple sclerosis [45]. These data suggest that induction of Nrf2 in astrocytes contributes to neuroprotection, BBB repair, and white matter recovery after various brain injuries.…”

Multiple sclerosis animal models: a clinical and histopathological perspective

“…Maybe most importantly, in contrast to EAE T-cells are not relevant for cuprizone-induced demyelination. This leads to oxidative stress (36) and in consequence to primary oligodendrocyte apoptosis which is closely followed by microglia and astrocyte activation (see Figure 4A). Furthermore, breakdown of the blood-brain barrier, a hallmark of MS and EAE, is not a characteristic feature of the cuprizone model (5).…”