Here, we use the cuprizone mouse model of MS to induce oxidative stress, selective oligodendrocyte loss, microglia and astrocyte activation as well as axonal damage in both wild type and Nrf2-deficient mice.
Although the understanding of the complex nature of NRF2 signaling continues to grow, there is only one therapeutic targeting NRF2 for clinical use, dimethyl fumarate, used for the treatment of multiple sclerosis.
Here we investigated the neuroprotective potential of SIRT1 or NRF2 gene transfer using adeno-associated virus (AAV) vectors in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.
Further, the expanding functions of NRF2 have elicited interest in the development of therapeutic modalities for inflammatory diseases, including multiple sclerosis and sickle cell disease.
Here, we focus on the relation between nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway induction under DMF therapy and the composition of the blood immune cell compartment and clinical efficacy in relapsing-remitting multiple sclerosis (MS) patients.
This study provides strong evidence that oxidative stress in oligodendrocytes activates endoplasmic reticulum stress response in a NRF2-dependent manner and, in consequence, might regulate oligodendrocyte degeneration in multiple sclerosis and other neurological disorders.
In other cell types MMF increases the expression of nuclear factor erythroid-derived 2-like 2 (Nrf2), a transcription factor that regulates cellular antioxidant responses, to reduce oxidative stress like that observed in inflammatory disorders such as multiple sclerosis.
To investigate the activation of Nrf2 pathway following ex vivo stimulation of human peripheral blood mononuclear cells (PBMCs) with DMF or MMF, and in DMF-treated patients from two Phase 3 relapsing MS studies DEFINE and CONFIRM.
Therefore, these findings indicate that TFM-735 is a potent Nrf2 inducer that inhibits inflammatory cytokine production and disease progression in mice with EAE and that TFM-735 is a promising therapeutic agent for MS.
Following this background, we expand our discussion to the role of Nrf2 in several major neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis.
Together, our findings suggest that persistent Nrf2-mediated transcription occurs in active MS lesions, but that this endogenous response is insufficient to prevent ROS-induced cellular damage, which is abundant in inflammatory MS lesions.
We identified a decrease in a transcription factor complex containing nuclear respiratory factor 2 (NRF-2) in nuclear extracts isolated from MS cortex.