Multiple sclerosis (MS) is the most common multifocal inflammatory demyelinating disease of the central nervous system (CNS). Due to the progressive neurodegenerative nature of MS, developing treatments that exhibit direct neuroprotective effects are needed. Tecfidera™ (BG-12) is an oral formulation of the fumaric acid esters (FAE), containing the active metabolite dimethyl fumarate (DMF). Although BG-12 showed remarkable efficacy in lowering relapse rates in clinical trials, its mechanism of action in MS is not yet well understood. In this study, we reported the potential neuroprotective effects of dimethyl fumarate (DMF) on mouse and rat neural stem/progenitor cells (NPCs) and neurons. We found that DMF increased the frequency of the multipotent neurospheres and the survival of NPCs following oxidative stress with hydrogen peroxide treatment. In addition, we showed that DMF reducedreactive oxygen species production induced by hydrogen peroxide. DMF also decreased oxidative stress-induced apoptosis. Using motor neuron survival assay, DMF significantly promoted survival of motor neurons under oxidative stress. (Abstract truncated as I can do have the time to to explain the rest).
Tecfidera is a long-lasting dimethyl fumarate, which people have suggested works via Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2. Nrf2 is a basic leucine zipper (bZIP) protein that regulates the expression of anti-oxidantproteins that protect against oxidative damage triggered by injury and inflammation.
Under normal or unstressed conditions, Nrf2 is kept in the cytoplasm by a cluster of proteins that degrade it quickly. Under oxidative stress, Nrf2 is not degraded, but instead travels to the nucleus where it binds to a DNA promoter and initiates transcription of anti-oxidative genes and their proteins.
Nrf2 is kept in the cytoplasm by Kelch like-ECH-associated protein 1 (Keap1) and Cullin 3 which degrade Nrf2 byubiquitination. Cullin 3 ubiquitinates its substrate, Nrf2. Keap1 is a substrate adaptor, which helps Cullin 3 ubiquitinate Nrf2. When Nrf2 is ubiquitinated, it is transported to the proteasome, where it is degraded and its components recycled. Under normal conditions Nrf2 has a half-life of only 20 minutes.Oxidative stress or electrophilic stress disrupts critical cysteine residues in Keap1, disrupting the Keap1-Cul3 ubiquitination system. When Nrf2 is not ubiquitinated, it builds up in the cytoplasm and moves into the nucleus. In the nucleus, it combines (forms a heterodimer) with a small Maf protein and binds to the anti-oxidant response element (ARE) in the upstream promoter region of many anti-oxidative genes, and initiates their transcription.
Tecfidera (and its metabolite, monomethyl fumarate) activates the Nrf2 pathway and in this study it is suggested that DMF promotes the survival of nerves.