Oxidative stress is central to the pathology of several neurodegenerative diseases, including multiple sclerosis (MS), and therapeutics designed to enhance antioxidant potential could have clinical value. The objective of this study was to characterize the potential direct neuroprotective effects of dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) on cellular resistance to oxidative damage in primary cultures of central nervous system (CNS) cells and further explore the dependence and function of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in this process. Treatment of animals or primary cultures of CNS cells with DMF or MMF resulted in increased nuclear levels (levels within the cell nucleus) of active Nrf2, with subsequent upregulation of antioxidant target genes. DMF-dependent upregulation of antioxidant genes in vivo was lost in mice lacking Nrf2 (Nrf2-/-). DMF or MMF treatment increased cellular redox potential, glutathione, ATP levels and mitochondrial membrane potential in a concentration-dependent manner. Treating astrocytes or neurons with DMF or MMF also significantly improved cell viability after toxic oxidative challenge in a concentration-dependent manner. This effect on viability was lost in cells that had eliminated or reduced Nrf2.
These data suggest that DMF and MMF are cytoprotective (protrcts the cell) for neurons and astrocytes against oxidative stress-induced cellular injury and loss, potentially via upregulation of an Nrf2-dependent antioxidant response. These data also suggest DMF and MMF may function through improving mitochondrial function. The clinical utility of DMF in multiple sclerosis is being explored through phase 3 trials with BG-12, which is an oral therapeutic containing DMF as the active ingredient.
Yesterday we were exploring ways that mtiochondrial energy depletion in astrocytes....and based on past posts nerves......may lead to nerve damage.
You wondered if there were an know causes and whether anything has been done about this. Well this study shows a way that something is being done about it.
There is a new oral drug called BG12 that has been found to be effective at inhibiting relapses (reduction of around 50%) in MSers in the phase III studies, but the question is whether it does other things that may be beneficial in progressive MS also?
This study suggests that there may be some potential. This drug may be working via a molecule called Nrf2 which acts to control oxidative stress that represents an imbalance between the production and manifestation of reactive oxygen species (damaging in high concentrations) and a biological systems ability to readily detoxify the reactive intermediates or to repair the resulting damage. But simplified means that it has anti-oxidant properties that will block some of the molecules that are known to block mitochondrial function that depletes the cells energy that can lead to nerve damage, as reported yesterday. Mice that lack Nrf2 do not do well when they are given an MS-like disease so a drug that can stimulate Nrf2 has the potential to be beneficial in MS. BG12 is based on a drug used to treat psorias for many years and so hopefully will have a good safety profile. Time will tell is there is any bnefit to be had in progressive MS, but there is some logical biology behind this hope.
CoI: This work was undertaken by Biogen Idec, the producers of BG12