Research: BG12 targeting Nrf2 to help save nerves

Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, Bista P, Zeng W, Ryan S, Yamamoto M, Lukashev M, Rhodes KJ. Fumarates Promote Cytoprotection of Central Nervous System Cells Against Oxidative Stress via the Nrf2 Pathway.J Pharmacol Exp Ther. 2012 Jan 20. [Epub ahead of print]

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

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  • Yes, and this is one of the reasons I asked Prof. G in the past whether BG12 would be a good add on after treatment with alemtuzumab, but as he said there's been no research into it as an add on. In the US, they have been studying using revimmune and then adding on copaxone, but who wants to go back to injecting themselves every day? Perhaps in 202?, when BG12 has been available and seen as safe, it might get the go ahead- depending on it's price and whether anything else has come along in the meantime.

  • Why is the mitochondrial depletion in the astrocytes of progressive MS'ers? Is it a virus, maybe EBV?

    I take it this is called 'apoptosis', is it not, because of the fact the cells are dying? What can be done about apoptosis in MS?

  • What ever you do, you use energy.

    It is the same for every cell in the body, its activities use energy.

    Therefore, if you lose energy you can not do as much as you would like. Likewise cells can not do as many things as they would normally do.

    In some instances this may be getting rid of damaging molecules.

    The processes described in the post are are unlikely to be restricted to progressive MSers but will probably occur in RR Mers also. Any damage by this route is very, very slow.

    It may be that viruses trigger the processes to occurs then other things such as nitric oxide etc. may cause the problem.

    The energy depletion to certain nerve cells appears to be a problem caused by the disease.

    If a cell dies it can do it in essentially one of two ways (a) apotosis. This is suicide and self destruction, where the cell collapses in onto itself. The other way is necrosis where the cell explodes and spreads its contents all over the place

  • Too much immunosuppression could lead to increased adverse side effects. Therefore care would need to be given about add ons. But an immunosuppressive + neuroprotective + etc will be the future. Whether this can come in one pill or a combination remains to be seen

  • Re: "Add-ons"

    Add-on studies will need to be done to show added benefit. Some of these drugs cost so much that it is hard the envision funders paying for expensive combination therapies.

  • Too much immunosuppression could lead to increased adverse side effects.

    If BG-12 is immunosuppressive, are the side effects we should be concnerned about the same as with the -mabs immunosuppressives, talking specifically about PML-would you expect to see this side effect in BG-12 or any of the other oral immunosuppressives?

  • If treatments are very effective as immunosuppressives then the side-effects such as PML must be a possibility.

    However based on published data BG12 is not quite as active as Tysabri, so the PML risk may be reduced and so far, I am not aware of PML being reported from anyone taking BG12.

    This type of drug has been used in psorasis for many years and the side effect profile has looked OK.

    Let us hope the BG12 has an accepttable safey profile.

    We will really find out once it become licenced and alot of people use it. Then the uncommon risks are better exposed. This is why drug companies look out for things after marketing.

  • I say try a all natural Nrf2 like Protandim that doesn't have the side effects and did better than this drug in the Biogen study.

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