Dimethyl fumarate's biological activity is via activation of the Nrf2 transcription factor through mild oxidative stress, i.e., oxidation of key thiols on Keap1, a protein which normally keeps Nrf2 inactive and sequestered in the cytoplasm. Once activated, Nrf2 enters the nucleus and induces the transcription of several antioxidant and cytoprotective enzymes such as NAD(P)H:-quinone oxidoreductase-1, heme oxygenase-1, glutamate cysteine ligase, glutathione S-transferase, glutathione peroxidase, and thioredoxin to name a few. The resultant increase in these enzyme's activity more than compensates for the mild oxidative stress induced by dimethyl fumarate and results in cytoprotection.
This is an interesting approach to dealing with MS as it does not involve immune suppression. However, dimethyl fumarate is not the only activator of Nrf2. Indeed, there are a plethora of natural phytochemicals that also activate Nrf2. Some of which, such as curcumin, are already known to be good for MS. Several of these are discussed in the following review which is freely available.
The activity of Nrf2 activators occurs through a chemical reaction known as michael addition. The molecules discussed in the above review have an electrophylic property which induces oxidation of Keap1's thiols (sulfhydryl (SH) groups on the amino acid cysteine). The molecular structure responsible for this activity, or pharmacophore, is easy to spot once you become familiar with it. It's a carbonyl group conjugated with a double bond, or another atom such as nitrogen, which can act as an electron donor to the carbonyl carbon during resonance. Examining figure 2 in the above review reveals that this pharmacophore is widespread through nature. However, not all molecules with this structure are beneficial. Indeed, if we reduce it to it's simplest form we wind up with the molecule acrolein which is also known as vinyl aldehyde. Acrolein is a small, toxic, highly reactive molecule that can covalently cross link DNA thereby interfering with gene activity. Thus, it's best to stick with phytochemicals with this pharmacophore which are known to be safe and beneficial.
In light of this research, there appears to be several choices of natural phytochemicals having biochemical activity similar to dimethyl fumarate (activation of Nrf2) which we can utilize and which should help with MS.
NHE
It was an unexpected variety of treatments.
