Old treatments, new tricks: Multiple Sclerosis

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Old treatments, new tricks: Multiple Sclerosis

Postby MSUK » Fri Aug 05, 2011 12:11 am

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In an analysis piece, the Bureau argued that there should be more research into Multiple Sclerosis treatments. At present, there are a number of generic drugs that have shown promise in initial MS trials.

However, none listed below have completed Phase III level of trialing. This phase of trial aims to be the definitive assessment of the drug’s effectiveness and so would be expected if the drug was to become an accepted standard treatment.

It is acknowledged that there are some inherent difficulties in reading too much into early stage trials, notably with animal models or small test groups. However, the lack of funding to take these trials to include a larger number of MS sufferers means that this is the only proof often available.

As such the data below still reflects as yet unproven treatments.... Read More - http://www.msrc.co.uk/index.cfm/fuseact ... w/pageid/7
MS-UK - http://www.ms-uk.org/
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Re: Old treatments, new tricks: Multiple Sclerosis

Postby euphoniaa » Fri Aug 05, 2011 3:11 am

squiffy2 wrote:Image

In an analysis piece, the Bureau argued that there should be more research into Multiple Sclerosis treatments. At present, there are a number of generic drugs that have shown promise in initial MS trials.

However, none listed below have completed Phase III level of trialing. This phase of trial aims to be the definitive assessment of the drug’s effectiveness and so would be expected if the drug was to become an accepted standard treatment.

It is acknowledged that there are some inherent difficulties in reading too much into early stage trials, notably with animal models or small test groups. However, the lack of funding to take these trials to include a larger number of MS sufferers means that this is the only proof often available.

As such the data below still reflects as yet unproven treatments.... Read More - http://www.msrc.co.uk/index.cfm/fuseact ... w/pageid/7

To add a bit of info to the above preview of the article, here's a list of treatments mentioned in it:

Vitamin D
Minocycline
Fumaric Acid Esters (FAE)
Parasitic Infection
Lipoic Acid
Low Dose Naltrexone (LDN)
Dx'd with MS & HNPP (hereditary peripheral neuropathy) 7/03 but must have had MS for 30 yrs before that. I've never taken meds for MS except 1 yr experiment on LDN. (I found diet, exercise, sleep, humor, music help me the most.)
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Postby Lyon » Fri Aug 05, 2011 10:47 am

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Last edited by Lyon on Sun Nov 20, 2011 3:59 pm, edited 1 time in total.
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Re: Old treatments, new tricks: Multiple Sclerosis

Postby euphoniaa » Fri Aug 05, 2011 11:08 am

Lyon wrote:Thanks! I did a quick look through this morning and didn't notice the part about parasite infection.
euphoniaa wrote:To add a bit of info to the above preview of the article, here's a list of treatments mentioned in it:

Vitamin D
Minocycline
Fumaric Acid Esters (FAE)
Parasitic Infection
Lipoic Acid
Low Dose Naltrexone (LDN)


That's why I decided to post the list for everyone. :) It was an unexpected variety of treatments.
Dx'd with MS & HNPP (hereditary peripheral neuropathy) 7/03 but must have had MS for 30 yrs before that. I've never taken meds for MS except 1 yr experiment on LDN. (I found diet, exercise, sleep, humor, music help me the most.)
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Re: Old treatments, new tricks: Multiple Sclerosis

Postby NHE » Sat Aug 06, 2011 2:10 am

euphoniaa wrote:To add a bit of info to the above preview of the article, here's a list of treatments mentioned in it:

Vitamin D
Minocycline
Fumaric Acid Esters (FAE)
Parasitic Infection
Lipoic Acid
Low Dose Naltrexone (LDN)


Biogen's new oral drug they are developing, BG-12 also known as dimethyl fumarate, is a fumaric acid ester.


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Re: Old treatments, new tricks: Multiple Sclerosis

Postby HarryZ » Sat Aug 06, 2011 6:21 am

Biogen's new oral drug they are developing, BG-12 also known as dimethyl fumarate, is a fumaric acid ester.


NHE


Fumaric acid has initially shown that it has the ability to protect nerve cells from toxic radicals caused by the inflammation process. Certainly a new twist in trying to treat MS.

While not addressing the cause of MS, which is unknown at this time, this is something quite different in MS medications. I just wonder how much Biogen will charge for this new treatment if it gets approved!

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Re: Old treatments, new tricks

Postby NHE » Tue Aug 16, 2011 2:07 am

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.


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Re: Old treatments, new tricks

Postby HarryZ » Tue Aug 16, 2011 6:17 am

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.


I wonder if this mechanism has anything to do with the recent discovery in the increase of certain genes within MS patients?

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Re: Old treatments, new tricks

Postby NHE » Fri Aug 26, 2011 1:24 am

A new interpretation for an old paper? Another Nrf2 activator?

Fasting raises blood levels of the sugar 2-buten-4-olide. This compound was found to inhibit EAE in Lewis rats.

    M. Naiki, et al. 1995. 2-Buten-4-olide (2-B4O) inhibits experimental allergic encephalomyelitis (EAE) in Lewis rats.
    J Autoimmunity 8(5): 727-739.

    Abstract:
    Starvation is well known to induce immune suppression. Moreover, the concentration of 2-B4O, an endogenous sugar acid, is elevated in the circulation during starvation. To determine if these events are related, the influence of 2-B4O on experimental allergic encephalomyelitis (EAE) in Lewis rats, a model of human multiple sclerosis (MS), was studied. EAE, characterized by paralysis of hind legs, was induced by immunization with residues 68 to 84 (MB 68-84) of the guinea pig myelin basic protein (MBP) in complete adjuvant H37Ra. Interestingly, the daily administration of 2-B4O intraperitoneally from the day of MB 68-84 immunization (day 0) to day 20 dramatically suppressed the clinical severity of EAE. The daily administration of 2-B4O intraperitoneally from day 0 to day 7 also markedly reduced the clinical symptoms of EAE. In fact, passively induced EAE, using Con A activated spleen cells from rats immunized with MB 68-84 in H37Ra, was also inhibited by daily administration of 2-B4O. Histological examination confirmed clinical findings and revealed that mononuclear cell infiltration into the central nervous system was significantly inhibited by 2-B4O. To clarify the mechanism(s) responsible for suppression of EAE, the effects of 2-B4O on the immune responses to MB 68-84 were examined. When rats were treated daily with 2-B4O for 15 days after immunization with MB 68-84 in H37Ra, the delayed-type hypersensitivity (DTH) response to MB 68-84 was significantly reduced in 2-B4O treated rats as compared with saline treated rats. The proliferative response to MB 68-84 of spleen cells from 2-B4O treated rats was also significantly lower than that of saline treated rats. Our data demonstrate that 2-B4O has the potential to suppress autoimmune responses in both inductive and effector phases. 2-B4O may have significant potential to treat autoimmune diseases.

The chemical structure of 2-buten-4-olide is a heterocyclic 5 member ring with an ester carbonyl conjugated with a carbon-carbon double bond. This would make it an ideal Nrf2 transcription factor activator and potentially put it in the same class of compounds, Nrf2 activators, as Biogen's new drug BG-12.

The structure of 2-buten-4-olide can be found here. Click on the "Names and Identifiers" section and then expand to view all synonyms. Compare this structure to the molecules listed in Fig. 2 of the second paper I've cited above. It has the same moiety consisting of an unsaturated double bond conjugated with a carbonyl group that's responsible for activating the Nrf2 transcription factor. My hypothesis is that the results of the 1995 paper with 2-buten-4-olide in rats can be reinterpreted through the lens of Nrf2 activation.


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Re: Old treatments, new tricks

Postby NHE » Sun Oct 30, 2011 1:43 am

NHE wrote: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.


A recently published paper adds to the understanding of how dimethyl fumarate exerts its biological activity. It may be the case that dimethyl fumarate induces a stronger oxidative stress than previously believed. Apparently, it modulates the immune system though depletion of glutathione. As glutathione is used as an important antioxidant for liver detoxification and also as an antioxidant providing reducing equivalents in nearly every cell in the body, a good question is what are the chronic effects of dimethyl fumarate treatment?

Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells.
J Exp Med. 2011 Oct 24;208(11):2291-303. Epub 2011 Oct 10.

    Fumarates improve multiple sclerosis (MS) and psoriasis, two diseases in which both IL-12 and IL-23 promote pathogenic T helper (Th) cell differentiation. However, both diseases show opposing responses to most established therapies. First, we show in humans that fumarate treatment induces IL-4-producing Th2 cells in vivo and generates type II dendritic cells (DCs) that produce IL-10 instead of IL-12 and IL-23. In mice, fumarates also generate type II DCs that induce IL-4-producing Th2 cells in vitro and in vivo and protect mice from experimental autoimmune encephalomyelitis. Type II DCs result from fumarate-induced glutathione (GSH) depletion, followed by increased hemoxygenase-1 (HO-1) expression and impaired STAT1 phosphorylation. Induced HO-1 is cleaved, whereupon the N-terminal fragment of HO-1 translocates into the nucleus and interacts with AP-1 and NF-κB sites of the IL-23p19 promoter. This interaction prevents IL-23p19 transcription without affecting IL-12p35, whereas STAT1 inactivation prevents IL-12p35 transcription without affecting IL-23p19. As a consequence, GSH depletion by small molecules such as fumarates induces type II DCs in mice and in humans that ameliorate inflammatory autoimmune diseases. This therapeutic approach improves Th1- and Th17-mediated autoimmune diseases such as psoriasis and MS by interfering with IL-12 and IL-23 production.


Another recent paper, this one in Nature, suggests that chronic activation of Nrf2 may be a method by which neoplasia promote cell survival by reduction of reactive oxygen species. A good question here would be could some neoplasia take advantage of the Nrf2 activation from dimethyl fumarate to enhance their own survival?

Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis
Nature. 2011 Jul 6;475(7354):106-9.

    Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer. Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keap1 (refs 2-5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic. Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. K-Ras(G12D), B-Raf(V619E) and Myc(ERT2) each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-Ras(G12D) and B-Raf(V619E), and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-Ras(G12D)-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis.


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Re: Old treatments, new tricks

Postby NHE » Fri Mar 09, 2012 3:40 pm

NHE wrote:My hypothesis is that the results of the 1995 paper with 2-buten-4-olide in rats can be reinterpreted through the lens of Nrf2 activation.


A proposed mechanism for how 2-buten-4-olide can act as an Nrf2 activator by oxidizing the thiols on the Nrf2 regulatory protein keap1.

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