Showing posts with label MS. Show all posts
Showing posts with label MS. Show all posts

Thursday, 26 September 2019

Treatable Human Endogenous Retroviruses (HERVs) in Multiple Sclerosis (MS), ALS and other Neurological Diseases – an Enemy from Within?

A microglial cell, labelled in green, contacts and attacks a myelinated axon (in red). In the presence of the pHERV-W envelope protein, this interaction leads to axonal injury. The blue structures are cell nuclei. Credit: HHU / Joel Gruchot / Patrick Küry

It is surprising that only about 2% of human DNA encodes the 20,000 or so genes we all have.  The other 98% used to be called junk DNA.

About 8% of your DNA is made up of Endogenous retroviruses (ERVs) that have been picked up during evolution and most of which have been inactivated and can indeed be regarded as junk. Some of these old viruses that became part of human DNA remain fully functional, can be activated; they are implicated in disease ranging from Multiple Sclerosis (MS), to cancer, to schizophrenia and ALS (motor neuron disease).

The best documented ERV is the one that affects some people with MS, it is called HERV-W  (the H is for Human).  Only in the presence of a protein encoded by this virus can the microglia cells attack the myelin layer on axons.  In this kind of MS, if you could switch off the HERV-W virus you would solve the remyelination problem.

The thing to remember is that MS is a family of conditions and HERV-W may only be relevant to specific sub-types.  The recent research (see below) produced the image at the start of today’s post, where we actually see the microglia (green) mistakenly attacking the healthy myelin on axons (red).

Multiple sclerosis: Endogenous retrovirus HERV-W key to nerve tissue damage

As outlined by first author Dr. David Kremer, the envelope (ENV) protein of the pathogenic human endogenous retrovirus type W (pHERV-W) was found to be a major contributor to nerve damage in MS. In collaboration with research teams in the U.S. and Canada, the authors demonstrated that the ENV protein drives CNS resident microglial cells to contact and damage myelinated axons.                                                                                      

There is a broad repertoire of immunomodulatory drugs that effectively treat the inflammatory aspects of relapsing multiple sclerosis (MS). However, axonal degeneration, which occurs mainly in progressive MS, is still not understood and cannot be treated pharmaceutically. As it is the major factor contributing to clinical disability in MS, it represents an unmet clinical need. A recently completed phase IIb study has demonstrated that anti-pathogenic human endogenous retrovirus type W (pHERV-W) envelope protein (ENV) treatment results in a significant decrease of neurodegenerative brain atrophy in treated MS patients. For these results, the work presented here offers an explanation by demonstrating that, via myeloid cells, pHERV-W ENV directly harms axons.

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.

Relapsing-Remitting Multiple Sclerosis (RRMS)

Most MS starts out as so-called Relapsing-Remitting Multiple Sclerosis (RRMS) and so is the focus of much research. An antibody called GNbAC1 has been developed to specifically target the protein MSRV-Env that is produced by the old human endogenous retrovirus type W.

GNbAC1 for RRMS 

In vitro and in vivo studies showed that GNbAC1 neutralizes MSRV-Env, reducing the inflammatory response and allowing the remyelination repair process to restart.

I think this is an excellent example of how to translate complicated science into a practical therapy.  I just hate to think how much money this therapy will cost.

Or just Antivirals?

I did wonder about a less expensive therapy to block the MSRV-Env protein from activating microglia to destroy myelin.  Why not use a relatively cheap antiviral drug to dampen the virus itself, so it does not make the harmful protein?

Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development.

Antiviral drugs normally have to be developed to target a specific virus, but you might just get lucky with an existing drug.

In the case of HIV, a combination of three drugs is used TDF (tenofovir), EFV (efavirenz) and either 3TC (lamivudine) or FTC (emtricitabine).  This therapy has been hugely successful.

The anti-herpes antivirals include valacyclovir (Valtrex), famciclovir (Famvir), and acyclovir (Zovirax).

In the case of Multiple Sclerosis, I did find a study that used acyclovir.  It did not cure the condition, but it did significantly reduce exacerbations.

I am afraid nobody seems to want a cheap drug for MS, when the other only partially effective ones can cost $50,000 a year. Acyclovir is much more expensive in the US than elsewhere but nothing like the price of the new MS drugs.

It may of course be a coincidence that Acyclovir reduces exacerbations in MS and may involve an entirely different mechanism.

Human endogenous retroviruses (HERVs) beyond MS

Drugs for MS are a huge business for pharmaceutical companies and this is why the research is advanced.

HERVs have been implicated in ALS (motor neuron disease) and schizophrenia.  There is even some research on HERVs and autism.

It is usually the Herpes virus that gets mentioned in the context of autism. It is probably one of hundreds of possible triggers that, when combined with other “hits” and genetic predispositions, may lead to autism.

Any virus can affect gene expression and so any virus has the potential to cause harm to a developing brain.  This is often all "autism" is, the result of some damage at a critical point in the brain's development. That same event in a teenager does no long term harm. 

Herpes virus may be a trigger for autism

“We’re not saying that HSV-2 is responsible for infecting the [fetal] brain and causing autism,” stresses senior author Ian Lipkin, an infectious disease expert and epidemiologist at Columbia. Indeed, fetal infection with HSV-2 is so serious that it frequently leads to miscarriages or stillbirths. Rather, Lipkin suspects that HSV-2 is just one among many environmental insults that, when they arrive at a vulnerable point in fetal development in women predisposed to damaging reactions, may trigger ASD in the fetus. That idea comports with a body of previous work, like this Swedish study that found that the hospitalization of a woman for any kind of infection during pregnancy increased the risk of the baby developing ASD by 30%.
Some scientists are skeptical that inflammatory molecules alone could be responsible, in part because of the big changes in brain structure that arise in autistic children in the first 2 years of life, just as symptoms of ASD emerge. For instance, a study published in Nature last week documents abnormal overgrowth of the surface of the brain in 6- to 12-month-old babies who go on to be diagnosed with ASD.

Are the 'viral' agents of MS, ALS and schizophrenia buried in our genome?

Viruses hid themselves in your ancestors' DNA; now they're waking up

What if the missing 'environmental' factor in some of our deadliest neurological diseases were really written in our genome? Researchers explain how viruses ended up in our DNA -- and what puts them in the frame in unsolved diseases like multiple sclerosis.

The enemy within
A whopping 8% of our DNA comes from viruses. Specifically, ones called retroviruses -- not because they're old, but because they reverse the normal process of reading DNA to write themselves into their host's genome.
Retroviruses are old though: they began merging with our earliest, primordial ancestors millions of years ago. Over the millennia, most of their remnants in our DNA -- known as human endogenous retroviruses or HERVs -- have been silenced by mutations. Others, which had evolved to fend off rival viruses, formed the prototypical immune system and to this day protect us from infection.
However, HERVs might also be the missing causative link in major 'unsolved' neurological diseases.
"HERVs have been implicated in the onset and progression of multiple sclerosis [MS], amyotrophic lateral sclerosis [ALS] and schizophrenia [SCZ]," says senior author Prof. Patrick Kuery. "Dormant HERVs can be reactivated by environmental factors such as inflammation, mutations, drugs, or infection with other viruses, so could provide a mechanism for their well-established epidemiological link to these disorders."

Full paper: -

Neural Cell Responses Upon Exposure to Human Endogenous Retroviruses

Human endogenous retroviruses (HERVs) are ancient retroviral elements, which invaded the human germ line several million years ago. Subsequent retrotransposition events amplified these sequences, resulting in approximately 8% of the human genome being composed of HERV sequences today. These genetic elements, normally dormant within human genomes, can be (re)-activated by environmental factors such as infections with other viruses, leading to the expression of viral proteins and, in some instances, even to viral particle production. Several studies have shown that the expression of these retroviral elements correlates with the onset and progression of neurological diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Further studies provided evidence on additional roles for HERVs in schizophrenia (SCZ). Since these diseases are still not well understood, HERVs might constitute a new category of pathogenic components that could significantly change our understanding of these pathologies. Moreover, knowledge about their mode of action might also help to develop novel and more powerful approaches for the treatment of these complex diseases. Therefore, the main scope of this review is a description of the current knowledge on the involvement of HERV-W and HERV-K in neurological disease specifically focusing on the effects they exert on neural cells of the central nervous system.

Importantly, several studies were able to show that inflammation plays a major role in HERV activation 

SCZ is a complex neuropsychiatric disorder characterized by a variety of cognitive, emotional, and perceptual disturbances. Pathophysiologically, SCZ features decreased brain volume, loss of myelin, and altered astrocyte function (Archer, 2010). In contrast to MS and ALS, both HERV-W and HERV-K have been weakly linked to SCZ based on PCR amplification from CSF and post-mortem brains as well as on protein antigenemia (Yolken et al., 2000Karlsson et al., 2001Frank et al., 2005Perron et al., 2008), while another study revealed upregulation of HERV-W ENV transcripts in plasma samples of SCZ patients (Huang et al., 2011). Moreover, a new study provides evidence that, in early stages of this disease, HERV-K methylation in peripheral blood is reduced (Mak et al., 2019). Of note, these observations contradict an earlier report suggesting that HERV-W expression is reduced in SCZ patients (Weis et al., 2007). The disparity between these reports may reflect different experimental approaches or a differential use of anti-psychotic medications in SCZ patients.

We here present collected evidence that endogenous retroviral elements acting either as viral particles or via their proteins influence neural cells in the context of degenerative CNS diseases. Once thought to be primarily involved in cell transformation (Grabski et al., 2019) and inflammation (Perron and Lang, 2010), emerging data suggests a direct role of these elements in glial and neuronal injury, which in fact goes beyond previous descriptions on the activity of a gliotoxin (Menard et al., 1998). In light of additional observations on the role of ERVs in regulating stem cell potential and fate acquisition (Gautam et al., 2017), the findings describing impacts on committed or mature cells of the CNS are probably not too surprising but warrant future investigations, even more so since neural stem cells are also involved in brain pathology and regeneration. Moreover, the currently still unmet clinical need to effectively treat neurodegeneration necessitates novel therapeutic approaches. Whether similar mechanisms also apply to activation of transposable elements implicated in, for example, chronic fatigue syndrome (CFS; Almenar-Perez et al., 2019) and to what degree currently used neutralizing antibodies can be exploited in order to prevent neural cell activation and/or neurodegeneration needs to be elucidated in the future. In this regard, it remains to be shown whether HERV-employed signaling pathways and epigenetic silencing mechanisms can be used for biomedical translation.


Figure 1 HERV-mediated effects on neural cells. This illustration summarizes origin and observed molecular effects of HERW-W and HERV-K on cells of the central nervous system. Arrow starting points indicate cellular sources of HERV particles or proteins (red dots), whereas arrowheads point to influenced cell types. Modulated processes are shown in gray boxes, and regulated molecules are highlighted in red next to each cell type. The question mark next to TDP-43 refers to its postulated regulation in neurons. Whether microglia and astroglia respond to HERVs in an auto- and/or paracrine way and whether neurons react to internal and/or extracellular HERVs remains to be shown. OPCs: oligodendroglial progenitor cells; NO: nitric oxide; CRP: C-reactive protein; BDNF: brain-derived neurotrophic factor; DRD3: dopamine receptor D3; TRPC3: short transient receptor potential channel 3; DISC1: disrupted in schizophrenia 1; TDP-43: TAR DNA-binding protein 43.

HERVs, retroviral sequences integrated into the genome during evolution, are now known to represent 8% of the human genome.

These were recently shown to comprise copies that retain potential to express retroviral proteins or particles, and can be abnormally expressed in autoimmune, neurodegenerative, chronic inflammatory diseases, and cancer.
Environmental factors such as specific viral infections were shown to potently activate HERVs under tissue-specific and temporal conditions.
Of several diseases in which abnormal activation and expression of HERV proteins have been reported, studies over recent decades have led to a proof of concept that HERVs play a key role in the pathogenesis of MS and ALS.
HERV-W and HERV-K Env proteins induce pathogenic effects in vitro and in vivo that are relevant to the pathognomonic features of these diseases.
These endogenous retroviruses are potential novel therapeutic targets that are now being addressed with innovative therapeutic strategies in clinical trials.
The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches.

HERVs Expression in Autism Spectrum Disorders


The percentage of HERV-H and HERV-W positive samples was higher among ASD patients compared to HCs, while HERV-K was similarly represented and HERV-E virtually absent in both groups. The quantitative evaluation shows that HERV-H and HERV-W are differentially expressed in the two groups, with HERV-H being more abundantly expressed and, conversely, HERV-W, having lower abundance, in PBMCs from ASDs compared to healthy controls. PMBCs from ASDs also showed an increased potential to up-regulate HERV-H expression upon stimulation in culture, unlike HCs. Furthermore we report a negative correlation between expression levels of HERV-H and age among ASD patients and a statistically significant higher expression in ASD patients with Severe score in Communication and Motor Psychoeducational Profile-3.


Specific HERV families have a distinctive expression profile in ASD patients compared to HCs. We propose that HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder.

Recent studies suggest that autism spectrum disorders (ASD) result from interactions between genetic and environmental factors, whose possible links could be represented by epigenetic mechanisms. Here, we investigated the transcriptional activity of three human endogenous retrovirus (HERV) families, in peripheral blood mononuclear cells (PBMCs) from Albanian ASD children, by quantitative real-time PCR. We aimed to confirm the different expression profile already found in Italian ASD children, and to highlight any social and family health condition emerging from information gathered through a questionnaire, to be included among environmental risk factors. The presence of increased HERV-H transcriptional activity in all autistic patients could be understood as a constant epigenetic imprinting of the disease, potentially useful for early diagnosis and for the development of effective novel therapeutic strategies.

Overall, the data obtained in the present study lead us to further support the hypothesis that HERV transcriptional activity is influenced by all the factors mentioned above. Additional work is required to determine if HERV-H expression could be proposed as a biological marker, useful for early detection of children at high risk for ASD, before the appearance of clinical symptoms and for the development of effective new therapeutic strategies. To this end, an in-depth characterization of the potential role of HERV-H in ASD is the major objective of a study currently in progress in murine models. Currently, up to 2% of children worldwide are estimated to be diagnosed with an ASD (Pedersen et al., 2014) and the consistent increment in the prevalence of ASD is considered a pressing challenge for the global public health system. Because children represent more than a third of the Albanian population (Albanian Institute of Statistics 2011) autism is a serious socio-economic problem and its early diagnosis could represent a significant improvement in the treatment of the disease. In fact, if the autistic condition is diagnosed early, a growing repertoire of evidence-based therapies can be applied to give children the best possible chance of life.

Etiotropic and Pathogenetic Therapy of Autism Spectrum Disorder: Case Series of 6 Children

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that reveals itself by social communication problems, restrictive/repetitive behavior, and language impairment. ASD is a growing problem in the USA and in the world with no commonly-accepted etiology resulting in the absence of effective methods of treatment. Based on more than 80 scientific publications we are proposing the following understanding of ASD: it is a genetic disorder, in which some changes in DNA are resulting from a congenital mother to fetus transmitted infection and maternal immune activation. The infections and maternal immune activation result in oxidative stress and production of pro-inflammatory cytokines and other mediators. Based on this understanding, we developed a method of long-term etiotropic and pathogenetic therapy tailored to major chronic/latent infections, inflammation and immune system aberration. We present six cases of ASD treatment, which included the antiviral medication Valacyclovir and five nutritional supplements. The presented results are based on five cycles of treatment continued for 5 months. In all six cases the treatment resulted in social communication skills and behavioral improvements well as positive changes in the physical and psychological conditions. These improvements covariated with a tendency to normalization of blood and immune parameters. Social communication skills, behavioral, physical and psychological improvements also positively affected parents whose subjected quality of life increased over course of the treatment. According to parents of these children, the proposed treatment had superior efficacy compared to other types of treatment that their children underwent before.

Valacyclovir improves cognition in bipolar patients

A 4-month course of the oral antiviral agent valacyclovir boosted cognition in herpes simplex virus-1–seropositive patients with bipolar disorder and cognitive impairment in a randomized, double-blind placebo-controlled clinical trial.

Anti herpes Virus–Specific Treatment and Cognition in Schizophrenia: A Test-of-Concept Randomized Double-Blind Placebo-Controlled Trial


To test our hypothesis that valacyclovir, an antiherpes virus–specific medication, added to antipsychotics (APs) would improve cognitive performance and psychopathology among schizophrenia subjects exposed to neurotropic herpes simplex virus, type 1 (HSV1).


Using a double-blind placebo-controlled design, we randomized 24 HSV1-seropositive schizophrenia subjects to receive either valacyclovir (n = 12) or placebo (n = 12) for 18 weeks in addition to stable doses of APs. Valacyclovir dose was stabilized at 1.5 g twice daily orally. At each visit, subjects were evaluated for severity of psychopathology and side effects using standardized scales and a study-specific semistructured checklist. A computerized neurocognitive battery validated on both schizophrenia and healthy subjects was administered at baseline and follow-up. Intent-to-treat analysis, using linear regression models that included all randomized subjects, were used to examine differential changes in cognition and psychopathology scores over 18 weeks between valacyclovir and placebo, accounting for placebo response.


Valacyclovir group improved in verbal memory, working memory, and visual object learning compared with placebo group. The effect sizes (Cohen’s d) were 0.79 for working memory, 1.14 for immediate verbal memory, and 0.97 for the visual object learning. Psychotic symptom severity did not improve.


Supplemental valacyclovir may alleviate impairments in cognitive domains that are often observed in schizophrenia but not psychotic symptoms in those exposed to HSV1. If replicated, this approach could provide a novel strategy to treat cognitive impairments in a subgroup of schizophrenia subjects who can be reliably identified using a blood test.


There is a great deal going on in the world of MS research and if you have MS you might as well consider becoming an early adopter.

As expected, the research on how these old viruses, that should be dormant in our DNA, might play a role in autism is not very advanced.

Some people with autism do take antiviral drugs and I think their caregivers think this relates to a virus they have acquired recently or comes from the mother. Perhaps it is an unidentified virus from that 8% of your DNA that has become activated?

In MS the story is complex but now we know for sure what the virus is, where it came from and what it does. You can defeat it with a tailor-made antibody called GNbAC1 or perhaps just beat it down a little with the common antiviral drug Acyclovir.

Note that antiviral drugs each only have an effect on certain types of virus.

Do HERVs really materially affect some people with autism, and its big brothers bipolar and schizophrenia? There is some limited evidence that they may.

People who report that their children with autism do indeed improve on an antiviral drug are unlikely to ever know which virus was the problem and it may not be the one they thought it was, but it is not a crazy idea.  If it reduces the symptoms of autism without causing troubling side effects, why not?  It is going to work for most autism? Probably not.

For people with Multiple Sclerosis (MS) the science is clear and unambiguous, you need to wipe out the protein called MSRV-Env.

As far as this blog is concerned, we already covered antibiotics in depth.

and today we covered antivirals.  These are the “anti- drugs” that our reader Tanya referred to as not being useful in her case of autism; I think she will be in the majority.  You have to treat your “minority” case of autism, which is what makes it difficult. 

Almost every common autism treatment strategy is misrepresented as a wonder therapy; that is how you sell books, supplements, lab tests and even now I see expensive "training" courses. The reality is somewhat messy and less convenient, but if you read the science great progress does seem to be possible in many cases.

Wednesday, 11 September 2019

DMF and MMF for Neuroprotection and Immunomodulation in MS, TBI, Parkinson’s and potentially much more

DMF is an inexpensive chemical and was used to stop mould growing on sofas shipped from China to Europe, until it was banned as a skin irritant. It is also an expensive drug, sold by Biogen.

DMF was discussed in an earlier post on ketones, because one of the anti-inflammatory effects of the ketone BHB can also be achieved using Dimethyl Fumarate (DMF). In the body DMF is converted to MMF by a chemical reaction with the body’s key antioxidant Glutathione (GSH). Surprisingly, DMF then goes on to improve GSH recycling and actually raise GSH levels.

Ketones and Autism Part 3 - Niacin Receptor HCA2/GPR109A in Autism, Colonic Inflammation, Psoriasis and Multiple Sclerosis

DMF is a very cheap chemical that has been sold as an extremely expensive drug, first in Germany to treat Psoriasis and later Multiple Sclerosis (MS). I did explain in an earlier post how a person unable to afford $50,000 a year for the Tecfidera drug version could achieve the same result for a couple of hundred dollars.

The drug form of DMF is cheaper in Europe, but still very pricey.

The good news is that some of Biogen’s patents are expiring and so new cheaper drug versions will appear, including one for MMF itself that may greatly reduce the GI side effects experienced by some people.

I do think that DMF, at much lower doses than used today, has potential to treat a wide range of inflammatory conditions. This will almost inevitably include some types of autism.  In one of Biogen’s patents they refer to a long list of potential applications: -

“The pharmaceutical composition according to any one of the above aspects is for use in the treatment of psoriasis (including moderate to severe plaque psoriasis), psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis including relapsing—remitting multiple sclerosis (MS including RR-MS and progressive MS), juvenile-onset diabetes mellitus, Hashimoto's thyroiditis, Grave's disease, SLE (systemic lupus erythematosus), Cutaneous Lupus Erythematosus, Sjogren’s syndrome, Pernicious anaemia, Chronic active (lupoid) hepatitis, Rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, optic neuritis, malignant melanoma, alopecia areata, cutaneous sarcoidosis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica/sciatic pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or granuloma annulare.”

An “overactive immune system” is a hallmark of much autism and Asperger’s.  I am thinking of all those Aspies with IBS, IBD, ulcerative colitis etc.  There is also the opposite group in autism with those people catching every possible virus and taking a long time to get better.

We have come across an ever-widening variety of anti-inflammatory drugs and do help in certain cases, including:-

·        Cheap NSAIDs, like Ibuprofen
·        The  cheap leukotriene receptor antagonist, Montelukast/Singulair, used to treat children with asthma
·        The Japanese PDE4 inhibitor Ibudilast, used to treat asthma and now MS
·        TSO parasites
·        Lipophilic Statins (Atorvastatin, Lovastatin etc)
·        Beta-lactam antibiotics, like Penicillin
·        Macrolide antibiotics, like Azithromycin (developed interestingly, Natasa, in Croatia by Pliva)
·        Biogaia Gastrus probiotic from Sweden
·        PEA (Palmitoylethanolamide) from Italy or alternatively CBD (Cannabidiol)
·        The ketone BHB (beta hydroxybutyrate)
·        Lenalidomide (an ultra-expensive idea trialed by Dr Chez, in Sacramento)

You will find case histories or small trials that support all of the above therapies, but nothing works for everyone.

Some of the above therapies have side effects, some are cheap and some are very expensive.

I have no doubt that some people with autism would respond to DMF and some will not. People who respond well to BHB ketone supplements could well respond to DMF, because they share one anti-inflammatory mode of action; they are both agonists of Niacin Receptor HCA2/GPR109A. BHB has other anti-inflammatory modes of action and so does DMF. DMF has potent anti-oxidant effects that act via Nrf-2.

We see today that DMF can treat Psoriasis, Multiple Sclerosis (MS) and possibly Parkinson’s Disease and Traumatic Brain Injury (TBI). There is a lot in this blog about COPD (Chronic Oppressive Pulmonary Disease) and via Nrf2, I think DMF looks quite likely to be therapeutic.  You may wonder how these totally different diseases can respond to the same drugs or similar drugs, but it is well known that they do. Otelzla/Apremilast is a very expensive PDE4 inhibitor approved to treat psoriasis; Daxas/Roflumilast is a much cheaper PDE4 inhibitor approved to treat COPD, both cause GI side effects because neither drug is sufficiently selective (there are sub-types of PDE4).

Biogen’s patent for DMF does mention neuropathy and I can say that a much lower dose than they suggest, it can be effective, (based on n=1 trial).

The problems with DMF

I think the main problem with the drug form of DMF is the price.  The active form of DMF, which is called MMF, is also being developed as a drug.

It is suggested that MMF will have less GI side effects than MMF, in part because you would need a lower dose.

DMF needs to be taken in an enteric capsule/coating and with food, or you may get quite extreme GI side effects.

I think low dose DMF (5-10mg) has great potential to treat minor chronic inflammatory conditions.   

The MS dosage of Tecfidera/DMF is usually 240mg twice a day and this brings in $1 billion a year to Biogen.  As usual it us far more expensive in the US than in Europe.

DMF as a chemical is extremely cheap.  You may even find a sachet of DMF inside your old sofa.

Immunomodulation vs Immunosuppression

Even people with an “over-active” immune system get sick and so any therapy to damp down an excessive immune response has to avoid suppressing the immune system.  Ideally you would just modulate the immune system to put it where it should have always been.

Immunomodulation is something that a clever immunologist may be able to help you with, but it is still an emerging area of medicine.

Effects of dimethyl fumarate on neuroprotection and immunomodulation


Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. These effects are presumed to originate from a combination of immunomodulatory and neuroprotective mechanisms. We aimed to clarify whether neuroprotective concentrations of dimethyl fumarate have immunomodulatory effects.


We determined time- and concentration-dependent effects of dimethyl fumarate and its metabolite monomethyl fumarate on viability in a model of endogenous neuronal oxidative stress and clarified the mechanism of action by quantitating cellular glutathione content and recycling, nuclear translocation of transcription factors, and the expression of antioxidant genes. We compared this with changes in the cytokine profiles released by stimulated splenocytes measured by ELISPOT technology and analyzed the interactions between neuronal and immune cells and neuronal function and viability in cell death assays and multi-electrode arrays. Our observations show that dimethyl fumarate causes short-lived oxidative stress, which leads to increased levels and nuclear localization of the transcription factor nuclear factor erythroid 2-related factor 2 and a subsequent increase in glutathione synthesis and recycling in neuronal cells. Concentrations that were cytoprotective in neuronal cells had no negative effects on viability of splenocytes but suppressed the production of proinflammatory cytokines in cultures from C57BL/6 and SJL mice and had no effects on neuronal activity in multi-electrode arrays.


These results suggest that immunomodulatory concentrations of dimethyl fumarate can reduce oxidative stress without altering neuronal network activity.

DMF protection involves glutathione recycling

DMF increased the mRNA abundance of various genes involved in the antioxidant response in HT22 cells including the enzymes glutamate-cysteine ligase (GCLC), NQO1, and peroxiredoxin 1, as well as the system Χc- subunit xCT while glutathione S-transferase 1 and heme-oxygenase 1 were downregulated. In primary cortical cultures, only xCT and NQO1 were upregulated by DMF (Figure 2A). We then asked whether inhibition of the function of the most upregulated transcripts, xCT and GCLC with S4-CPG and buthionine sulfoximine (BSO), respectively, abolished the protective activity of DMF. However, DMF was capable of protecting against both compounds (Figure 2B). DMF was also still able to raise glutathione levels when GCLC was inhibited or when system Χc- activity was abrogated by incubation in cysteine-free medium (Figure 2C). Therefore, DMF can still exert protection in neuronal cells when de novo glutathione synthesis is blocked, suggesting that it enhances glutathione recycling.
Our main finding is that DMF at low concentrations protects neuronal cells from oxidative stress by elevating cellular glutathione, and that similar concentrations also reduce production of proinflammatory cytokines from splenocytes. In our experiments, DMF protection needed less time to develop than protection induced by MMF. The induction of the antioxidant response leading to glutathione synthesis seems to be the consequence of an initial and short-lived oxidative stress, since DMF decreased the glutathione content immediately after its addition to the cells. Most likely DMF as an unsaturated carboxylic acid ester initially binds and sequesters glutathione. The long-term effect of DMF in neuronal cells is most probably mediated via Nrf2 as other reported mechanisms such as the inhibition of the nuclear translocation of NF-κB were not evident in these cells and because the increase in GSH synthesis was abolished in cells lacking Nrf2.
In summary, our findings demonstrate that DMF at low concentrations exerts protective effects on neuronal cells and diminishes the production of TNF-α, IL-2, and IL-17 in splenocytes from C57BL/6 mice and the production of all cytokines measured in splenocytes from SJL mice. Although higher concentrations of DMF can cause cell death of primary splenocytes, this is probably not necessary for its immunomodulatory effect. These observations might be relevant for understanding the drug’s presumed mechanism of action as we assume that the active metabolite MMF has similar effects that merely need a longer time to develop.
Here, we first investigated the concentration and time dependence of DMF-mediated protection in neuronal cells using a model of endogenous oxidative stress, oxidative glutamate toxicity, where extracellular glutamate blocks the glutamate-cystine antiporter system Χc-. This leads to deprivation of cystine and its reduced form cysteine, the rate-limiting substrate for the synthesis of glutathione. The subsequent glutathione depletion gives rise to the accumulation of reactive oxygen species and cell death by oxidative stress (recently reviewed [13]). We show herein that neuroprotective concentrations of DMF suppress cytokine production by splenocytes from two different mouse strains without effecting apoptosis and do not impact neuronal network activity studied with dissociated cortical cultures grown on multi-electrode arrays [14] which allows a highly sensitive and reproducible assessment of network activity. Our results suggest that low doses of DMF may promote cellular resistance against oxidative stress and cause immunomodulation independent of T cell apoptosis or alterations in endogenous brain activity.                                                     
Patent for Low Dose DMF
Below is an excerpt from one of Biogen’s patents for DMF.

They are talking about 400mg a day as a low dose, whereas I am talking about a dose of 5-10mg for chronic low-level inflammation.

Pharmaceutical composition containing dimethylfumarate for administration at a low daily dose


The present invention relates to pharmaceutical compositions containing dimethyl fumarate (DMF), More specifically, the present invention relates to a pharmaceutical composition for oral use in treating hyperproliferative, inflammatory or autoimmune disorders by administering a low daily dosage in the range of 410 mg±5% or 400 mg±5% dimethyl fumarate, wherein the pharmaceutical formulation is in the form of an erosion matrix tablet.

The pharmaceutical composition according to any one of the above aspects is for use in the treatment of psoriasis (including moderate to severe plaque psoriasis), psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis including relapsing—remitting multiple sclerosis (MS including RR-MS and progressive MS), juvenile-onset diabetes mellitus, Hashimoto's thyroiditis, Grave's disease, SLE (systemic lupus erythematosus), Cutaneous Lupus Erythematosus, Sjögren's syndrome, Pernicious anemia, Chronic active (lupoid) hepatitis, Rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, optic neuritis, malignant melanoma, alopecia areata, cutaneous sarcoidosis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica/sciatic pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or granuloma annulare.

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2


Dimethyl fumarate (DMF) (BG-12, Tecfidera), a fumaric acid ester (FAE), is a commonly prescribed oral therapy for multiple sclerosis (MS), a CNS autoimmune inflammatory demyelinating disease that may result in sustained neurologic damage. It is thought that the benefit of DMF in MS therapy is mediated through activation of the antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, the role of Nrf2 in the antiinflammatory effects of DMF has not been fully elucidated. Here, we investigated the role of Nrf2 in DMF treatment of the MS model, experimental autoimmune encephalomyelitis (EAE), and demonstrated DMF can modulate T cells, B cells, and antigen-presenting cells, and reduce clinical and histologic EAE, independent of Nrf2.

Dimethyl fumarate (DMF) (BG-12, Tecfidera) is a fumaric acid ester (FAE) that was advanced as a multiple sclerosis (MS) therapy largely for potential neuroprotection as it was recognized that FAEs are capable of activating the antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, DMF treatment in randomized controlled MS trials was associated with marked reductions in relapse rate and development of active brain MRI lesions, measures considered to reflect CNS inflammation. Here, we investigated the anti-inflammatory contribution of Nrf2 in DMF treatment of the MS model, experimental autoimmune encephalomyelitis (EAE). C57BL/6 wild-type (WT) and Nrf2-deficient (Nrf2−/−) mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35–55 (p35–55) for EAE induction and treated with oral DMF or vehicle daily. DMF protected WT and Nrf2−/− mice equally well from development of clinical and histologic EAE. The beneficial effect of DMF treatment in Nrf2−/− and WT mice was accompanied by reduced frequencies of IFN-γ and IL-17–producing CD4+ cells and induction of anti-inflammatory M2 (type II) monocytes. DMF also modulated B-cell MHC II expression and reduced the incidence of clinical disease in a B-cell–dependent model of spontaneous CNS autoimmunity. Our observations that oral DMF treatment promoted immune modulation and provided equal clinical benefit in acute EAE in Nrf2−/− and WT mice, suggest that the anti-inflammatory activity of DMF in treatment of MS patients may occur through alternative pathways, independent of Nrf2.


DMF probably has multiple therapeutic targets. In this regard, MMF is a potent agonist of the hydroxycarboxylic acid receptor 2 (HCAR2) (GPR109A). It was also observed that HCAR2 deficiency prevented the beneficial effects of DMF treatment in acute EAE in mice, suggesting that HCAR2 may, indeed, be a principal target in DMF therapy of EAE. Our results in this report, highlighting the importance of the Nrf2-independent immunologic and clinical effects of DMF, are complementary with studies that identified HCAR2 as a potential target for DMF. However, the clinical and immunologic effects of DMF treatment of EAE were not completely inhibited by HCAR2 deficiency, indicating that HCAR2 is not the sole target of DMF therapy. One should recognize that the therapeutic response to DMF in MS is dose dependent, and it is possible that individual targets may vary in their sensitivity to different levels of MMF exposure. In this study, the plasma MMF levels obtained in DMF treatment of mice were severalfold higher than those in healthy volunteers treated with DMF doses used in MS. Of interest, when DMF was administered in vivo at a higher dose than was used in either our investigation of Nrf2-deficient mice or the study that evaluated HCAR2-deficient mice, it was observed that a majority of genes induced in spleen cells by DMF treatment were Nrf2 dependent. Thus, in vivo DMF treatment likely mediates its effects through activation of both Nrf2 and HCAR2, and possibly additional targets. Just as MMF covalently attaches to cysteine 151 of Keap1, it also conjugates to other Keap1 cysteine residues and may therefore also modify other cysteine-containing proteins involved in immune regulation. Our results in this report should stimulate exploration for additional potential targets of DMF therapy.


DMF/MMF for Parkinson’s Disease?

I found it interesting that the Parkinson’s researchers took a different view of the potential of DMF and its metabolite MMF. They see the merit in using the active substance, the metabolite MMF, as the drug and in doing so reduce the potential for GI side effects.

In the Parkinson’s reality they seek to develop MMF as a drug.

This may well also have something to do with patents and the intellectual property held by Biogen. 


Metaboliteof multiple sclerosis drug could be safe, effective therapy for Parkinson's disease

The metabolite of a drug that is helping patients battle multiple sclerosis appears to significantly slow the onset of Parkinson's disease, researchers say.
The oral drug, dimethyl fumarate, or DMF, and its metabolite, monomethylfumarate, or MMF, both increase activity of Nrf2, a protein that helps protect the body from oxidative stress and inflammation, hallmarks of both diseases, said Rd. Bobby Thomas, neuroscientist in the Department of Pharmacology and Toxicology at the Medical College of Georgia at Augusta University.
But the new study provides the first evidence that the metabolite, which is essentially the active portion of the parent drug, more directly targets Nrf2, potentially reducing known side effects of the parent drug that include flushing, diarrhoea, nausea, vomiting, abdominal pain and the brain infection encephalopathy, said Thomas, corresponding author of the study in The Journal of Neuroscience.
Particularly, the gastrointestinal side effects can exacerbate some problems patients with Parkinson's already experience, said Dr. John Morgan, neurologist, neuroscientist and Parkinson's disease specialist in the MCG Department of Neurology. In addition to destroying neurons in the brain that produce dopamine, a neurotransmitter that enables movement and learning, Parkinson's causes nerve cell death in the gastrointestinal tract and related problems such as severe constipation.
"Nrf2 is a natural protective mechanism we have for oxidative stress," Thomas said. The fact that multiple sclerosis and Parkinson's have in common evidence of declining activity of the Nrf2 pathway has generated interest in the drug for Parkinson's and other neurodegenerative diseases.
DMF was approved for multiple sclerosis three years ago by the Food and Drug Administration. While its metabolite MMF is not quite as potent as the parent drug in increasing Nrf2 activity, the new study indicates that its action is sufficient to dramatically slow the loss of dopamine-producing neurons as well as the parent drug, in an animal model of Parkinson's.
In their model, mice given the neurotoxin MPTP experience a dramatic loss of dopamine-producing neurons, losing about half within a handful of days, and rapidly develop Parkinson's-like symptoms. Patients, on the other hand, slowly develop symptoms over many years. By the time they seek medical care, patients may have lost 30-50 percent of their dopaminergic neurons, said Morgan, a study coauthor. "Presentation is after the disease is kind of out of the gate."
To accommodate the very compressed timeline in their model and the fact that several daily doses are needed before the drug starts to work, the researchers first gave the mice either the drug or metabolite the day before they started the toxin.
Dopamine-producing neurons are located in a darker-pigmented central portion of the brain called the substantia nigra. Even in the absence of disease, making dopamine is a stressful job for these neurons that makes them generally more fragile and actually results in oxidative stress even in a healthy scenario, Morgan said. To make a difficult situation worse, increased oxidative stress can make dopamine toxic to neurons, he said.
To increase Nrf2 activity, the parent drug DMF also appears to first make bad matters worse. DMF increases oxidative stress by depleting the natural antioxidant, glutathione, and reduces the power of cell powerhouses, called mitochondria, by limiting their ability to use oxygen and glucose to make energy leading to reduced viability of dopamine-producing cells, Thomas said.
The metabolite MMF appears to more directly activate Nrf2, and actually increases glutathione and improves mitochondrial function, brain cell studies showed. While the parent drug ultimately produces a higher Nrf2 activation, the researchers found the MMF effect was sufficient to stop the dramatic neuron loss in the animal model.
Both DMF and MMF slowed neuron loss to a more normal level, and the neurons that survived continued to make dopamine. Inflammation and oxidative stress levels also were significantly reduced, the researchers said.
As a next step, they are working toward a clinical trial of MMF in patients with early Parkinson's disease. Although the metabolite could be easily formulated for humans, it has not yet been done, Thomas notes.


Repurposing the NRF2Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease

Aims: This preclinical study was aimed at determining whether pharmacological targeting of transcription factor NRF2, a master controller of many homeostatic genes, might provide a disease-modifying therapy in the animal model of Parkinson's disease (PD) that best reproduces the main hallmark of this pathology, that is, α-synucleinopathy, and associated events, including nigral dopaminergic cell death, oxidative stress, and neuroinflammation. Results: Pharmacological activation of NRF2 was achieved at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the treatment of multiple sclerosis. Daily oral gavage of DMF protected nigral dopaminergic neurons against α-SYN toxicity and decreased astrocytosis and microgliosis after 1, 3, and 8 weeks from stereotaxic delivery to the ventral midbrain of recombinant adeno-associated viral vector expressing human α-synuclein. This protective effect was not observed in Nrf2-knockout mice. In vitro studies indicated that this neuroprotective effect was correlated with altered regulation of autophagy markers SQTSM1/p62 and LC3 in MN9D, BV2, and IMA 2.1 and with a shift in microglial dynamics toward a less pro-inflammatory and a more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature. Innovation: These experiments provide a compelling rationale for targeting NRF2 with DMF as a therapeutic strategy to reinforce endogenous brain defense mechanisms against PD-associated synucleinopathy. Conclusion: DMF is ready for clinical validation in PDAntioxid. Redox Signal. 25, 61–77.
The global results of this study are presented in an idealized graph in Supplementary Figure S6. It is predicted that overexpression of human α-SYN leads to a rapid, less than 3-week, intoxication of nigrostriatal dopaminergic neurons of Nrf2+/+ and Nrf2−/− mice. This injury is slightly higher in the Nrf2−/− mice (Fig. 3). In parallel to neuron intoxication, we find microglial activation that will elicit an inflammatory response and remove neuronal debris but will cease once α-SYN intoxicated neurons have disappeared. Microglial activation will be lower in DMF-treated Nrf2+/+ mice, because they exhibit less neuron damage (Figs. 5 and 3, respectively). Astrocytes are activated in parallel to neuronal intoxication but contrary to the microglia, they remain detectable after the phase of injury, creating a scar in the damaged tissue (Fig. 4). The astroglial scar is smaller in the DMF-treated mice, because the death of dopaminergic neurons was attenuated by this drug. Further work may be required for obtaining a fine analysis of the participation of DMF and NRF2 in prevention of proteinopathy, but from a clinical perspective, DMF is now ready for clinical analysis for the treatment of PD.

SUPPLEMENTARY FIG. S6. DMF effects on PD mouse model. Diagram of the molecular events triggered by a-SYN and the protective way of action of DMF through NRF2 activation. PD, Parkinson’s disease.
Biogen, maker of Tecfidera, dismissed its lawsuit against Banner in September 2018, in which Biogen claimed that monomethyl fumarate would infringe on patents 7,320,999 and 8,399,514 related to Tecfidera. The FDA’s final approval of monomethyl fumarate is expected once Biogen’s current patent no. 7,619,001 for dimethyl fumarate expires on June 20, 2020.  
A key feature offered by monomethyl fumarate is its lower dose when compared to dimethyl fumarate. Whether a lower dose of a different application of this class of drug will result in fewer side effects is yet to be explored in a clinical trial.  

Immunometabolism as therapeutic target

Dimethyl fumarate (DMF) is an immunomodulatory compound used to treat multiple sclerosis and psoriasis whose mechanisms of action remain only partially understood. Kornberg et al. found that DMF and its metabolite, monomethyl fumarate, succinate the glycolytic enzyme GAPDH (see the Perspective by Matsushita and Pearce). After DMF treatment, GAPDH was inactivated, and aerobic glycolysis was down-regulated in both myeloid and lymphoid cells. This resulted in down-modulated immune responses because inflammatory immune-cell subsets require aerobic glycolysis. Thus, metabolism can serve as a viable therapeutic target in autoimmune disease.
Activated immune cells undergo a metabolic switch to aerobic glycolysis akin to the Warburg effect, thereby presenting a potential therapeutic target in autoimmune disease. Dimethyl fumarate (DMF), a derivative of the Krebs cycle intermediate fumarate, is an immunomodulatory drug used to treat multiple sclerosis and psoriasis. Although its therapeutic mechanism remains uncertain, DMF covalently modifies cysteine residues in a process termed succination. We found that DMF succinates and inactivates the catalytic cysteine of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in mice and humans, both in vitro and in vivo. It thereby down-regulates aerobic glycolysis in activated myeloid and lymphoid cells, which mediates its anti-inflammatory effects. Our results provide mechanistic insight into immune modulation by DMF and represent a proof of concept that aerobic glycolysis is a therapeutic target in autoimmunity.

Dimethylfumarate inhibits microglial and astrocyticinflammation by suppressing the synthesis of nitric oxide, IL-1β, TNF-α andIL-6 in an in-vitro model of brain inflammation

Brain inflammation plays a central role in multiple sclerosis (MS). Dimethyl fumarate (DMF), the main ingredient of an oral formulation of fumaric acid esters with proven therapeutic efficacy in psoriasis, has recently been found to ameliorate the course of relapsing-remitting MS. Glial cells are the effector cells of neuroinflammation; however, little is known of the effect of DMF on microglia and astrocytes. The purpose of this study was to use an established in vitro model of brain inflammation to determine if DMF modulates the release of neurotoxic molecules from microglia and astrocytes, thus inhibiting glial inflammation.


Primary microglial and astrocytic cell cultures were prepared from cerebral cortices of neonatal rats. The control cells were treated with LPS, an accepted inducer of pro-inflammatory properties in glial cells, and the experimental groups with LPS and DMF in different concentrations. After stimulation/incubation, the generation of nitric oxide (NO) in the cell culture supernatants was determined by measuring nitrite accumulation in the medium using Griess reagent. After 6 hours of treatment RT-PCR was used to determine transcription levels of iNOS, IL-1β, IL-6 and TNF-α mRNA in microglial and astrocytic cell cultures initially treated with DMF, followed after 30 min by LPS treatment. Moreover, we investigated possible involvement of the ERK and Nrf-2 transduction pathway in microglia using western blot analysis.


Pre-treatment with DMF decreased synthesis of the proinflammatory mediators iNOS, TNF-α, IL-1β and IL-6 at the RNA level in activated microglia and astrocytes in vitro, associated with a decrease in ERK phosphorylation in microglia.


Collectively, these results suggest that the neuroprotective effects of DMF may be in part functionally attributable to the compound's ability to inhibit expression of multiple neuroinflammatory mediators in brain of MS patients.

Systemic inflammation is associated with increased cognitive decline and risk for Alzheimer’s disease. Microglia (MG) activated during systemic inflammation can cause exaggerated neuroinflammatory responses and trigger progressive neurodegeneration. Dimethyl fumarate (DMF) is an FDA-approved therapy for multiple sclerosis. The immunomodulatory and anti-oxidant properties of DMF prompted us to investigate whether DMF has translational potential for the treatment of cognitive impairment associated with systemic inflammation.


Primary murine MG cultures were stimulated with lipopolysaccharide (LPS) in the absence or presence of DMF. MG cultured from nuclear factor (erythroid-derived 2)-like 2-deficient (Nrf2 −/−) mice were used to examine mechanisms of DMF actions. Conditioned media generated from LPS-primed MG were used to treat hippocampal neuron cultures. Adult C57BL/6 and Nrf2 −/− mice were subjected to peripheral LPS challenge. Acute neuroinflammation, long-term memory function, and reactive astrogliosis were examined to assess therapeutic effects of DMF.


DMF suppressed inflammatory activation of MG induced by LPS. DMF suppressed NF-κB activity through Nrf2-depedent and Nrf2-independent mechanisms in MG. DMF treatment reduced MG-mediated toxicity towards neurons. DMF suppressed brain-derived inflammatory cytokines in mice following peripheral LPS challenge. The suppressive effect of DMF on neuroinflammation was blunted in Nrf2 −/− mice. Importantly, DMF treatment alleviated long-term memory deficits and sustained reactive astrogliosis induced by peripheral LPS challenge. DMF might mitigate neurotoxic astrocytes associated with neuroinflammation.


DMF treatment might protect neurons against toxic microenvironments produced by reactive MG and astrocytes associated with systemic inflammation.

Emerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple Sclerosis

Dimethyl Fumarate Attenuates Neuroinflammation and Neurobehavioral Deficits Induced by Experimental Traumatic Brain Injury

Traumatic brain injury (TBI) is a serious neuropathology that causes secondary injury mechanisms, including dynamic interplay between ischemic, inflammatory, and cytotoxic processes. Fumaric acid esters (FAEs) showed beneficial effects in pre-clinical models of neuroinflammation and toxic oxidative stress, so the aim of the present work was to evaluate the potential beneficial effects of dimethyl fumarate (DMF), the most pharmacologically effective molecules among the FAEs, in a mouse model of TBI induced by controlled cortical impact (CCI). Mice were administered DMF orally at the doses of 1, 10, and 30 mg/kg 1 h and 4 h after CCI. We performed histological, molecular, and immunohistochemistry analysis on the traumatic penumbral areas of the brain 24 h after CCI. DMF treatment notably reduced histological damage and behavioral impairments, reducing neurodegeneration as evidenced by assessments of neuronal loss, Fluoro-Jade C, and TUNEL staining; also, treatment with DMF blocked the apoptosis process increasing B-cell lymphoma 2 (Bcl-2) expression in injured cortex. Further, DMF treatment up-regulated antioxidant Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor pathway, inducing activation of manganese superoxide dismutase and heme-oxygenase-1 and reducing 4-hydroxy-2-nonenal staining. Also, regulating the NF-κB pathway, DMF treatment decreased the severity of inflammation through a modulation of neuronal nitric oxide synthase, interleukin 1, tumor necrosis factor, cyclooxygenase 2, and myeloperoxidase activity, reducing ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein expression. Our results support the thesis that DMF may be an effective neuroprotectant after brain trauma and warrants further study.

Dimethyl fumarate alters microglia phenotype and protects neurons against proinflammatory toxic microenvironments


·         Pharmacokinetic study provides evidence for direct brain exposure of dimethyl fumarates (DMF).
·         DMF, but not monomethyl fumarate (the primary metabolite of DMF) significantly decreases proinflammatory cytokine/chemokine and nitric oxide levels in classically activated microglia culture.
·         The inhibitory effect of DMF on cytokine is NRF2-independent.
·         DMF reduces the toxicity of classically activated microglia towards primary naïve neurons.


Delayed-release dimethyl fumarate (DMF) is an approved treatment for multiple sclerosis (MS). Microglia are considered central to MS pathophysiology, however the effects of DMF and the primary metabolite monomethyl fumarate (MMF) on microglia are not well characterized. We demonstrated that DMF and MMF altered transcriptional responses in primary microglia related to the nuclear factor (erythroid-derived 2)-like 2 pathway. Additionally, through an NRF2 independent manner, DMF, but not MMF significantly reduced production of proinflammatory mediators in classically activated microglia, and further rescued mitochondrial respiratory deficits in primary cortical neurons that were induced by activated microglia. These data suggest the mechanism of action of DMF may involve modulation of microglia inflammatory responses and attenuation of neurotoxicity.

Dimethylfumarate inhibits NF-κB function at multiple levels to limit airway smooth muscle cell cytokine secretion

The antipsoriatic dimethylfumarate (DMF) has been anecdotically reported to reduce asthma symptoms and to improve quality of life of asthma patients. DMF decreases the expression of proinflammatory mediators by inhibiting the transcription factor NF-κB and might therefore be of interest for the therapy of inflammatory lung diseases. In this study, we determined the effect of DMF on platelet-derived growth factor (PDGF)-BB- and TNFα-induced asthma-relevant cytokines and NF-κB activation by primary human asthmatic and nonasthmatic airway smooth muscle cells (ASMC). Confluent nonasthmatic and asthmatic ASMC were incubated with DMF (0.1–100 μM) and/or dexamethasone (0.0001–0.1 μM), NF-κB p65 siRNA (100 nM), the NF-κB inhibitor helenalin (1 μM) before stimulation with PDGF-BB or TNFα (10 ng/ml). Cytokine release was measured by ELISA. NF-κB, mitogen and stress-activated kinase (MSK-1), and CREB activation was determined by immunoblotting and EMSA. TNFα-induced eotaxin, RANTES, and IL-6 as well as PDGF-BB-induced IL-6 expression was inhibited by DMF and by dexamethasone from asthmatic and nonasthmatic ASMC, but the combination of both drugs showed no glucocorticoid sparing effect in either of the two groups. NF-κB p65 siRNA and/or the NF-κB inhibitor helenalin reduced PDGF-BB- and TNFα-induced cytokine expression, suggesting the involvement of NF-κB signaling. DMF inhibited TNFα-induced NF-κB p65 phosphorylation, NF-κB nuclear entry, and NF-κB-DNA complex formation, whereas PDGF-BB appeared not to activate NF-κB within 60 min. Both stimuli induced the phosphorylation of MSK-1, NF-κB p65 at Ser276, and CREB, and all were inhibited by DMF. These data suggest that DMF downregulates cytokine secretion not only by inhibiting NF-κB but a wider range of NF-κB-linked signaling proteins, which may explain its potential beneficial effect in asthma. 

Dimethyl Fumarate Reduces Inflammatory Responses in Experimental Colitis

Background and Aims:
Fumaric acid esters have been proven to be effective for the systemic treatment of psoriasis and multiple sclerosis. We aimed to develop a new treatment for colitis.

We investigated the effect of dimethylfumarate [DMF, 10-30-100mg/kg] on an experimental model of colitis induced by dinitrobenzene sulphuric acid [DNBS]. We also evaluated the therapeutic activity of 7 weeks’ treatment with DMF [30mg/kg] on 9-week-old IL-10KO mice that spontaneously develop a T helper-1 [Th1]-dependent chronic enterocolitis after birth, that is fully established at 8–10 weeks of age. The mechanism of this pharmacological potential of DMF [10 μM] was investigated in colonic epithelial cell monolayers [Caco-2] exposed to H 2 O 2 . The barrier function was evaluated by the tight junction proteins.
The treatment with DMF significantly reduced the degree of haemorrhagic diarrhoea and weight loss caused by administration of DNBS. DMF [30 and 100mg/kg] also caused a substantial reduction in the degree of colon injury, in the rise in myeloperoxidase [MPO] activity, and in the increase in tumour necrosis factor [TNF]-α expression, as well as in the up-regulation of ICAM-1 caused by DNBS in the colon. Molecular studies demonstrated that DMF impaired NF-κB signalling via reduced p65 nuclear translocalisation. DMF induced a stronger antioxidant response as evidenced by a higher expression of Mn-superoxide dismutase. Moreover, DMF protected human intestinal epithelial cells against H 2 O 2 -induced barrier dysfunction, restoring ZO-1 occludin expression, via the HO-1 pathway.
DMF treatment reduces the degree of colitis caused by DNBS. We propose that DMF treatment may be useful in the treatment of inflammatory bowel disease.

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2 


Dimethyl fumarate (DMF) (BG-12, Tecfidera), a fumaric acid ester (FAE), is a commonly prescribed oral therapy for multiple sclerosis (MS), a CNS autoimmune inflammatory demyelinating disease that may result in sustained neurologic damage. It is thought that the benefit of DMF in MS therapy is mediated through activation of the antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, the role of Nrf2 in the antiinflammatory effects of DMF has not been fully elucidated. Here, we investigated the role of Nrf2 in DMF treatment of the MS model, experimental autoimmune encephalomyelitis (EAE), and demonstrated DMF can modulate T cells, B cells, and antigen-presenting cells, and reduce clinical and histologic EAE, independent of Nrf2.


Dimethyl fumarate (DMF) (BG-12, Tecfidera) is a fumaric acid ester (FAE) that was advanced as a multiple sclerosis (MS) therapy largely for potential neuroprotection as it was recognized that FAEs are capable of activating the antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, DMF treatment in randomized controlled MS trials was associated with marked reductions in relapse rate and development of active brain MRI lesions, measures considered to reflect CNS inflammation. Here, we investigated the antiinflammatory contribution of Nrf2 in DMF treatment of the MS model, experimental autoimmune encephalomyelitis (EAE). C57BL/6 wild-type (WT) and Nrf2-deficient (Nrf2−/−) mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35–55 (p35–55) for EAE induction and treated with oral DMF or vehicle daily. DMF protected WT and Nrf2−/− mice equally well from development of clinical and histologic EAE. The beneficial effect of DMF treatment in Nrf2−/− and WT mice was accompanied by reduced frequencies of IFN-γ and IL-17–producing CD4+ cells and induction of antiinflammatory M2 (type II) monocytes. DMF also modulated B-cell MHC II expression and reduced the incidence of clinical disease in a B-cell–dependent model of spontaneous CNS autoimmunity. Our observations that oral DMF treatment promoted immune modulation and provided equal clinical benefit in acute EAE in Nrf2−/− and WT mice, suggest that the antiinflammatory activity of DMF in treatment of MS patients may occur through alternative pathways, independent of Nrf2.

Control of Oxidative Stress and Inflammation in Sickle Cell Disease with the Nrf2 Activator Dimethyl Fumarate

Aims: Heme derived from hemolysis is pro-oxidative and proinflammatory and promotes vaso-occlusion in murine models of sickle cell disease (SCD), suggesting that enhanced detoxification of heme may be beneficial. Nuclear factor erythroid-2-related factor-2 (Nrf2) transcription pathway is the principal cellular defense system responding to pro-oxidative and proinflammatory stress. Dimethyl fumarate (DMF), a drug approved for treatment of multiple sclerosis, provides neuroprotection by activating Nrf2-responsive genes. We hypothesized that induction of Nrf2 with DMF would be beneficial in murine SCD models. Results: DMF (30 mg/kg/day) or vehicle (0.08% methyl cellulose) was administered for 3-7 days to NY1DD and HbSS-Townes SCD mice. Vaso-occlusion, a hallmark of SCD, measured in sickle mice with dorsal skinfold chambers, was inhibited by DMF. The inhibitory effect of DMF was abrogated by the heme oxygenase-1 (HO-1) inhibitor tin protoporphyrin. DMF increased nuclear Nrf2 and cellular mRNA of Nrf2-responsive genes in livers and kidneys. DMF increased heme defenses, including HO-1, haptoglobin, hemopexin, and ferritin heavy chain, although plasma hemoglobin and heme levels were unchanged. DMF decreased markers of inflammation, including nuclear factor-kappa B phospho-p65, adhesion molecules, and toll-like receptor 4. DMF administered for 24 weeks to HbSS-Townes mice decreased hepatic necrosis, inflammatory cytokines, and irregularly shaped erythrocytes and increased hemoglobin F, but did not alter hematocrits, reticulocyte counts, lactate dehydrogenase, plasma heme, or spleen weights, indicating that the beneficial effects of DMF were not attributable to decreased hemolysis. Innovation: These studies identify Nrf2 activation as a new therapeutic target for the treatment of SCD. Conclusion: DMF activates Nrf2, enhances antioxidant defenses, and inhibits inflammation and vaso-occlusion in SCD mice. 

Dimethyl fumarate treatment after traumatic brain injury prevents depletion of antioxidative brain glutathione and confers neuroprotection.



Dimethyl fumarate (DMF) is an immunomodulatory compound to treat multiple sclerosis and psoriasis with neuroprotective potential. Its mechanism of action involves activation of the antioxidant pathway regulator Nuclear factor erythroid 2-related factor 2 thereby increasing synthesis of the cellular antioxidant glutathione (GSH). The objective of this study was to investigate whether post-traumatic DMF treatment is beneficial after experimental traumatic brain injury (TBI). Adult C57Bl/6 mice were subjected to controlled cortical impact followed by oral administration of DMF (80 mg/kg body weight) or vehicle at 3, 24, 48, and 72 h after the inflicted TBI. At 4 days after lesion (dal), DMF-treated mice displayed less neurological deficits than vehicle-treated mice and reduced histopathological brain damage. At the same time, the TBI-evoked depletion of brain GSH was prevented by DMF treatment. However, nuclear factor erythroid 2-related factor 2 target gene mRNA expression involved in antioxidant and detoxifying pathways was increased in both treatment groups at 4 dal. Blood brain barrier leakage, as assessed by immunoglobulin G extravasation, inflammatory marker mRNA expression, and CD45+ leukocyte infiltration into the perilesional brain tissue was induced by TBI but not significantly altered by DMF treatment. Collectively, our data demonstrate that post-traumatic DMF treatment improves neurological outcome and reduces brain tissue loss in a clinically relevant model of TBI. Our findings suggest that DMF treatment confers neuroprotection after TBI via preservation of brain GSH levels rather than by modulating neuroinflammation.

Emerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple Sclerosis

Dimethyl fumarate (DMF) is an effective treatment option for relapsing–remitting multiple sclerosis (MS), but its therapeutic mechanism of action has not been fully elucidated. A better understanding of its mechanism will allow for the development of assays to monitor its clinical efficacy and safety in patients, as well as guide the development of the next generation of therapies for MS. In order to build the foundation for determining its mechanism, we reviewed the manner in which DMF alters lymphocyte subsets in MS patients, its impact on clinical efficacy and safety, as well as its molecular effects in cellular and animal models. DMF decreases absolute lymphocyte counts, but does not affect all subsets uniformly. CD8+ T-cells are the most profoundly affected, but reduction also occurs in the CD4+ population, particularly within the pro-inflammatory T-helper Th1 and Th17 subsets, creating a bias toward more anti-inflammatory Th2 and regulatory subsets. Similarly, B-lymphocyte, myeloid, and natural killer populations are also shifted toward a more anti-inflammatory stateIn vitro and animal models demonstrate a role for DMF within the central nervous system (CNS) in promoting neuronal survival in an Nrf2 pathway-dependent manner. However, the impact of DMF directly within the CNS of MS patients remains largely unknown.


I think DMF and MMF could have wide application in numerous inflammatory conditions and at much lower doses that those envisaged by Biogen.

No very low dose versions are produced as drugs, the lowest is the 30mg “starter” version for psoriasis. It is not cheap. This tablet can of course be subdivided and placed into enteric capsules to give whatever dose is required and taken after a large meal. Enteric capsules will not dissolve in the gastric acids of the stomach (pH ~3), but they will in the alkaline (pH 7–9) environment present in the small intestine. DMF is an irritant to the stomach and your skin.

Do some of the big-time responders to BHB salts and esters also respond to a tiny dose of DMF? My feeling is that some will.  

It looks like anyone who has oxidative stress and neuroinflammation might potentially benefit and that is most of "autism".  In our case all that is left of allergy-triggered summertime raging/SIB is some anxiety; increasing the NKCC1 blocking with a second daily dose improves cognition but may have a side effect of increasing this anxiety. I was recently asked to fix it. This anxiety disappears with 5mg of DMF, with no side effects. 

There has also been an increase in speech, somewhat reminiscent of what happened several years ago when starting sulforaphane/broccoli sprouts. Sulforaphane and DMF both activate Nrf-2, which functions like an antioxidant switch. The effect of sulforaphane/broccoli sprouts does fade.  

More speech in our case does not mean the social "chit-chat", which you might hope for, but it nonetheless is speech. I was just talking to Monty's assistant about this subject. She is working on developing more conversational speech during some of the free time at school. When your goal is conversational speech you may totally ignore the new speech the student does produce - better to engage in whatever subject he actually does want to "talk" about and build from there.

BHB does have multiple potentially helpful-to-autism modes of action, but so does DMF.

DMF accelerates wound healing, but only in diabetics (this is observed, but not fully understood). Diabetics do suffer foot ulcers that often lead to amputations, so DMF would have a very obvious application.

Neuralgia is a chronic problem affecting many people, DMF may well be an effective new therapy.

It looks like activating the Nrf-2 pathway should protect brains affected by Parkinson’s and maybe these researchers will push for DMF/MMF to get approved.  I do not think anyone has thought of using DMF to treat COPD (severe asthma).  I am glad that at least one paper does mention the potential to use DMF to reduce inflammation in Alzheimer’s.

I think some people with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD) would very likely respond and MMF is the obvious choice, so as to avoid the GI side effects of DMF.

Even though it is usually stated that DMF is a prodrug while MMF is the active substance, it is clear that this is an over simplification. The effects of DMF and MMF are slightly different.  The effect on GSH (the antioxidant Glutathione) levels is very different, because GSH is consumed in the chemical transition from DMF to MMF, so in the short-term oxidative stress increases if you take DMF.  Perhaps people taking large doses of DMF for Multiple Sclerosis should indeed take NAC to avoid GSH being depleted and also be told not to take Paracetamol for pain (since it further depletes GSH).

For the time being the only commercial product available is DMF.  

Low dose DMF placed in an enteric capsule and taken after a main meal appears to have no GI side effects. It does indeed have an immunomodulatory effect even at a tiny dose of 5 to 8 mg.  Low dose DMF taken without an enteric capsule does have GI effects that you would rather avoid.  I looked up patient feedback from those taking the 100 time higher psoriasis dose of DMF and many report an awful time for the first 2-3 months, before things settle down.

DMF does cause dose dependent side effects. This is why doses far lower than envisaged by Biogen are interesting, if they do actually have a genuine clinical effect in that person. The daily dose for psoriasis is 720 mg. DMF/MMF crosses the blood brain barrier very easily.

DMF, at high psoriasis doses, has been widely used in Germany for many years.

As with many things mentioned in this blog, realistically I doubt much will be made of DMF/MMF in the near future beyond Multiple Sclerosis (MS) and Psoriasis; this is a shame, but not really a surprise.  It does get added to my list of options to modulate the immune system in autism.

·        Cheap NSAIDs, like Ibuprofen
·        The  cheap leukotriene receptor antagonist, Montelukast/Singulair
·        The Japanese PDE4 inhibitor Ibudilast (has less GI side effects than the Western drug Daxas/Roflumilast)
·        TSO parasites
·        Statins
·        Beta-lactam antibiotics, like Penicillin
·        Macrolide antibiotics, like Azithromycin
·        Biogaia Gastrus probiotic
·        PEA (Palmitoylethanolamide) or alternatively CBD (Cannabidiol)
·        The ketone BHB (beta hydroxybutyrate)
·        Lenalidomide (an ultra-expensive drug)
·        5mg DMF (Dimethyl Fumarate) taken in an enteric capsule just after a large meal

All of the above would raise eyebrows as autism therapies, but perhaps less so if you use the term autoimmune encephalopathy.  

The thing to bear in mind is that all the above immuno-modulating therapies have the potential to cause a negative reaction.  You have to match the therapy to the specific immune dysfunction, if indeed there is one at all. Hopefully the field of immunology will move forward and not leave you to ponder these issues yourself. 

I will pursue DMF further.