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Wednesday, 5 September 2018

September 05, 2018

Ketones and Autism Part 4 � Inflammation, Activated Microglia, CtBP, the NLRP3 Inflammasome and IL-1�

This series of posts on ketones and the ketogenic diet (KD) is nearly finished and I am glad that I made favourable comments about the KD earlier on in this blog, before I knew all the nitty-gritty of the science. (no re-editing required)

Inflammasome Inhibition: Putting Out the Fire                                                                                                                       

There is more than one anti-inflammatory mechanism involved in the ketogenic diet (KD); in Part 3 we covered Niacin Receptor HCA2, today in Part 4 we look at NLRP3 and CtBP.
The reason I am going into all this detail is because if you knew why someone responds to ketones in a favourable way, there might actually be an even more potent therapy using an entirely different substance.
CtBP represses the transcription of certain tumour supressing genes and some other genes involved in the development of cancer, i.e. they promote tumorigenesis.  CtBP is often overexpressed in certain cancers and indicates a worse prognosis. In these cancers you would want to inhibit CtBP.
Just to complicate matters, CtBP also supresses the activity of certain inflammatory genes. So, in certain diseases like diabetes you might benefit from keeping CtBP permanently in its active state. In particular, this would apply to when the microglia are activated, which is the case in much autism.
The coconut oil doctors have the idea that the key problem in autism is activated microglia in the brain.  Microglia mediate immune responses in the central nervous system, clearing cellular debris and dead neurons via a process called phagocytosis. These doctors propose coconut oil to calm the microglia.
Microglia can be in a resting or activated state, the research suggests that in much autism the microglia are permanently activated.
Some research suggests that microglia act like an �immunostat� reflecting not just what is going on in the brain, but elsewhere in the body.  I favour this view.
A small trial using a drug to calm the microglia did not impact autism.
Personally, I believe that microglia being activated is not a good thing, but that it is part of a much more complex picture than the coconut doctors suggest. 
As we learn later in this post, to get the CtBP benefit to microglia, it appears that you need the kind of ketosis you achieve only in the full ketogenic diet, not the transient mild ketosis that you achieve from two heaped tablespoons of coconut oil, or any of the keto supplements. 

NLRP3 inflammasome
The complicated-sounding NLRP3 inflammasome relates to diseases where the proinflammatory cytokine IL-1� is elevated; this includes Alzheimer�s, MS, Inflammatory Bowel Disease (IBD) and often autism.
For the details of how NLRP3 works see below; the important thing to note is that the result is elevated levels of IL-1�, which, at least in blood, is easy to measure.  It is an open question whether this represents the level inside the brain.  If your child has elevated IL-1� then it is worth studying NLRP3.

Schematic illustration of the NLRP3 inflammasome activation. Upon exposure to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs), Toll-like receptors (TLRs) are phosphorylated and subsequently activate NF-?B. In the nucleus, NF-?B promotes the transcription of NLRP3, proIL-1�, and proIL-18, which, after translation, remain in the cytoplasm in inactive forms. Thus, this signal (depicted in red as �Signal 1�) is a priming event. A subsequent stimulus (shown as �Signal 2� in black) activates the NLRP3 inflammasome by facilitating the oligomerization of inactive NLRP3, apoptosis-associated speck-like protein (ASC), and procaspase-1. This complex, in turn, catalyzes the conversion of procaspase-1 to caspase-1, which contributes to the production and secretion of the mature IL-1� and IL-18. Three models have been proposed to describe the second step of inflammasome activation: (1) Extracellular ATP can induce K+/potassium e?ux through a purogenic P2X7-dependent pore, which, leads to the assembly and activation of the NLRP3 inflammasome. Calcium flux is also involved in this process. (2) PAMPs and DAMPs trigger the generation of ROS that promote the assembly and activation of the NLRP3 inflammasome. (3) Phagocytosed environmental irritants form intracellular crystalline or particulate structures leading to lysosomal rupture (magenta box) and release of lysosomal contents like cathepsin B. These induce NLRP3 inflammasome assembly and activation. In addition, other factors and mechanisms have been implicated in the assembly and activation of the NLRP3 inflammasome, including mitochondrial damage, autophagic dysfunction, and thioredoxin-interacting protein (TXNIP).

Proinflammatory cytokine IL-1� 
My public enemy number 1 cytokine is actually IL-6, today we primarily look at IL-1�, which for many people with a neurological disorder is a big part of their problem. IL-6 and IL-1� are actually interrelated, as we see later.
For a summary of the role of this cytokine in autism, I will leave it to Paul Ashwood:-  

Interleukin (IL)-1B

IL-1? is an inflammatory cytokine expressed very early in immune responses. In tissue, IL-1? propagates inflammation by activating local immune cells and the vascular endothelium. Systemically, IL-1? stimulates IL-6 production and eventually an acute phase response in the liver. Systemic IL-1? can cross the blood brain barrier and stimulate its own expression in the hypothalamus, which leads to neuroendocrine changes associated with fever and sickness behavior . IL-1? receptors are structurally related to toll-like receptors (TLRs), and signaling is achieved through NF-?B and MAP kinase (MAPK) signaling cascades. IL-1? belongs to an evolutionarily conserved family of proteins that function beyond immunity. It shares structural homology with fibroblast growth factors, which are critical in embryonic neurodevelopment, and are implicated in autism and schizophrenia.
Genes for IL-1?, its receptor, and its receptor-associated proteins are associated with intellectual disability, schizophrenia, and autism. Children and adults with autism have increased plasma IL-1? and skewed cellular IL-1? responses following stimulation. Compared to controls, monocytes from children with ASD produce excessive IL-1? following LPS exposure, and lower levels following exposure to TLR 9 agonists. The IL-1 antagonist, IL-1ra, is also increased among ASD subjects. IL-1ra reduces inflammation by competing for the IL-1? receptor, and increased levels may represent an attempt to counteract inflammation in ASD. Postmortem brains from ASD subjects had normal IL-1? levels, but given that peripheral IL-1? can enter the brain, increased systemic levels could directly impact neurological processes
IL-1? disruption can have a variety of neurological consequences relevant to autism. The cytokine and its receptors are found throughout the nervous system during critical developmental periods. IL-1? induces neural progenitor cell proliferation in some CNS regions, while inhibiting it in others. This could contribute to the region-specific overgrowth and undergrowth observed in the ASD brain. Excitatory synapse formation is partially mediated by the IL-1 receptor and receptor-associated proteins.
Altering these proteins can tip the balance between excitatory and inhibitory signaling, which might underlie neurological features of autism. Increased IL-1ra in autism suggests an attempt to counterbalance IL-1? and may or may not be beneficial. Following brain injury, IL-1ra upregulation serves a neuroprotective role by dampening excessive inflammation. However, if administered during critical windows of neurodevelopment, IL-1ra can negatively impact neurogenesis, brain morphology, memory consolidation, and behavior. This shows that some level of IL-1B signaling is essential during development. In adulthood, IL-1? is implicated in CNS disorders like Alzheimer�s disease and the advancement of amyloid-containing plaques. While excessive IL-1B contributes to pathology in some cases, it may have a protective role in others. For example, IL-1? limits neuronal damage following excitotoxic exposures, and mice lacking IL-1? fail to undergo remyelination following experimental autoimmune encephalitis (EAE) induction. IL-1? is involved in higher order brain processes and is induced in the hippocampus during learning processes, and is critical for maintenance of long-term potentiation (LTP) Both over expression and under expression of IL-1 beta are associated with impairments in memory and learning.

At the table in the kitchen, there were three bowls of porridge.  Goldilocks was hungry.  She tasted the porridge from the first bowl.
"This porridge is too hot!" she exclaimed.
So, she tasted the porridge from the second bowl.
"This porridge is too cold," she said
So, she tasted the last bowl of porridge.
"Ahhh, this porridge is just right," she said happily and she ate it all up. 

In summary, IL-1? participates in neurological processes, and appears to have a role in both CNS pathology and healing. Normal, homeostatic levels of IL-1? and its antagonist IL-1ra are necessary for proper brain development and function. This �Goldilocks� state is typical of many cytokines, where too much or too little is not desirable. Alterations in IL-1? systems due to genetic mechanisms or environmental exposures may contribute to autism. 

CtBP (C-terminal-binding protein) 
In 2017 research led by Dr Raymond Swanson, a professor of neurology at the University of California, San Francisco, suggested CtBP as an additional possible mechanism by which the ketogenic diet can reduce brain inflammation.   CtBP activation turns off key inflammatory genes.
In the case of CtBP, I doubt that the very partial ketosis achieved with BHB and C8 supplements will be enough, I think you would need the full ketogenic diet. 
Restricting the glucose metabolism with the ketogenic diet lowers the NADH/NAD+ ratio which activates CtBP. There is no direct role played by ketones in this process, it is just the presence of large amounts of ketones reduces the role of glucose.

Factors that reduce glucose flux through glycolysis, such as reduced glucose availability or glycolytic inhibitors, reduce NADH levels and thereby reduce NADH:NAD+ ratio, whereas factors that inhibit oxidative metabolism, such as hypoxia and mitochondrial inhibitors, have the opposite effect. Glutamine provides ketone bodies (a-ketoglutarate) to fuel mitochondrial ATP production in the absence of glycolysis. Lactate dehydrogenase (LDH) maintains the lactate:pyruvate ratio in equilibrium with the cytosolic NADH:NAD+ ratio.

BHB is not directly a CtBP activator.
A drug that acts as an CtBP activator would be great for diabetes and anyone with brain inflammation.
Using BHB and C8 you would need to create enough ketones in your blood to reduce the glucose metabolism substantially, not by a trivial amount.
The easy to read version:- 

New research uncovers and replicates the mechanism by which a ketogenic diet curbs brain inflammation. The findings pave the way for a new drug target that could achieve the same benefits of a keto diet without having to actually follow one.

A keto state lowers brain inflammation
A keto diet changes the metabolism, or the way in which the body processes energy. In a keto diet, the body is deprived of glucose derived from carbs, so it starts using fat as an alternative source of energy.

In the new study, Dr Swanson and his colleagues recreated this effect by using a molecule called 2-deoxyglucose (2DG).
The 2DG molecule stopped glucose from metabolizing and created a ketogenic state in rodents with brain inflammation as well as in cell cultures. Levels of inflammation were drastically reduced - almost to healthy levels - as a result.
"We were surprised by the magnitude of our findings," said Dr Swanson. "Inflammation is controlled by many different factors, so we were surprised to see such a large effect by manipulating this one factor. It reinforces the powerful effect of diet on inflammation."
The restricted glucose metabolism lowered the so-called NADH/NAD+ ratio
"Cells convert NAD+ to NADH, as an intermediary step in generating energy from glucose, and thus increase the NADH/NAD+ ratio," he added.
When this ratio is lowered, the CtBP protein gets activated and attempts to turn off inflammatory genes. As Dr. Swanson told us, "CtBP is a protein that senses the NADH/NAD ratio and regulates gene expression depending on this ratio."
So, the scientists designed a molecule that stops CtBP from being inactive. This keeps the protein in a constant "watchful" state, blocking inflammatory genes in an imitation of the ketogenic state. Dr. Swanson said, "Our findings show that it is [...] possible to get the anti-inflammatory effect of a ketogenic diet without actually being ketogenic
The findings could apply to other conditions that are characterized by inflammation. In diabetes, for example, the excessive glucose produces an inflammatory response, and the new results could be used to control this dynamic.
"[The] ultimate therapeutic goal would be to generate a [drug] that can act on CtBP to mimic the anti-inflammatory effect of [the] ketogenic diet," Dr. Swanson concluded. 

Full Paper:- 

The innate inflammatory response contributes to secondary injury in brain trauma and other disorders. Metabolic factors such as caloric restriction, ketogenic diet, and hyperglycemia influence the inflammatory response, but how this occurs is unclear. Here, we show that glucose metabolism regulates pro-inflammatory NF-?B transcriptional activity through effects on the cytosolic NADH:NAD+ ratio and the NAD(H) sensitive transcriptional co-repressor CtBP. Reduced glucose availability reduces the NADH:NAD+ ratio, NF-?B transcriptional activity, and pro-inflammatory gene expression in macrophages and microglia. These effects are inhibited by forced elevation of NADH, reduced expression of CtBP, or transfection with an NAD(H) insensitive CtBP, and are replicated by a synthetic peptide that inhibits CtBP dimerization. Changes in the NADH:NAD+ ratio regulate CtBP binding to the acetyltransferase p300, and regulate binding of p300 and the transcription factor NF-?B to pro-inflammatory gene promoters. These findings identify a mechanism by which alterations in cellular glucose metabolism can influence cellular inflammatory responses.

The innate inflammatory response contributes to secondary injury in brain trauma and other disorders. Metabolic factors such as caloric restriction, ketogenic diet, and hyperglycemia influence the inflammatory response, but how this occurs is unclear. Here, we show that glucose metabolism regulates pro-inflammatory NF-?B transcriptional activity through effects on the cytosolic NADH:NAD+ ratio and the NAD(H) sensitive transcriptional co-repressor CtBP. Reduced glucose availability reduces the NADH:NAD+ ratio, NF-?B transcriptional activity, and pro-inflammatory gene expression in macrophages and microglia. These effects are inhibited by forced elevation of NADH, reduced expression of CtBP, or transfection with an NAD(H) insensitive CtBP, and are replicated by a synthetic peptide that inhibits CtBP dimerization. Changes in the NADH:NAD+ ratio regulate CtBP binding to the acetyltransferase p300, and regulate binding of p300 and the transcription factor NF-?B to pro-inflammatory gene promoters. These findings identify a mechanism by which alterations in cellular glucose metabolism can influence cellular inflammatory responses.

One way that CtBP regulates gene transcription is through interactions with the histone acetyltransferase HDAC1. 

Taken together, our findings indicate that metabolic influences that alter the cytosolic NADH:NAD+ ratio regulate NF-?B transcriptional activity through an NADH-dependent effect on CtBP dimerization. Conditions that reduce glycolytic flux, such as ketogenic diet and caloric restriction, can thereby suppress NF-?B activity, while conditions that increase glycolytic flux may increase it. These interactions provide a mechanism for the suppressive effects of ketogenic diet and caloric restriction on brain inflammation after brain injury. By extension, these interactions may also contribute to the pro-inflammatory states associated with diabetes mellitus and metabolic syndrome. 

Inhibiting NLRP3 and/or activating CtBP

You do not need to be a genius to see that inhibiting NLRP3 and/or activating CtBP, using the ketogenic diet, is likely to benefit some people with autism.
On the flipside, someone with colon cancer, where CtBP is over-expressed to the point where the cancer depends on it for growth, certainly would not want the ketogenic diet.
This cancer flipside we have seen before, antioxidants like NAC and Sulforaphane (via activating the redox switch Nrf2) are chemoprotective for healthy people, but bad for you if you have developed cancer.  Oxidative stress is very damaging to cancer cells and so it becomes a good thing. Some people who develop cancer then choose to improve their diet to include new healthy foods, sadly for some people this may actually be counterproductive.
Estrogen is another case in point, it has many positive effects and has been suggested to be one reason why women like longer than men. If you develop estrogen positive breast cancer, more estrogen is the last thing you would want.  

Other NLRP3 inhibitors 


Coll et al. (2015) discovered that MCC950, a diarylsulfonylurea-containing compound known to inhibit caspase-1-dependent processing of IL-1�, also inhibits both canonical and non-canonical activation of the NLRP3 inflammasome. MCC950 inhibits secretion of IL-1� and NLRP3-induced ASC oligomerization in mouse and human macrophages. It reduces secretion of IL-1� and IL-18, alleviating the severity of EAE and CAPS in mouse models. Coll et al. (2015) further showed that MCC950 acts specifically on the NLRP3 inflammasome

Note that MCC950 is the new name for a drug Pfizer originally called CP-456773 or CRID3, which was not successful as a treatment for arthritis, but now has a second chance

Youm et al. (2015) discovered that the ketone metabolite �-hydroxybutyrate (BHB), but not acetoacetate or the short-chain fatty acids butyrate and acetate, reduced IL-1�, and IL-18 production by the NLRP3 inflammasome in human monocytes. Like MCC950, BHB appears to block inflammasome activation by inhibiting NLRP3-induced ASC oligomerization. Their in vivo experiments showed that BHB or a ketogenic diet alleviate caspase-1 activation and caspase-1-mediated IL-1� production and secretion, without affecting the activation of NLRC4 or AIM2 inflammasomes. BHB inhibits NLRP3 inflammasome activation independently of AMP-activated protein kinase, ROS, autophagy, or glycolytic inhibition. These studies raise interesting questions about interactions among ketone bodies, metabolic products, and innate immunity. BHB levels increase in response to starvation, caloric restriction, high-intensity exercise, or a low-carbohydrate ketogenic diet. Vital organs such as the heart and brain can exploit BHB as an alternative energy source during exercise or caloric deficiency. Future studies should examine how innate immunity, particularly the inflammasome, is influenced by ketones and other alternative metabolic fuels during periods of energy deficiency 
Although both MCC950 and BHB inhibit NLRP3 inflammasome activation, their mechanisms differ in key respects. BHB inhibits K+ e?ux from macrophages, while MCC950 does not. MCC950 inhibits both canonical and non-canonical inflammasome activation, while BHB affects only canonical activation. Nevertheless both inhibitors represent a significant advance toward developing therapies that target IL-1� and IL-18 production by the NLRP3 inflammasome in various diseases. 

Type I Interferon (IFN) and IFN-�

In contrast to these newly described, NLRP3-specific inflammasome inhibitors, type I interferons (IFNs), including IFN-a and IFN-�, have been used for some time to inhibit the NLRP3 and other inflammasomes in various auto-immune and auto-inflammatory diseases. These diseases include multiple sclerosis, systemic-onset juvenile idiopathic arthritis caused by gain-of-function NLRP3 mutations, rheumatic diseases and familial-type Mediterranean fever.

These studies highlight the efficacy of type I IFN therapy and the need for future studies to elucidate the mechanisms of NLRP3 inflammasome inhibition. This work may improve clinical approaches to treating multiple sclerosis and other auto-immune and auto-inflammatory diseases.

Other Kinds of NLRP3 Inflammasome Inhibitors
Several additional ways for inhibiting the NLRP3 inflammasome have opened up in recent years. Autophagy, a self-protective catabolic pathway involving lysosomes, has been shown to inhibit the NLRP3 inflammasome, leading researchers to explore the usefulness of autophagy-inducing treatments  

Cannabinoid receptor 2 (CB2R) is an already demonstrated therapeutic target in inflammation-related diseases (Smoum et al., 2015). Work from our own laboratory (Shao et al., 2014) has shown that autophagy induction may help explain why activation of the anti-inflammatory CB2R leads to inhibition of NLRP3 inflammasome priming
Thus CB2R agonists similar to the HU-308 used in our work may become an effective therapy for treating NLRP3 inflammasome-related diseases by inducing autophagy.
Several other microRNAs have been reported to be involved in the activation of the NLRP3 inflammasome, including microRNA-155, microRNA-377, and microRNA-133a-1. Reducing the levels of these factors may be useful for treating inflammasome-related disease 

Conclusion regarding NLRP3 inhibitors

At this point in time BHB is clearly the best choice; at some point it would be expected that Pfizer will commercialize MCC950. 

 Further relevant papers: 

Inflammasomes are newly recognized, vital players in innate immunity. The best characterized is the NLRP3 inflammasome, so-called because the NLRP3 protein in the complex belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as �pyrin domain-containing protein 3�. The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic fever syndrome, as well as other auto-immune and auto-inflammatory diseases. Several NLRP3 inflammasome inhibitors have been described, some of which show promise in the clinic. The present review will describe the structure and mechanisms of activation of the NLRP3 inflammasome, its association with various auto-immune and auto-inflammatory diseases, and the state of research into NLRP3 inflammasome inhibitors. 

NLRP3-inflammasome activates caspase-1 and processes pro-IL-1� and pro-IL-18 into the active cytokines. Two recent studies describe specific inhibitors of NLRP3 inflammasome that inhibit IL-1� release and inflammation. The specificity and potency of these compounds gives hope that a targeted approach to inhibit NLRP3-driven inflammation may be just around the corner

Activation of the inflammasome is implicated in the pathogenesis of an increasing number of inflammatory diseases, including Alzheimer�s disease (AD). Research reporting inflammatory changes in post mortem brain tissue of individuals with AD and GWAS data have convincingly demonstrated that neuroinflammation is likely to be a key driver of the disease. This, together with the evidence that genetic variants in the NLRP3 gene impact on the risk of developing late-onset AD, indicates that targeting inflammation offers a therapeutic opportunity. Here, we examined the effect of the small molecule inhibitor of the NLRP3 inflammasome, MCC950, on microglia in vitro and in vivo. The findings indicate that MCC950 inhibited LPS + A�-induced caspase 1 activation in microglia and this was accompanied by IL-1� release, without inducing pyroptosis. We demonstrate that MCC950 also inhibited inflammasome activation and microglial activation in the APP/PS1 mouse model of AD. Furthermore, MCC950 stimulated A� phagocytosis in vitro, and it reduced A� accumulation in APP/PS1 mice, which was associated with improved cognitive function. These data suggest that activation of the inflammasome contributes to amyloid accumulation and to the deterioration of neuronal function in APP/PS1 mice and demonstrate that blocking assembly of the inflammasome may prove to be a valuable strategy for attenuating changes that negatively impact on neuronal function. 

Scientists say new treatments for inflammatory diseases could be on the way

New treatments for inflammatory diseases could be on the way thanks to a significant discovery made by an international group of scientists, including some at Trinity College Dublin. 
The treatments could be used for a whole range of inflammatory disease including arthritis, Alzheimer's, multiple sclerosis, Parkinson's, gout, asthma and Muckle-Wells syndrome.

The researchers have found that a molecule, previously developed and then abandoned by a multinational pharmaceutical company, can block one of the key drivers of a plethora of inflammatory conditions.
The molecule, MCC950, was produced by Pfizer two decades ago as a possible treatment for arthritis.
However, the company discontinued its efforts to bring the drug to market, and the intellectual property rights on it subsequently lapsed.
Around eight years ago, scientists at Trinity's Biomedical Sciences Institute led by Professor of Biochemistry Luke O'Neill came across the compound and began to explore its potential uses.
They subsequently discovered that it could effectively block the NLRP3 inflammasome.
Inflammasomes are a complex of molecules that trigger inflammation when exposed to infection or stress.
They have been identified as promising therapeutic targets for researchers in recent years.
The NLRP3 inflammasome has been found to be a common activator of a key process in certain inflammatory diseases.
The discovery by the research team, details of which are published in the journal Nature Medicine, confirms that all inflammatory diseases share a common process, although the part of the body which experiences the inflammation might differ.
The scientists subsequently carried out trials on mice and found that the molecule stopped the progression of multiple sclerosis and sepsis.
They also carried out testing on samples taken from humans with Muckle-Wells syndrome, a rare auto-inflammatory disorder, and discovered it was equally effective.
The scientists also say that it is likely the drug could produce fewer common side-effects, such as susceptibility to infection, than other anti-inflammatory drugs, and could prove cheaper and capable of being administered orally.
The next stage will involve testing the compound on humans and a wider group of diseases.
The researchers say for certain conditions, like Muckle-Wells syndrome and asthma, such trials could take place as early as two to three years from now, as the drug had already undergone some human testing by Pfizer.
However, even if the trials prove the drug is safe and effective, they stress that it could be ten-15 years before it could be fully approved for use in humans for the treatment of more complex diseases like multiple sclerosis or Alzheimer's.
They also stress that while the molecule could become an effective treatment, it will not be a cure, though it is possible it could be effective in undoing some of the damage done by well progressed cases of certain diseases.
Prof O'Neill and his team now plan to form a company to further develop and test the compound.
MCC950 is also currently being tested on mice in the US for anti-ageing properties, as there is a growing school of thought that inflammation is responsible for much of the ageing process - a theory which has come to be known as "inflammaging".
The study, part funded by Science Foundation Ireland and the European Research Council, was carried out by a collaboration of six institutions, including the Universities of Queensland, Michigan, Massachusetts and Bonn. 


I am amazed at all the potentially good things that ketones and KD can do for many people�s health and it is all based on science from very serious institutions. 

Thursday, 30 August 2018

August 30, 2018

�ric Fombonne on Sloppy Autism Statistics

The reason I have a short list of talented researchers as my Dean�s List for this blog, is because of the generally low standard of much you can read about autism, even sometimes from governmental bodies like the CDC (Centers for Disease Control and Prevention) in the in the US and NICE (National Institute for Health and Care Excellence) in the UK.

I suppose these days it�s just called Fake News

My contribution is to highlight the researchers I think are worth paying attention to.
When it comes to the prevalence of autism, �ric Fombonne is a researcher who has more than his share of common sense.  Fombonne is a French psychiatrist and epidemiologist who also worked in the UK and Canada before moving to the US.
He recently gave the interview below, which highlights glaring errors/weaknesses in reports which are picked up by the mass media and put forward as facts. 

�� the CDC does not attempt to assess everybody in a population. Instead, it looks in the medical and special education records of each child in a certain region to determine whether a child meets criteria for its surveillance definition of autism. Children with no relevant notations of social problems in their records are assumed not to have autism.�
�In a study designed to validate these, researchers found that between 20 and 40 percent of children who met the CDC definition of autism did not actually have autism�
�Another issue is that of every 100 children the CDC researchers determine to have autism, only 80 have a reference to autism specifically in their medical or school records. So, one in five 8-year-old children the CDC decides has autism had never been picked up as autistic by any professional. At age 8, how is this likely?�
�I led a team that verified autism diagnoses prior to inclusion in a neuroimaging study. Trained researchers performed independent state-of-the-art assessments of over 200 children with an existing autism diagnosis. At least 30 percent of these children turned out to not have autism. It was mind-boggling.�
�In my clinics 25 years ago, I remember explaining to parents who had no clue about autism why their child qualified for the diagnosis. Things have now reversed. Nowadays, some parents and professionals push for that diagnosis and resist a �not autism� conclusion because it may come with less support.�

I did a while back do my own review of autism prevalence, based on two studies carried out by �ric Fombonne.
My conclusion then was that prevalence is about 1% and that you can split it roughly into thirds.
      One third has severe autism, which we can also call SDA (Strictly Defined Autism), or DSM3 autism.  DSM 3 autism is what medical professionals called autism 30 years ago, when it was rare. At that time it appears that many people with autism were only given a diagnosis of mental retardation (MR), which recently became intellectual disability (ID). The number of people diagnosed with MR/ID has fallen substantially as the number of people diagnosed with autism has increased, a clear case of substitution. 
      One third have true Asperger�s, by which I mean above average IQ, no speech delay in childhood, but with substantial issues getting on with typical people.

      The remaining third are people without MR/ID or a high IQ, may or may not have had a speech delay, but face significant challenges interacting with the wider world.  Surprisingly many people who today hold an Asperger�s diagnosis have below average IQ.

While someone with Down Syndrome (DS) will fit the diagnostic criteria of MR/ID and quite possibly autism, I think giving multiple diagnoses is unhelpful.
It is clear from the statistics that doctors stopped diagnosing people with MR/ID and instead switched many of these people to an autism diagnosis. 
Autism really should be seen as just a catch-all observational diagnosis, pending an accurate biological diagnosis, like Rett syndrome, Mitochondrial Disease etc.

The increase in prevalence of SDA
Due to the broadening of the definition of autism from DSM3 to DSM5 and, as Fombonne highlights, the very poor application of those ever moving diagnostic guidelines, we are left unable to draw any reliable conclusions about any increase in prevalence of SDA.
I certainly cannot prove it, but I believe the prevalence of SDA has increased substantially and most likely will continue to rise as society moves further from where it came from. This takes us back to the idea of the holobiont/hologenome.

The hologenome concept of evolution, considers a human as a community, or a holobiont - the host plus all of its symbiotic microbes. The collective genomes of the holobiont form a hologenome.

This becomes very relevant in human disease because in modern life humans have become separated from part of their evolutional holobiont (symbiotic microbes).  As a result all kinds on immune disease have become more prevalent.

To reduce the incidence of future SDA, steps could be taken now, just like public health tries to reduce the incidence of future heart disease.
You cannot stop random genetic mutations that lead to features diagnosed as autism, but you can influence many of the environmental factors and very likely you could take protective measures to increase the robustness of the mother and baby�s defensive mechanisms.

Thursday, 16 August 2018

August 16, 2018

Summer in the City

Typical children usually enjoy their long summer break and once they are teenagers they do not need much supervision; that is not the case with people with more severe autism. Most kids with this kind of autism are counting the days till they can go back to school. 
 In the US, many such people have an extended school year, which keeps them occupied, but this does not exist in most of the world.  The US actually has a very short standard school year, just 180 days; in Japan they are in school for 220 days a year.

This year Monty, now age 15 with ASD, has been much more energetic since he started taking a little scoop of Agmatine before breakfast, 11 months ago. He now completes a lot of physical activities, by anyone�s standards.
He enjoyed running at school last year and was good at it, so I started taking him to a running track in the holidays. It is 1.2km (0.75 miles) long and runs through a forest, so it is mostly out of the sun.
The first step was to decide not to run with him; one risk of having so much 1:1 attention is that you grow up not being able to cope without it.
People with autism do wander off, they get side-tracked, they can get into awkward situations with strangers, but at the same time you do want your child to develop independence. Monty had a yellow shirt on and by standing in the centre of the running circuit; I could see him much of the time through the trees. Since the circuit has a red surface and most people are running the same way around it, it would be hard to get lost.
Monty never got lost and just counted out loud the number of each lap, as I waited at the start point. We soon agreed that running four times round the track is what he would do.  After a pause and a shower it was off for swimming and he now does this quite seriously.
Monty�s school assistants come in the summer, and they also got into the exercise program.  Monty never mastered riding a bicycle till this summer, but after two months of practise in the mornings, today he made a 7km (4 mile) circuit round a lake.
Another day he made two laps (14km /8 miles) on rollerblades.
This level of activity might be nothing special for a typical teenager, but it is a big change for Monty.  It is also very hot - 33 Celsius/92 Fahrenheit, when he is out.
It is much easier to be accepted by typical teenagers when you have some skills they can relate to, even if big differences remain.
One morning Monty was out with his assistant where a basketball team were having their training run on another circuit. These were large 2m (6 foot 6 inches) tall giants, compared to Monty. What would they make of his intrusion into their training? Monty�s assistant explained to the basketball coach and then every time Monty completed a lap and shouted out the lap number the older boys cheered.  That is what I call inclusion and everybody was happy.
Exercise has numerous benefits and where we live most children are very active; overweight kids are a tiny minority. Some do take it to extremes; Monty�s friend from the Netherlands came to visit and told us that her 16 year old sister is cycling to Rome (1,600 km or 1,000 miles). As you might expect, they are both tall and slim.

Thursday, 9 August 2018

August 09, 2018

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

 Repurposing a German psoriasis treatment for the second time?
First for Multiple Sclerosis and second for some Autism?

Today�s post is about one anti-inflammatory aspect of ketones; part 4 in this series will look at Ketones and their effect on the NLRP3 inflammasome, which also relates to inflammation; but it would be too much for one post. If you have elevated levels of the inflammatory cytokine IL-1�, common in much autism and Alzheimer�s, part 4 of this series will be very relevant.
Today we just look at HCA2, which should be interesting for people with Multiple Sclerosis (MS), psoriasis and anyone with autism who responds to HCA2 activation.
In Germany a tailor-made solution already exists for a potential clinical trial to evaluate the effect of HCA2 activation; and even with low dose tablets.
Activating HCA2 should have profound neuroprotective effects; the ways to activate it include: -

        BHB (�-hydroxybutyrate) from the ketogenic diet

        Butyric acid produced by bacteria and fiber in your intestines (or by eating rancid butter, or Tibetan Yak butter tea)

        Butyrate supplements

        Niacin (Vitamin B3 /nicotinic acid)

        Dimethyl fumarate (an ultra-expensive US drug called Tecfidera, or an old German drug called Fumaderm) 

Activating HCA2 inside the gut can be used to reduce colonic inflammation; for this you would need your HCA2 activator to be in your colon, so the ketogenic diet would not help whereas fiber and the right probiotic bacteria would help.
For some autism and multiple sclerosis, you would think we just want to activate HCA2 receptors in the brain, but it may not be so simple.
There is no perfect solution to activate HCA2, mainly because it can cause flushing. 
The flushing effect is due to HCA2 activation of ERK 1/2 MAP kinase. Activation of MAP kinase in turn causes release of prostaglandin D2 (PGD2) from Langerhans cells in the skin and this causes flushing. 
The same PGD2 released in the brain is metabolized to another substance, 15-d-PGJ(2), which is a PPAR? agonist.  PPAR gamma has been covered elsewhere in this blog, because agonists should be beneficial in some autism, however using a tangeretin/nobiletin supplement, that is a mild PPAR? agonist, the positive effect lasts just a few days.
There are potent new drugs in development that may avoid flushing.

All the above options have other effects.
BHB from BHB supplements inevitably contain large amounts of Ca, K, Na or Mg, which will have their own effects.
Niacin causes flushing at higher doses.
Butyric acid has many potential beneficial effects, but too much may have some negative effects, at least in some people. It is an HDAC inhibitor, giving potential epigenetic effects.
Dimethyl fumarate (DMF) is likely the most potent current HCA2 agonist and can work wonders for severe psoriasis, some arthritis and some multiple sclerosis, but at these high doses does have some side effects.
Dimethyl fumarate (DMF) for psoriasis is not a cream, rather a coated tablet, the kind you are not supposed to cut in half. The adult dose can be 240mg three times a day, but as you can see in the photo at the start of this blog a 30mg tablet exists.  So, a practical low dose Dimethyl fumarate exists as a mild HCA2 agonist, but quite possibly it is more potent than niacin.
DMF as a drug is a bit pricey in Germany and exorbitantly expensive in the US. DMF as a chemical is very cheap. 

HCA2 and Neuroinflammation                       

Much is already known about how activating HCA2 can reduce neuroinflammation.
Putting out the fire, so to speak, is doubly important in much autism because inflammation makes chloride levels rise inside neurons (via increasing NKCC1 and reducing KCC2 expression). Elevated chloride levels make the neurotransmitter GABA work �in reverse� as excitatory; our current drug, bumetanide, to lower chloride levels lacks potency. If inflammation increases there comes a point when bumetanide no longer is able to maintain chloride at a low enough level; it then appears as �bumetanide has stopped working�. 

Nutritional or pharmacological activation of HCA (2) ameliorates neuroinflammation.

Neuroinflammation is a pathology common to many neurological diseases, including multiple sclerosis (MS) and stroke. However, therapeutic attempts to modulate neuroinflammation have proved difficult. Neuroinflammatory cells express HCA2, a receptor for the endogenous neuroprotective ketone body �-hydroxybutyrate (BHB) as well as for the drugs dimethyl fumarate (DMF) and nicotinic acid, which have established efficacy in the treatment of MS and experimental stroke, respectively. This review summarizes the evidence that HCA2 is involved in the therapeutic effects of DMF, nicotinic acid, and ketone bodies in reducing neuroinflammation. Furthermore, we discuss the mechanisms underlying the beneficial effects of HCA2 activation in neuroinflammatory diseases and the therapeutic potential of recently developed synthetic ligands of HCA2.


Figure 1. Potential anti-neuroinflammatory role of HCA2 as a target of monomethyl fumarate (MMF) and nicotinic acid (NA).  Based on the expression of HCA2 in neutrophils, monocytes, macrophages, and dendritic cells, several mechanisms underlying the immunomodulatory and anti-inflammatory effects of MMF and NA can be envisioned.  Both drugs may have systemic effects on monocytes, macrophages, or neutrophils outside the central nervous system (CNS) (1) that indirectly affect neuroinflammatory processes by altering the capacity of immune cells to enter the CNS or to promote neuroinflammation. There is also evidence that MMF and NA are able to directly inhibit neutrophil and possibly also monocyte infiltration through the blood�brain barrier (2) and they may also affect their inflammatory function within the CNS (3).  Finally, as antigen-presenting cells (APCs) that reactivate T cells in the perivascular space may also express HCA2, inhibition of APC function through HCA2 may contribute to the anti-neuroinflammatory effects of HCA2 agonists (4).

Figure 3. HCA2 mediates the neuroprotective effect of b-hydroxybutyrate (BHB).  On a normal diet, glucose (from the blood) serves as the main energy substrate of the brain (green arrows).  It is transported by GLUT1 over the blood�brain barrier (BBB) and metabolized. During fasting, adipocytes release large quantities of free fatty acids (FFAs) from stored triglycerides (TGs) (red arrows).  Alternatively, a high-fat, low-carbohydrate ketogenic diet leads to elevated FFA supply.  In the liver FFAs are metabolized to the ketone bodies acetoacetate (AcAc) and BHB.  In a negative feedback circuit, BHB binds to its receptor HCA2 on adipocytes and inhibits the release of TG. In the periphery, or after being transported into the central nervous system (CNS) by monocarboxylate transporter (MCT) 1 or 2, BHB also binds to HCA2 on neutrophils, microglia, and monocyte-derived cells and dampens neuroinflammation.  In addition, BHB is a substrate for mitochondrial energy production in neurons. 

BHB is not only a metabolic intermediate but also a signaling molecule that activates HCA2 and inhibits the G protein-coupled receptor GPR41 and histone deacetylase (HDAC) 1, 3, and 4 [94,95]. This led to the hypothesis that BHB induces neuroprotective effects through specific actions on receptors or enzymes. The IC50 values for inhibition of HDAC and GPR41 by BHB are higher than the EC50 for activation of HCA2 [94,95], suggesting HCA2 as the preferred target when BHB levels rise. 

The ketone body �-hydroxybutyrate (BHB) is an endogenous factor protecting against stroke and neurodegenerative diseases, but its mode of action is unclear. Here we show in a stroke model that the hydroxy-carboxylic acid receptor 2 (HCA2, GPR109A) is required for the neuroprotective effect of BHB and a ketogenic diet, as this effect is lost in Hca2(-/-) mice. We further demonstrate that nicotinic acid, a clinically used HCA2 agonist, reduces infarct size via a HCA2-mediated mechanism, and that noninflammatory Ly-6C(Lo) monocytes and/or macrophages infiltrating the ischemic brain also express HCA2. Using cell ablation and chimeric mice, we demonstrate that HCA2 on monocytes and/or macrophages is required for the protective effect of nicotinic acid. The activation of HCA2 induces a neuroprotective phenotype of monocytes and/or macrophages that depends on PGD2 production by COX1 and the haematopoietic PGD2 synthase. Our data suggest that HCA2 activation by dietary or pharmacological means instructs Ly-6C(Lo) monocytes and/or macrophages to deliver a neuroprotective signal to the brain.
DMF (Dimethyl fumarate) is in effect a prodrug, it is converted in the body by our friendly antioxidant glutathione (GSH) into MMF (monomethyl fumarate).
It is MMF that is the active substance.
DMF has long been used as a drug to treat severe psoriasis, an inflammatory condition of the skin. It was later found that in people psoriasis and MS, that when they took DMF for their skin problem their multiple sclerosis symptoms reduced.

DMF and Niacin for Multiple Sclerosis
Since we assume that DMF improves MS by activating HCA2, it would be logical to look at the effect of other activators of this niacin channel in MS.
You do not have to look far to find the so-called Klenner Protocol for MS, which treats it with large doses of niacin

We now have a hugely expensive FDA approved therapy for MS, based on the DMF used in Germany to treat psoriasis.
What about other HCA2 activators? Perhaps some in your kitchen?
Here is one long list: - 

One that caught my eye was Cinnamic Acid. Sure, it has less affinity for the receptor than some of the other substances, but it is an HCA2 activator.
When you eat cinnamon, the cinnamaldehyde present is converted into cinnamic acid by oxidation. In the liver, this cinnamic acid is �-oxidized to benzoate that exists as sodium benzoate.                                                                                           

Phenolic acids are found in abundance throughout the plant kingdom. Consumption of wine or other rich sources of phenolic acids, such as the �Mediterranean diet,� has been associated with a lower risk of cardiovascular disease. The underlying mechanism(s), however, has remained unclear. Here, we show that many phenolic acids, including those from the hydroxybenzoic and hydroxycinnamic acid classes, can bind and activate GPR109A (HM74a/PUMA-G), the receptor for the antidyslipidemic agent nicotinic acid. In keeping with this activity, treatment with a number of phenolic acids, including cinnamic acid, reduces lipolysis in cultured human adipocytes and in fat pats isolated from wild-type mice but not from mice deficient of GPR109A. Oral administration of cinnamic acid significantly reduces plasma levels of FFA in the wild type but not in mice deficient of GPR109A. Activation of GPR109A by phenolic acids may thus contribute to a cardiovascular benefit of these plant-derived products. 

Our data clearly show that many of the phenolic acids could act as ligands of the nicotinic acid receptor GPR109A, and activation of GPR109A by the phenolic compounds leads to a reduction of adipocyte lipolysis. Activation of GPR109A may lead to differential downstream effects on lipolysis and flushing response. For example, a number of GPR109A pyrazole agonists were found capable of inhibiting lipolysis but failed to elicit a flushing response and can antagonize nicotinic-acid-mediated flushing response (22). It is unclear if any of the phenolic acids from plant products, such as wine, could function as pyrazole agonist of GPR109A, thus leading to an escape of a flushing res

Phenolic acids are highly present in the Mediteranean Diet and so you might wonder if this diet is protective.  Apparently it is.

Mediterranean diet (MD) adherence and risk of multiple sclerosis: a case-control study.


Our study suggests that a high quality diet assessed by MD may decrease the risk of MS.

So how about cinnamon as a home remedy for MS? Well is seems to help mice with MS. 

Although the central nervous system (CNS) is separated from the immune system by blood-brain barrier and traditionally considered �immune privileged�, our immune cells are capable of targeting the brain, leading to the development of CNS autoimmune disorders. Multiple sclerosis (MS) is one such autoimmune disorder of the CNS in which myelin components are particularly targeted by the immune system resulting in demyelination of axons and associated debilitating symptoms [13]. In spite of intense investigations, no effective therapy is available for this disease. Therefore, a safe and effective therapeutic option is necessary for MS.
Fortunately, we have been endowed with enormous natural remedies to take care our health issues. For example, cinnamon, the brown bark of cinnamon tree, that has already been being used for centuries throughout the world as spice or flavouring agent. Furthermore, medieval physicians used cinnamon for medical purposes to treat a variety of disorders including arthritis, coughing, hoarseness, sore throats, etc. Recent studies are indicating that this natural product may be helpful for MS [46]. Although the etiology of MS is poorly understood, it is becoming clear that widespread inflammation, loss of regulatory T cells (Tregs), hyperactivity of autoimmune Th1 and Th17 cells, breakdown of blood-brain barrier (BBB) and blood-spinal cord barrier (BSB), and loss of neuroprotective molecules in the CNS are critical for the manifestation of demyelinating pathology in MS [13]. Interestingly, cinnamon treatment is capable of modifying these pathological features in mice with experimental allergic encephalomyelitis (EAE), an animal model of MS [4,6].


        DMF may act in neurodegeneration and inflammation by activating the Nrf2 pathway. 
        DMF and MMF downregulates the immune response through HCA2/GPR109A pathway. 
        Nrf2 and HCA2/GPR109A pathways activation may explain DMF�s efficacy and safety profile.  

Conclusion: Although the DMF/MMF mechanism of action remains unclear, evidence suggests that the activation of HCA2/GPR109A pathway downregulates the immune response and may activate anti-inflammatory response in the intestinal mucosa, possibly leading to reduction in CNS tissue damage in MS patients.

The mechanisms of action of MMF and DMF are not well understood, but a growing body of evidence has demonstrated that DMF may act on both the neurodegenerative and inflammatory response of MS patients. The majority of the data related to the mechanism of action of DMF/MMF demonstrates the association of the compounds with the activation of the nuclear factor-(erythroid-derived 2) related factor 2 (Nrf2) pathway. Nrf2 activation leads to a type II antioxidant response, reducing both inflammatory responses and oxidative stress 11, which play a major role in demyelination and neurodegeneration in MS.   
In addition to the Nrf-2 signaling pathway, recent observations demonstrated that MMF/DMF could also downregulate the immune response through a on-Nrf2 related pathway. MMF has been shown to be an agonist of the hydroxycarboxylic acid receptor 2 (HCA2) signaling pathway, also known as niacin receptor 1 or nicotinic acid receptor GPR109A.12-14 Thus, it appears that DMF could also activate HCA2/GPR109A in addition to its effects on the Nrf2 pathway (unpublished data, Biogen). In this communication, we discuss DMF/MMF-induced HCA2/GPR109A pathway activation and its implications in the immune response and treatment of MS.  

Moreover, Parodi and colleagues described a novel HCA2/GPR109A signaling pathway modulating microglial activation in an in vitro study .13 MMF binding to HCA2/GPR109A led to subsequent activation of the G1-type G protein signaling cascade by a possible release of the ?? subunit of G-protein. The increase of Ca2+ induced the activation of AMP-activated protein kinase (AMPK) by calcium/modulin�dependent protein kinase 2 (CaMKK2). In addition, the authors provided evidence that AMPK activation led to an increase in NAD+ generation through phospho-AMPK (pAMPK) and finally activation of SIRT1 (sirtuin 1), which resulted in further inhibition of NF-kB signaling. NF-kB inhibition suppresses pro-inflammatory cytokines and reduces the migration of immune cells into the CNS in the EAE model. In addition, cultured microglial cells also showed reduced pro-inflammatory responses contributing to regulation of synaptic activity.13 All these previous data confirm that both DMF and/or MMF are effective in reducing the severity of EAE.  

A growing body of evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in autoimmune diseases, such as MS and its experimental models.33 Mucosal tolerance studies have shown that activation of tolerogenic intestinal immune cells can reduce the inflammatory response of autoimmune disease in the CNS.34 The oral administration of myelin basic protein (MBP) significantly reduced the severity of EAE34, at the same time activating and increasing the frequency of TGF�-producing regulatory T-cells in the gut.35 HCA2/GPR109A is a receptor for butyrate and mediates some of beneficial effects of short-chain fatty acids produced by the gut microbiota.36 Ongoing microbiome studies have highlighted the importance of commensal bacteria both in induction and suppression of autoimmune diseases and this is being actively studied as a potential target for the treatment of immune-mediated maladies.37 A previous study demonstrated that administration of short-chain fatty acids to mice with EAE ameliorated symptomatic disease and reduced axonal damage through activation of regulatory T cells (T-reg) in intestinal mucosa.33 Other studies demonstrated that G protein-coupled receptors such as HCA2/GPR109A are potentially involved in increased extrathymic differentiation of T-reg cells. The activation of HCA2/GPR109A by butyrate metabolites from commensal microbiota increased the generation of colonic Tregs.38 Also, HCA2/GPR109A signaling promoted anti-inflammatory properties in colonic macrophages and dendritic cells and enabled them to induce differentiation of T-reg cells, which suppress colonic inflammation and carcinogenesis.39 The same study demonstrated that the activation of HCAR2 receptors is crucial to generate T-regs since colonic DCs and macrophages from Niacr1-/- mice are defective in inducing differentiation of these cell population.39     In addition to the generation of T-reg cells, the activation of HCA2/GPR109A in epithelial cells in the small intestine may induce the production of PGE2,15 which contributes to the anti-inflammatory response. PGE2 suppresses the production of proinflammatory cytokines and enhances the synthesis of anti-inflammatory cytokines.40 Therefore, PGE2 is not only a proinflammatory molecule but also a modulator of immune responses40. We hypothesize that DMF/MMF may amplify the anti-inflammatory response by binding to HCA2/GPR109A in gut cells (dendritic and epithelial), inducing the production of PGE2. Since DMF is metabolized in the gut, further studies are necessary to demonstrate whether the DMF/MMF stimulation of anti-inflammatory response in the gut may also contribute to the reduction of the tissue damage in the CNS of MS patients. 

The complete mechanism of action of DMF in the treatment of MS remains to be elucidated. Recent observations highlight the importance of the activation of HCA2/GPR109A pathway by DMF/MMF in the downregulation of the immune response. Binding of DMF or MMF to HCA2/GPR109A on dendritic cells inhibits the production of pro-inflammatory cytokines in vitro and in EAE. There is a possibility that anti-inflammatory responses in intestinal mucosa are activated by DMF or MMF binding to HCA2/GPR109A, which is expressed on the surfaces of both immune cells and gut epithelial cells. Both forms can activate HCA2/GPR109A to differing extents, and therefore this possibility requires more study before an HCA2/GPR109A -mediated GI role for a specific form of fumarate can be determined. Given the extension of the gastrointestinal tract and the amount of cells expressing HCA2/GPR109A in intestinal mucosa, the immunomodulatory response in this compartment is relevant and may contribute to the reduction of tissue damage of CNS in patients with MS

MS (Multiple Sclerosis) Treatment

Most MS is the relapsing remitting kind.
Acute episodes are generally treated with steroids, which are inexpensive.

Some people�s autism is episodic; there is a base level and then there are periods when it becomes much more severe.
While there are no cures for MS there are disease modifying treatments that aim to reduces the frequency of the acute periods and reduce the damage that they cause. Since MS is essentially an auto-immune conditions, these treatments are all based on modifiying the immune system. They can have the side effect of overly reducing the immune response and then not fighting off a dangerous virus.

        Interferons are used particularly to reduce the level of the proinflammatory cytokine IL-1beta.
        Monoclonal antibodies are used to strengthen the blood brain barrier (and leaky gut barrier in Crohn�s) and so reduce the ability of inflammatory cytokines to enter the brain.
        Classical immune-modulators include glatiramer acetate. Administration of glatiramer acetate shifts the population of T cells from proinflammatory Th1 T-cells to regulatory Th2 T-cells that suppress the inflammatory response. Dimethyl Fumarate was recently approved in the US and Europe as an MS drug in this category
In terms of potency and value, the UK�s review body was pretty upbeat about Dimethyl Fumarate.
All the disease modifying treatments for MS are hugely expensive, which must limit their use. 

Interestingly, estrogen receptor beta (ER�) is very relevant to MS, as we have seen it is to autism and also SATB2.  The most potent accessible agonist of ER� is estrogen/estradiol, but unfortunately it also affects ERa. The ideal solution would be a brain specific selective agonist of ER�. This does actually exist; it is called DHED, but it has not been commercialized. 
I think DHED would be helpful in MS, SATB2 and much idiopathic autism.
It is not surprising that MS mainly affects females and not surprisingly it gets worse post menopause. You would think someone would make the connection and treat this (with an ER� agonist).

PDE4 inhibition

Another very logical therapy for MS is to use a PDE4 inhibitor to improve remyelination, this happens via activating PKA. PDE4 inhibition will also be broadly anti-inflammatory and this is why it is effective in asthma and COPD.

The good news is that the Japanese have been using a PDE4 inhibitor (Ibudilast)  for decades to treat asthma. So its safety profile is well known.

Not surprisingly under the new name MN-166, Ibudilast is showing promise.

               A Phase II Trial of Ibudilast in Progressive Multiple Sclerosis

In Western world Roflumilast (Daxas) is the widely used PDE4 inhibitor. It looks to me that the Japanese created a better drug - more selective and fewer side effects. In the long term MS trial of Ibudilast it was found that while GI side effects did occur at higher doses, they settled in 2-4 days; so no bid deal. Daxas does cause nausea, Ibudilast seems not to.

PDE4 inhibition is a very logical therapy choice for some autism and SATB2.

Relevance of MS to Autism
There are features of MS that are relevant to some autism, just like some MS features relate to Crohn�s. So, there is merit in understanding the current knowledge of MS treatment.
In terms of personalized medicine, we can see this broadens the potential toolkit to treat aberrant immune responses.
You can also see how someone with MS might benefit from reading autism science. They really should be making sure they produce enough butyric acid to   maintain tight epithelial barriers.  Butyrate not only causes a tightening of the intestinal epithelial barrier, but also the blood brain barrier. So if a leaky BBB is a feature of MS, then you want either to ferment butyric acid in your colon or a take sodium butyrate orally.

Budget MS Therapy
You can see that in a developing country, with no universal healthcare provision, a person could self-treat their own MS on a very modest budget. Tighten up the blood brain barrier, activate HCA2 and activate ER�
In Chinese medicine there are treatments for postmenopausal osteoporosis, not surprisingly they are herbal ER� agonists. The one recommended in a recent paper based on potency and safety was something called EXD (Er-Xian Decoction), more potent than Icariin as favoured by our reader Aspie1983.
Among the EXD, EBH, and ICA, EXD was found to have superior efficacy and safety profile.

Consuming soy will also activate ER�, but you would need to eat it like a Japanese (lots of it).
Butter tea, as found in Tibet and nearby, would be rich in butyric acid and so should improve a leaky blood brain barrier.
I drank this very tea, made with Yak butter, decades ago and still recall the taste/smell.

I did stumble across one Australian psoriasis sufferer, who was self-treating with cheap non-medical DMF bought overseas. He seemed very happy with the result. If he develops MS he might just need to increase the dose.

Which HCA2 activator for some autism?
Well if you respond to BHB from ketone supplements it looks to me that HCA2 activation likely is involved, at least to some extent, particularly if your level of the cytokine IL-1� is normal. (If IL-1� is elevated, wait for part 4 of this series on ketones and autism.)
The simplest strategy would be to just up the BHB treatment.  The other options might include: -

        Niacin, which at high doses is used by some people with schizoprenia

        Acipimox, a niacin derivative drug to lower cholesterol. 

        DMF (Dimethyl fumarate) 
I have written about cinnamon before on this blog and I like the things it does, but if I was making a clinical trial I would go straight for the one that really should work, which is DMF. 
At high doses many people get side effects from DMF, but they usually fade over time.
Since BHB is not such a potent HCA2 activator, I doubt a large dose of DMF would be needed.

DMF as a drug        
Most readers of this blog are in North American, home of expensive drugs. Today you may be shocked at just how much is charged for DMF in the US.
In the form of Fumaderm, it available for free in some European countries.

Very recently a Spanish company has started to market DMF as a drug called Skilarence, so hopefully the price will eventually fall. 

DMF History and Cost
Dimethyl fumarate (DMF) is actually an inexpensive bulk chemical that is widely available.
Originally it was used in Germany to treat psoriasis.  Assuming a defect in the citrate cycle as the cause of his own psoriasis, Walter Schweckendiek, a German chemist, treated himself with large doses of succinic acid. When this first attempt was ineffective, he turned to the next metabolite in the cycle, fumaric acid, and experienced a �cure� from his disease, as he reported in 1959.
To improve the gastrointestinal tolerance of fumaric acid he later used esters of fumaric acid. Although Schweckendiek published his own case report in a well-known German medical journal, his discovery first remained largely unrecognized by the academic medical community and spread mainly among alternative practitioners. This is how Hans-Peter Strobel, a Swiss village pharmacist, learned about the alleged efficacy of fumaric acid esters in 1982. 
One year later he founded the company Fumapharm AG, which further investigated fumaric acid esters leading to a Phase III study against psoriasis headed by Peter Altmeyer in 1994. This study earned fumaric acid esters the approval for treatment of psoriasis in Germany. Fumaderm, a preparation comprising mainly DMF, was on the German market for several years when neurologists in Germany recognized its efficacy against MS. In 2006 Biogen Idec bought Fumapharm and further developed DMF for the treatment of MS.
In the US Biogen sell Dimethyl Fumarate as Tecfidera, a single 240 mg tablet costs $120.
In Germany, the local company, also owned by Biogen of the US, still sells it as a treatment for psoriasis; a single tablet of Fumaderm 120mg for $4.
In China you can buy 100g for $6.
It looks like China is the place to be if you have MS. The Chinese just buys a bag of empty enteric capsules, measures out his DMF with his $10 micro scales.
Enteric capsules dissolve in the lower intestine where it is alkaline. Some drugs cannot survive in acidity earlier on in the digestive process.

His cost of 240g twice a day for a year

730 enteric capsules           $20

175g of DMF                     $10

Microscales                        $10

            Total                                 $40

His US counterpart (or his insurer) would pay $87,600 at the full price.
A German pharmacy would charge $5,840. The UK NHS will for sure have a discount on the German price and now they have switched to the Spanish version, Skilarence.
I think Walter Schweckendiek, the pioneering German chemist, who did all the original self-experimentation, would go for the �Chinese option� and treat himself for the annual cost of 3 Wiener Schnitzels.

HCA2/Gpr109a and colonic inflammation
We know that some people with autism have terrible GI inflammation; by activation HCA2 (also called Gpr109a) some people with colon inflammation may get some relief.
In the study below, they refer to the HCA2 activator butyric acid, but any HCA2 activator that end up in the colon should have the same effect.  To produce butyric acid, eat fiber and a butyric acid producing bacteria, as covered in earlier post. 

         Commensal metabolite butyrate and niacin induce IL-18 in colon via Gpr109a
         Butyrate and niacin induce IL-10 and Aldh1a in APCs in a Gpr109a-dependent manner
         Niacr1 -/- mice exhibit increased risk for colitis and colon cancer 
         Gpr109a signaling protects colon health during deficiency of gut bacteria and dietary fiber

It also is proposed that activating HCA2 in the gut has a positive effect in the brain for people with MS.  

HCA2 activation looks very interesting and I would love to know if this is a mechanism by which BHB/C8 supplements are improving autism for some readers of this blog.
It looks highly plausible. In one of the papers it was suggested that this is more likely than HDAC inhibition, because the effect of the ketone BHB on HCA2 is much larger than on HDAC 1, 3 or 4.
I am also interested that PPAR gamma is also activated via HCA2-PGD2 and then its metabolite 15d-PGJ, because the PPAR? agonists tangeretin/nobiletin in the supplement Sytrinol gives an improvement in autism for some people but for most, like my son, it only last 3 or 4 days.  The more potent PPAR? agonists used to treat Type 2 diabetes are reported in studies to improve some autism.
Cinnamon also seemed to have an effect in my trial, but there are several different substances in cinnamon that might be helping. I had not considered Cinnamic acid until this post.
People do use niacin for autism but based on the same level of science that made some people think that Multiple Sclerosis was caused by vitamin B3 deficiency (it is not).
The MS research raises the possibility that inflammation in the intestinal mucosa may be driving inflammation in the brain and that the effectiveness of HCA2 activation is in part driven by what is happening to the HCA2 receptors in your intestines rather than those in your brain.
I really do think some researcher should trial those little 30mg Fumaderm starter pills on people with autism. They use these lower dose pills before building up to the full psoriasis dose. The MS dose in the US is very much higher, 240mg twice a day.