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Showing posts with label parasite. Show all posts
Showing posts with label parasite. Show all posts

Thursday, 17 August 2017

Viruses, Bacteria, Fungi, Parasites and Altered Gene Expression, Relevant to Autism






Today’s post started life as a review of how some viruses affect gene expression and may help cause, or just trigger flare-ups in, some neurological disorders ranging from autism to MS (multiple sclerosis). 
Some people with autism are treated with anti-viral drugs and, anecdotally, some do respond well.  This is not yet an area with hard facts and definitive clinical trials.  
It is actually better to first take a few steps back and consider how all microorganisms can play a role in human health by modifying the gene expression of the host (which is you).  There are four broad categories of microorganism.
Each type of microorganism can be countered by a matching category of pharmaceutical.

·        Antibacterials/antibiotics for bacteria

·        Antifungals to kill or prevent further growth of fungi

·        Antivirals to minimize (but often not eradicate) viruses

·        Antiparasitics to kill parasites  (protists)

All of the above categories of microorganism can affect the expression of multiple genes. By either up or down-regulating important genes at critical times during development, long lasting effects can be created, or there may be just transient effects.
Changes in gene expression likely play a role in many neurological conditions and in particular in what I call “flare-ups”, for example in autism, PANS, PANDAS and indeed schizophrenia.
Not all changes in gene expression are bad. The TSO parasites that do seem to help some people’s autism, by down regulating their immune response, very likely are modifying the host’s gene expression, which then reduces their immune response. This is the mechanism developed by the parasite to protect itself from the host (you) and ensure it is not eradicated.
Steroids affect the expression of multiple genes. When a bacteria of virus triggers PANDAS/PANS the positive effect of steroid therapy may well be by “resetting” the expression of certain important genes.  Here again, even though PANDAS/PANS is now treated clinically in the US, much remains unknown.
For those interested, earlier this summer revised treatment guidelines were published for PANDAS/PANS.

In "
Part I–Psychiatric and Behavioral Interventions," Margo Thienemann, MD, Stanford University and coauthors present consensus guidelines for treating the psychiatric and behavioral symptoms of children with PANS/PANDAS. Symptom improvement is aimed at decreasing suffering, improving functioning, and making it easier for the children to adhere to therapeutic interventions.

In "
Part II–Use of Immunomodulatory Therapies," Jennifer Frankovich, MD, and coauthors provide recommendations to help guide the use of therapies targeting the neuroinflammation and post-infectious autoimmunity that are common in PANS-PANDAS.

In “
Part III–Treatment and Prevention of Infections," Michael Cooperstock, MD, MPH, University of Missouri School of Medicine (Columbia) and coauthors representing the PANS PANDAS Consortium, present a consensus guideline for managing the infection components of these neuropsychiatric conditions.

There is research on what virus/bacteria affects which specific gene, but this area of science is in its infancy.
MS (Multiple Sclerosis) a condition that features faulty remyelination, is likely a much simpler condition than autism and yet nobody knows for sure what causes it. It has been suggested that a virus may be the trigger of at least some types of MS, but researchers are decades away from proving anything. So when it comes to microorganisms and autism, it is mainly a case of speculation and the odd N=1 case study. 

Viral triggers of multiple sclerosis 


The relationship between infections and autoimmune diseases is complex and the mechanisms by which infectious pathogens could trigger MS are likely dynamic, i.e., they might change over time and not be mutually exclusive. Epidemiological observations indicate that viral infections could contribute to MS development not only as triggers of disease exacerbations but also as etiological agents, i.e., long before the disease becomes clinically apparent. The two- to three-folds increased risk of developing MS among individuals with history of IM compared with subjects who acquired EBV without symptoms, the almost universal seropositivity for EBV in adults and children with MS, and the steep and monotonic increase in MS risk with increasing titers of antibodies to EBV in apparently healthy adults could suggest that EBV infection is causally linked to MS development. The mechanisms responsible for this association are far from understood. Moreover, the incidence of IM in Western countries (≥ 5%)  exceeds the prevalence of MS in comparable populations (0.1%) by far (more than 50-fold) suggesting that yet unidentified genetic and/or additional environmental factors determine whether symptomatic EBV infection indeed predisposes to MS.

Although one particular MS-causing agent might still be discovered, current data suggest that multiple infections along with noninfectious environmental factors trigger the development of MS. These factors are likely ubiquitous, i.e., highly prevalent in the general population, and they require a permissive genetic background that predisposes for MS development. Future studies investigating infectious pathogens in a complex and heterogenous disease such as MS will benefit from careful and detailed clinical, pathological, and neuroimaging-based patient characterizations and from reproducibility in different study populations. In addition, novel humanized animal models of autoimmune diseases that are simultaneously permissive for viral pathogens which usually infect only humans  should allow investigation of specific aspects of host–pathogen interactions during autoimmune CNS inflammation in vivo. The integration of these data might eventually allow us to better define the role of viruses in the etiology and pathogenesis of MS and how virus–host interactions could be targeted for MS therapy.  

The ubiquitous human herpesvirus 6 may play a critical role in impeding the brain's ability to repair itself in diseases like multiple sclerosis. These findings may help explain the differences in severity in symptoms that many people with the disease experience
What is still not fully understood is the relationship between the extent of the viral infection in the brain and the severity of diseases like multiple sclerosis and other demyelinating diseases such as leukodystrophies and Vanishing White Matter disease. For example, do the number of infected cells need to reach a certain threshold before OPC function is impeded? Are individuals who have congenital HHV6 more vulnerable to severe forms of these diseases?
"More research is needed to understand by which mechanisms the virus impedes the function of OPCs and what impact this has on the progression of these diseases," said Mayer-Proschel. "But it is clear that HHV6, while not necessarily the cause of demyelinating diseases, is limiting the ability of the brain to repair damage to myelin thereby potentially accelerating the progression of these diseases."  

Mainstream and “Alternative” Research  
Not all published research fits with the current mainstream scientific consensus. The mainstream is clearly moving towards the realization that all kinds of things can affect gene expression. One currently fashionable area is the gut microbiota, as in this article:-

Some researchers develop hypotheses that go much further, like this one regarding autism’s elder brother, schizophrenia.


Many genes have been implicated in schizophrenia as have viral prenatal or adult infections and toxoplasmosis or Lyme disease. Several autoantigens also target key pathology-related proteins. These factors are interrelated. Susceptibility genes encode for proteins homologous to those of the pathogens while the autoantigens are homologous to pathogens' proteins, suggesting that the risk-promoting effects of genes and risk factors are conditional upon each other, and dependent upon protein matching between pathogen and susceptibility gene products. Pathogens' proteins may act as dummy ligands, decoy receptors, or via interactome interference. Many such proteins are immunogenic suggesting that antibody mediated knockdown of multiple schizophrenia gene products could contribute to the disease, explaining the immune activation in the brain and lymphocytes in schizophrenia, and the preponderance of immune-related gene variants in the schizophrenia genome. Schizophrenia may thus be a “pathogenetic” autoimmune disorder, caused by pathogens, genes, and the immune system acting together, and perhaps preventable by pathogen elimination, or curable by the removal of culpable antibodies and antigens.

And this one by the same author:-

Herpes simplex virus 1 (HSV-1) can promote beta-amyloid deposition and tau phosphorylation, demyelination or cognitive deficits relevant to Alzheimer's disease or multiple sclerosis and to many neuropsychiatric disorders with which it has been implicated. A seroprevalence much higher than disease incidence has called into question any primary causal role. However, as also the case with risk-promoting polymorphisms (also present in control populations), any causal effects are likely to be conditional. During its life cycle, the virus binds to many proteins and modifies the expression of multiple genes creating a host/pathogen interactome involving 1347 host genes. This data set is heavily enriched in the susceptibility genes for multiple sclerosis (P = 1.3E-99) > Alzheimer's disease > schizophrenia > Parkinsonism > depression > bipolar disorder > childhood obesity > chronic fatigue > autism > and anorexia (P = 0.047) but not attention deficit hyperactivity disorder, a relationship maintained for genome-wide association study data sets in multiple sclerosis and Alzheimer's disease. Overlapping susceptibility gene/interactome data sets disrupt signalling networks relevant to each disease, suggesting that disease susceptibility genes may filter the attentions of the pathogen towards particular pathways and pathologies. In this way, the same pathogen could contribute to multiple diseases in a gene-dependent manner and condition the risk-promoting effects of the genes whose function it disrupts.

Back to Autism
As we have seen previously in this blog, autism is usually polygenic, meaning very many different genes are affected. This does not mean that anything is necessarily defective in those genes, it just means those genes are either over or under-expressed, this means you end up with either too much, or too little, of whatever that gene makes.
So for a polygenic condition, where in one person hundreds of your 22,000 individual genes are likely over or under-expressed, we really do not want anything to come along and further miss-express critical genes.
Many genes are inter-related and so miss-expression of one can trigger a wave of further effects. This can be either good or bad.
The science is still in its infancy, so it will be many decades before it is translated into medicine, but we can certainly already say what may be happening.
The interactome is a relatively new word to describe the whole set of molecular interactions in a particular cell.
 For example, the well-known bacteria H.pylori that can cause stomach ulcers:- 

Over 1,200 interactions were identified between H. pylori proteins, connecting 46.6% of the proteome.

Just this one common bacterium affects half of the entire set of proteins expressed by a genome (the so called proteome).
So we should not be surprised if some bacteria or viruses have a bad, or indeed good, effect on autism.
This also bring us back to the idea of the holobiont and hologenome, which was introduced in an earlier post. The idea is that what really matters in human health is not just your genome, but the totality of what surrounds you, so that means everything living in you, on you and around you. That includes bugs, bacteria and also those of your pet dog.
All of these factors influence how your genes are expressed. During evolution your body has got used to things and if you make rapid changes, you may indeed upset the balance. So while chlorinating water may have an overall good effect, by killing all those bacteria your body had been expecting, there may be some negative effects. Humans evolved living close to animals, be it dogs or farm animals. We saw earlier that pregnant mothers who live with pets produce children with a lower incidence of asthma.
We also reviewed the hygiene hypothesis, which basically says that a bit of dirt is good for you.
So this post, rather than narrowing things down, really broadens them out.  Everything affects everything.  If you rock the evolutionary boat, don’t be surprised if strange things happen.
Taking Somali refugees to live in Sweden increased their incidence of autism. Is that really a surprise? Recall the Somali autism clusters in Sweden and San Diego.
Apparently, the Amish in the US have a low prevalence of autism. Is that really a surprise?  One reader recently suggested sending autistic people to live with the Amish, as a therapy. The possibly effective therapy would have been to send the parents to live with the Amish for a couple of years before the child was born.
So perhaps we should consider much autism, and indeed conditions like asthma, as collateral damage from modern living?  Life expectancy has risen, infant mortality has been greatly reduced, but the downside is that we now have much more autoimmune disease and that includes autism.

Autism and Microorganisms
Now back to autism and the four categories of microorganism.
Can parasites cause autism? Actually we know they can; for example cerebral malaria can result in it. But how often is this case? Probably very rarely.
Can fungi cause autism? Perhaps, but we know from many examples (including in the comments on this blog) that some fungi can make autism worse.  Is the fungus candida albicans growing in the intestines really an issue in most autism? I seriously doubt it, but oral thrush/candidiasis caused by inhaled steroids does seem to make autism worse and is reversible by removing the fungus. The effect seems more likely to be from the candida than the steroid, since inhaled steroids only mildly enter the bloodstream.
Can bacteria cause autism? Well streptococcus bacteria can cause OCD and cognitive impairment (PANDAS).
Can a virus cause autism? Antonio Persico, one of the more serious autism researchers, has suggested that some autism may be caused by polyomaviruses transmitted at conception from father to mother.
https://spectrumnews.org/news/could-a-virus-cause-autism/

Can the rubella virus cause autism? Some serious people do see a possibility, even in people who have been vaccinated.

These both remain controversial hypotheses; but can viruses cause flare ups in autism, later in life? This is also controversial, but I think quite plausible.  It all depends which genes the virus causes to get miss-expressed.
Enough is known to say that odd changes in autism may potentially be triggered by the appearance of specific types of microorganism, but quite possibly most microorganisms have little, or no, negative effect in most people. So it is not a case of all viruses/bacteria will make autism worse, but it is likely true that some may have the potential to do so.
In trying to figure out possible causes of autism flare-ups, due consideration should be given to microorganisms.  This is another case of personalized medicine, with all its potential pitfalls.
The big risk is potentially becoming obsessed with non-existing bacteria, viruses, fungi or parasites.  


Back to Antivirals and Autism 
Finally we come back to where the original idea for this post came from; is there any basis of the use of antiviral drugs to treat autism?
DAN-type doctors do prescribe the antiviral drugs Valtrex, Famvir or Acyclovir.


Antiviral drugs do not destroy their target virus they just inhibit its development.
Most of the antiviral drugs now available are designed to help deal with HIV, herpes viruses, the hepatitis B and C viruses, and influenza A and B viruses.
You identify a virus by looking for antibodies to that specific virus in the blood. You can test for antibodies that suggest if the infection is new and active, called IgM antibodies and you can test for antibodies that show the infection occurred sometime in the past, called IgG antibodies.
You would need to know which virus to test for, the common ones are:-

HSV 1:  Herpes Simplex Virus 1 causes canker sores in the mouth

HSV 2: Herpes Simplex Virus 2 causes genital herpes.

HHV 6: Human Herpes Virus 6 is commonly known as Roseola virus

EBV: Epstein-Barr Virus, causes the illness known as infectious mononucleosis

Measles

Rubella  


“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.” 

Conclusion: Rate of contact with HSV1 and HSV2 assessed by the mean of detection of specific antibodies was similar between children with ASD and healthy controls.

Conclusion: Levels and seropositivity rate of antibodies to HHV-6 and HHV-8 do not differ between children with ASD and controls.
CONCLUSION: Titre and seropositivity rate of antibodies to CMV and EBV are similar between children with ASD and healthy controls.


Valtrex 
Valtrex seems to be the antiviral most commonly prescribed in autism.  This is an off-label use, meaning Valtrex is not approved to treat autism.  Valtrex is active against most species in the herpesvirus family. In descending order of activity:

So we might assume the people with autism who respond to Valtrex might have one of the above, or similar, viruses. Unless Valtrex has some other modes of action, unrelated to being an anti-viral, which remains a possibility. 

Mitochondrial Disease and Viral Infections
Since this post is already full of speculation, I will add some more. Some people say that their child’s mitochondrial disease was preceded by a viral infection, so how likely is it that a virus can trigger mitochondrial disease and then autism?  Again, this is not something anyone can prove, one way or the other, but it does look like your mitochondria are particularly vulnerable to viruses.
The virus will exploit the mitochondria to further its own development, perhaps in doing so, in some people with a pre-disposition, this triggers a process to chronic mitochondrial dysfunction.  Read the papers below for more on this subject.


Highlights


Mitochondrial dynamics influences mitochondrial and cellular functions.
Mitochondrial dynamics is affected during viral infections.
Viruses exploit mitochondrial dynamics and mitophagy to benefit infectious process.
Virus-altered mitochondrial dynamics determines the outcome of infection.
Disruption of mitochondrial dynamics promotes viral pathogenesis.

If a virus can trigger mitochondrial disease, as we have seen a vaccination can, is there any possible merit in using antivirals years later?
Is there merit treating regressive autism, which is likely to be mitochondrial disease, immediately with antiviral drugs?
Is there merit treating autism flare-ups, that do not respond to PANDAS/PANS therapies, with antiviral drugs?
Is there merit treating MS (multiple sclerosis) immediately on diagnosis with antiviral drugs? Would MS flare-ups respond to antivirals?

My take
If I was to develop MS tomorrow, given there is currently no cure, I think I might want to try an antiviral, just in case it might actually do some good.
My son with classic autism did have a PANDAS-like regression last year, with sudden onset OCD and strange verbalizations. It all went away after a couple of weeks, having been treated as a PANDAS flare-up, as documented in an old post on this blog. If after a viral infection he developed a sudden onset regression I would certainly reread this post.
Readers of this blog with a clear case of mitochondrial disease might want to check for the commonly implicated viruses, since if one was never suppressed this might be something to consider.
So do antivirals have a place in treating autism?  There is no hard evidence to support their use, but I would not at all be surprised if a minority do genuinely benefit. I think the most likely group might be those who have a sudden regression from near typical. As with PANDAS/PANS, the sooner the treatment commences, the better the likely outcome. 
Could antivirals help control flare-ups that can occur in those already with autism? They could well help; ideally you would confirm the presence of the virus first.   

Conclusion
I recently watched an expert clinician talking about irritable bowel syndrome (IBS); he was very open about his opinion that science likely only understands about 30% of the disorder. When it comes to autism I think science may be only at the 10% mark. As a result you have to be very careful about saying anything definitive.
We know that very many things contribute to the prevalence of autism.  It looks more than likely that viruses, bacteria, fungi and parasites may, on occasion, play a role in some people’s autism.
But, just like we know that in some people vaccination can trigger mitochondrial disease and result in an autism diagnosis, this does not mean it is a common cause of autism. Vaccinations have saved hundreds of millions of lives, but it has long been known that they can have side effects and that is why there is a large industry-funded compensation scheme in the US.
So while parasites can in some circumstances lead to autism, this does not mean feeding bleach to children with autism is a clever idea. Nor does filling them with antibiotics to treat a non-existing bacteria.
You can see why mainstream medicine is not eager to treat autism.
Nonetheless, applying that meagre sounding 10% of understanding can yield results, when applied with caution.










Saturday, 24 June 2017

Modulating Wnt Signaling in Autism and Cancer








In earlier posts I have covered various signaling pathways such as Wnt, mTOR and the unusually sounding Hedgehog.
You can go into huge detail if you want to understand these pathways, or just take a more superficial view. In most cases, things only start to go wrong if you are hypo/hyper (too little/too much) in these pathways.
We saw with mTOR that most people with autism are likely to have too much activity and so might benefit from mTOR inhibition, but a minority will have the opposite status and stand to benefit from more mTOR activity.
When it comes to Wnt signaling the research suggests the same situation. Wnt signaling is likely to be aberrant, but both extremes exist.

Given the large volume of genetic data, analyzing each gene on its own is not a feasible approach and will take years to complete, let alone attempt to use the information to develop novel therapeutics. To make sense of independent genomic data, one approach is to determine whether multiple risk genes function in common signaling pathways that identify signaling “hubs” where risk genes converge. This approach has led to multiple pathways being implicated, such as synaptic signaling, chromatin remodeling, alternative splicing, and protein translation, among many others. In this review, we analyze recent and historical evidence indicating that multiple risk genes, including genes denoted as high-confidence and likely causal, are part of the Wingless (Wnt signaling) pathway. In the brain, Wnt signaling is an evolutionarily conserved pathway that plays an instrumental role in developing neural circuits and adult brain function.
While the human genetic data is an important supporting factor, it is not the only one. There are a number of mouse genetic knockout (KO) models targeting Wnt signaling molecules, describing molecular, cellular, electrophysiological, and behavioral deficits that are consistent with ASD and ID. Furthermore, the genes involved in Wnt signaling are of significant clinical interest because there are a variety of approved drugs that either inhibit or stimulate this pathway.
There are many drugs developed and tested as modulators of Wnt signaling in the cancer field that could potentially be repurposed for developmental cognitive disorders. In cases where a reduction in Wnt signaling is thought to underlie the pathology of the disorder, usage of compounds that elevated canonical Wnt signaling could be applied. An example of this is GSK-3β inhibitors that have failed in cancer trials but may be effective for ASDs and ID (e.g., Tideglusig, ClinicalTrials.gov identifier: NCT02586935). In cases where elevated Wnt signaling is thought to contribute to disease pathology, there are many potential options to inhibit canonical Wnt signaling using chemicals (Fig. 1) that inhibit the interaction between β-catenin and its targets (e.g., inhibiting β-catenin interaction with the TCF factors), disheveled inhibitors (through targeting of the PDZ domain which generally inhibit the Frizzled–PDZ interaction), and tankyrase inhibitors (e.g., XAV939, which induces the stabilization of axin by inhibiting the poly (ADP)-ribosylating enzymes tankyrase 1 and tankyrase 2)

In recent years, strong autism ties have cropped up for one group of genes in particular: those that make up a well-known signaling pathway called WNT, which also has strong links to cancer. This pathway is especially compelling because some people with autism carry mutations in various members of it, including one of its central players: beta-catenin1. What’s more, studies from the past year indicate that several of the strongest autism candidate genes, including CHD8 and PTEN, interact with this pathway.
“There might be a particular subgroup of genes associated with autism that could all be feeding into or be regulating this pathway,” says Albert Basson, reader in developmental and stem cell biology at King’s College London, who studies CHD8 and WNT. “That clearly has emerged as a relatively major theme over the last few years.”

The connection between cancer and some autism is over-activated pro-growth signaling pathways. Many signaling pathways have growth at one extreme and cell death at the other. In cancer you actually want cell death to suppress tumor growth; in much autism there is also too much growth.  
Many cancers are associated with elevated signaling of mTOR, Wnt and indeed Hedgehog.  These are targets for cancer drug therapy and so there is already a great deal known.
A complication is that in a developmental neurological condition, like autism, it also matters when these signaling pathways were/are disturbed. For example Wnt signaling is known to play a role in dendritic spines and synaptic pruning, some of this is an ongoing process but other parts are competed at an early age, so it would matter when you intervene to modulate these pathways.
Historically cancer therapies involve potent drugs, often with potent side effects, however in recent years there has been growing awareness that some safe existing drugs can have equally potent anti-cancer effects. Many of these drugs are anti-parasite drugs, but even the very widely used diabetes drug Metformin has been shown to have significant anti-cancer effects, not to forget Simvastatin.
Many autism pathways/genes play a role in cancer (RAS, PTEN) and the upstream targets considered in cancer research are also autism targets.  For example many human cancers are RAS dependent and in theory could be treated by a RAS inhibitor, but after decades of looking nobody has found one. So instead scientists go upstream to find another target that will indirectly reduce RAS. This led to the development of PAK1 inhibitors that will reduce RAS.
RAS plays a role in some types of intellectual disability and indeed autism. The collective term is RASopathy.  Logically, drugs that modulate RAS to treat cancer might be helpful in modulating RAS for some autism.
Most types of cancers are complex and so there are multiple potential targets to attack them, but also the same target can have multiple possible approaches. RAS dependent cancers can be targeted via Wnt and even Hedgehog signaling.
This may sound all very complicated but does it have any relevance to autism?
It apparently does because almost all these pathways are known to be disturbed hypo/hyper in autism.  This means that clever insights developed for cancer can be repurposed for autism.


Anti-parasite drugs and Cancer
It is indeed remarkable how many anti-parasite drugs have an anticancer effect and indeed there is a much maligned theory to justify this.



Quite possibly it is just a coincidence.
There are many ways to kill parasites, one of which involves starving them of ATP. ATP is the fuel that is produced in your mitochondria.
Cancer cells and many parasites use a very inefficient way to produce ATP that does not require oxygen. In normal human cells the process followed is known as OXPHOS, by which glucose and oxygen from the blood is converted into ATP (energy) is very efficient. Only when you run low on oxygen, like a marathon runner at the end of the race, can you run into trouble because there is not enough oxygen for OXPHOS.  What happens next is anaerobic respiration, when a different process takes over to make ATP. It is much less efficient and causes lactic acidosis which makes marathon runners' muscles hurt.
A cheap anti-parasite drug Pyrvinium targets anaerobic respiration and starves the parasite of ATP and thus kills it. Another common children’s anti-parasite drug albendazole also works by starving the parasite of ATP.
Other anti-parasite drugs work in different ways.
We already know from the autism trials of Suramin, another anti-parasite drug,  that it works via P2X and P2Y purinergic channels.
Ivermectin  binds to glutamate-gated chloride channels (GluCls) in the membranes of invertebrate nerve and muscle cells, causing increased permeability to chloride ions, resulting in cellular hyper-polarization, followed by paralysis and death.  Fortunately in mammals ivermectin does not cross the BBB.
Ivermectin is also a PAK1 inhibitor and a positive allosteric modulator of P2X7.
Both PAK1 and P2X7 are relevant to many cancers and so not surprisingly research shows that Ivermectin has an anti-cancer effect.
Ivermectin appears to have a positive effect in some autism, but strangely it does not cross the BBB.
Mebendazole is another extremely cheap children’s anti-parasite drug which has remarkable potential anti-cancer properties. It inhibits hedgehog signaling and, via the inhibition of TNIK, it is a Wnt inhibitor.
Unfortunately in the US the private sector has also noticed the anticancer effects of Mebendazole and albendazole and they have recently become astronomically expensive. Mebendazole (MBZ), which costs almost nothing in many countries, now costs hundreds of dollar per dose in the US under the name Emverm. Outside of the US, Mebendazole is OTC in many developed countries. In poor countries it is donated free by big pharma.
In the cancer research they consider taking advantage of the fact that cimetidine (a cheap H2 antihistamine) interacts with Mebendazole to increase its bioavailability. Cimetidine is by chance another generic drug also being considered to be repurposed for cancer.
While some anti-parasite drugs like Suramin have side effects or cannot be taken regularly like Ivermectin, others are seen as safe for continued use even at high doses (e.g. Mebendazole and albendazole).  

Anti-parasite drugs and Autism
Just as many anti-parasite drugs seem to have a positive effect on some cancers it looks likely that the same may be true for autism.  This does not mean that parasites cause either cancer or autism.
We know from Professor Naviaux that some people respond to Suramin.
Two people who comment on this blog have found their child responds to PAK1 inhibitors, one of which is the drug Ivermectin.
There are groups of people on the internet who think parasites cause autism and you will find some of them if you google “autism mebendazole”, but there are some very valid reasons why some people’s autism may respond to mebendazole, but nothing to do with little worms.

Potency of Anticancer drugs
Failed anticancer drugs are already considered as possible drugs to treat neurological conditions.
The same pathways do seem to be involved in some cancer and some neurological conditions, but the severity by which that pathway is affected may be very different, so a new drug may lack potency to treat a type of cancer but be potent enough to benefit others.
In the case of the anti-parasite drugs Ivermectin and indeed mebendazole the dosage being used in current cancer studies are very much higher than normally used.
Very little mebendazole makes its way out of your intestines and so researchers counter this by using a dose 15 times higher and even taking advantage of the interaction with the H2 antagonist cimetidine to boost bioavailability.
The standard human dose of Ivermectin is 3mg, but in the cancer trials (IVINCA trial - IVermectin IN CAncer) in Switzerland and Spain the trial dose is 12, 30 and 60 mg.
So when it comes to autism and the possible repurposing of these drugs, the cancer studies will give valuable safety information, but the likely dose required to fine-tune these signaling pathways will likely be a tiny fraction of the cancer dose.
The newly developed cancer drugs that fail in clinical trials, may have potential in autism but it is unlikely that anyone will develop them, test them and bring them to the market.
The clever thing for autism seems to be to keep an eye on the existing generic drugs considered to benefit the overlapping cancer pathways.

Conclusion
Aberrant Wnt signaling has been identified by researchers as playing a key role in autism; the Simons Foundation is among those now funding further research.

In practical terms you can be either hypo or hyper, but hyper seems more likely. It may be a case of shutting the stable door after the horse has bolted, because the ideal time to modulate Wnt signaling is probably as a baby, or before. Nonetheless some older people may indeed benefit from modulating Wnt; the Simons Foundation must also believe so.
In the case of people with hyperactive Wnt signaling, there is a case to make for the potential use of the cheap anti-parasite drug Mebendazole.
The drug Mebendazole (MBZ) can found in three states/polymorphs called Polymorph A, B or C. This is relevant because they do not cross the blood brain barrier to the same extent.


To treat brain tumors, or indeed potentially some autism, you need MBZ-B or MBZ-C, it looks like MBZ-A does not cross the blood brain barrier.
Fortunately, MBZ-C is  the polymorph found most commonly in generic mebendazole tablets.  
Ivermectin is known not to cross the blood brain barrier but yet has been shown to show anti-tumor activity in brain cancer. The anti-cancer effect is thought to be as a PAK1 inhibitor, but this effect must be occurring outside the brain. Some people do use Ivermectin for autism.
The people using Ivermectin for autism are told they cannot use it continuously. Perhaps as the high dose cancer trials evolve the safety advice may change.





Wednesday, 18 March 2015

The Role of Microglia in the Puzzle of Neuro-inflammation in Autism





Regular readers of this and similar blogs will have noticed that the human body functions in quite irrational ways.  We know why this is; we are the product of a very slow evolutionary process, rather than being a clean-sheet design like your smart phone or iPad.

As a result, nothing is ever quite as simple as it seems and at times the cleverer you are, the less likely you are to find a medical therapy effective in humans.

Such is the case with autism, inflammation and microglia.

It might seem that you can track back inflammation in autism to its “root cause”, which could appear to be those immune cells in the brain, called microglia.  We know they are “activated” in autism and we know that autism is typified by an “over-activated” immune response.

Working with the assumption that autism is a brain dysfunction, you would assume that the effective therapy should be inside the so-called blood brain barrier (BBB).

You would then just look for a potent drug that could “stabilize” the microglia/immune cells in the brain, to calm things down.  Having achieved this, you would sit back and marvel at the behavioral change and improvement in cognitive function.

This was exactly the thought process a few years ago when the US  National Institute of Mental Health (NIMH) got together with the Johns Hopkins researchers to follow up on their findings of chronic inflammation in the brains of people with autism.  Subsequent, third party, research has also confirmed that the microglial cells are “activated” in autism


Trial Description


There is a subgroup of children with autism that appear to develop typically for a period of time, and then lose skills, or regress. A recent study by Vargas and co-workers at Johns Hopkins has demonstrated that the regressive subtype of autism is associated with chronic brain neuroinflammation as exemplified by activation of microglia and astroglia and the abnormal production of inflammatory cytokines and growth factors assayed in both tissue samples (brain banks) and CS. The authors remarked that these responses were similar to those seen in some neurodegenerative disorders such as amyotrophic lateral sclerosis, and that chronic microglia activation appears to be responsible for a sustained neuroinflammatory response that facilitates the production of multiple neurotoxic mediators. Chronic neuroglial activation could be the result of an abnormal persistence of a fetal development pattern. In this scenario neuroglial activation could play a role in initiating and in maintaining the pathology. Alternatively, neuroglial activation may only be a secondary response to the initiating causal factor(s) and not a direct effector of injury. Since neuroglial activation requires the nuclear translocation of the pro-inflammatory transcription factor NF-kappa B, and since inhibitors of NF-kappa-B with good CNS penetrance are available, the role of neuroinflammation in initiating and sustaining the autistic condition can be probed.
The antibiotic minocycline is a powerful inhibitor of microglial activation, apparently through blockade of NF-kappa-B nuclear translocation. Minocycline is neuroprotective in mouse models of amyotrophic lateral sclerosis (ALS) and Huntington's disease and has been recently shown to stabilize the course of Huntington's disease in humans over a 2-year period.
To evaluate the possibility of benefit in autistic children, we propose to conduct an open-label trial of the anti-inflammatory antibiotic minocycline, an agent that reduces inflammation by blocking the nuclear translocation of the proinflammatory transcription factor NF-kappa-B. Minocycline is Food and Drug Administration (FDA)-approved for treatment of a variety of infections and has been widely used for the treatment of adolescent acne. Minocycline is currently in phase III trials for the treatment of Huntington's disease and amyotrophic lateral sclerosis.
This proposal is for an initial 6-month, single-arm, off label, open-label study (with a 3 month extension phase offered to responders) that will evaluate dose safety and efficacy of minocycline in 10 children, ages 3 to 12 years, with a primary diagnosis of autism and a history of developmental regression. The subjects will be evaluated by a diagnostic/behavioral assessment, and the extent of neuroinflammation judged by CSF cytokine/chemokine profiles before and after the 6-month treatment. Subjects will also be given 0.6 mg/kg vitamin B6 twice a day as a prophylactic for possible minocycline induced nausea and vomiting. If the results of this feasibility study are encouraging, we expect to conduct a double-blind, placebo-controlled trial of minocycline therapy.


Nothing happens fast in the world of autism and so this six month study of 10 people (who completed the actual trial) was conceived in 2006, was actually concluded in 2013.  Here is the resulting paper:-
  


Conclusions
Changes in the pre- and post-treatment profiles of BDNF in CSF and blood, HGF in CSF and CXCL8 (IL-8) in serum, suggest that minocycline may have effects in the CNS by modulating the production of neurotrophic growth factors. However, in this small group of children, no clinical improvements were observed during or after the six months of minocycline administration.

Unfortunately, this study showed that a treatment, known to effectively stabilize microglial cells, had no positive effect on autism and actually seemed in some cases to make it worse.

We can conclude from this that stabilizing the microglia will not be the “holy grail” for treating autism.  Rather, the activated microglia is just one part of a complex, and only partially understood process.


Microglia as the Immunostat 

In a recent post we saw how Rodney Johnson referred to the microglia as the “immunostat” of the body.  Like the thermostat on the wall in your home central heating system.



This is indeed an interesting analogy and might explain some of what is going on.

We saw in Johnson’s paper all the ways that the immune system outside the blood brain barrier (BBB) was able to communicate with the microglia.  We should assume that this communication works both ways; something that is usually overlooked.

In a perfectly functioning body, as in a perfectly functioning house, the immunostat/thermostat gives a good indication of the actual state/temperature, as well as the one you intended.  So if you set your room thermostat to 72 Fahrenheit / 22 Celsius  you expect the actual temperature to be 72 Fahrenheit / 22 Celsius.

However, in the real world things do not work like this.

We live in a house with very large south facing windows, a big fireplace, underfloor heating in some places and European-style hot water radiators (in the US they do have them).  So we have at least four sources of heat.  In spite of having clever German electronics to control our heating system, the thermostat in the centre of the house, by itself, is not adequate.

Something similar is happening in body and brain of people with autism, just replace temperature with inflammation.

Just as my house has multiple systems resulting in heating, the human body has numerous processes leading to “inflammation”.  Some of these inflammatory processes are interconnected and some are not.  The net result at any one time can be measured by looking at various cytokine levels, gene expression, microglial activation and numerous other things; there is no single measurable thing called “inflammation”.

There will never be a single wonder anti-inflammatory treatment.

The activated state of the microglia rather than being the ultimate target for intervention may just be a reflection of inflammation elsewhere in the body, or alternatively it may be just the result of oxidative stress in the brain.

Just like after a few years you may need to replace your wall thermostat, because it is giving false data, the clever immunostat, that may be the microglia, could have been disrupted by all that oxidative stress in the brain.  It might even be sending its proinflammatory signal in reverse, back across the BBB, to the rest of the body. Not such a crazy idea?


The future of anti-inflammatory interventions

The NIMH and Johns Hopkins would naturally be disappointed by the results of their study; but it was a study well worth doing.  Hopefully they will pursue other avenues of thought.

We already know that there are numerous ways to achieve a degree of immuno-modulatory change and that in some types of autism there can be a profound behavioral impact.

These range from simple Ibuprofen, to steroids like Prednisone; not to mention those Kv1.3 blockers and ShK-peptides.  These will likely all affect the microglia, but it is not their main mode of action.


Insights

As is often the case, there are useful insights that you can learn from a “failed” trial.

I would imagine that an autistic person with ulcerative colitis would also have activated microglia. Treating that person with minocycline should have some stabilizing influence on the microglia, but without resolving the ulcerative colitis, the pro-inflammatory signals continue to be sent around the body.

Turning down the thermostat in my house, when I have a big log fire blazing, has no effect on the temperature. 

The microglia in the brain of people with autism probably should not be activated; we really need to know why they are activated.

If you can work on the numerous processes/pathways leading to “inflammation” you would most likely also achieve some deactivation of the microglia.

Therefore we should look at things like PPAR gamma which are directly relevant to the pathology of autism, and agonists of PPAR gamma also happen to be “anti-inflammatory” and indeed, in the test tube, some can stabilize microglia.

One, far away, day they will bring those ShK-peptides to the market. 

In the meantime, my current targets are Tangeretin and Nobiletin, flavonoids found in tangerines.


For the scientists among you:-

In addition to being a PPAR gamma agonist, Tangeretin is also a known P2Y2 receptor antagonist.  Both properties are potentially useful.

PPAR gamma has been covered in this blog already.  P2 receptors are a class of Purinergic receptor.  Within the field of purinergic signalling, these receptors have been implicated in learning and memory, locomotor and feeding behavior, and sleep. 

Suramin is used in research as a broad-spectrum antagonist of P2 receptors.

It is Suramin that Robert Naviaux, at UC San Diego, has been researching as a potent autism therapy.  He has shown it effective in mouse models, but the problem is that it is not safe for long term use in humans.  Regular readers should note that, yet again, an anti-parasite drug has been found to have an effect in autism.  Parasites do not cause autism, but understanding them better would be a potential advantage.

Why Suramin, a Century-Old, Anti-Parasitic Drug May Hold the Key to Understanding Autism


Dr. Robert Naviaux's recent finding suggests reversible metabolic syndrome could be at core of autism



The full paper is below:-




In particular, P2Y11 is a regulator of immune response.  There are big gaps in the science and I have no idea if tangeretin affects P2Y11.