More Wnt Modulation for Autism and More Inexpensive Potential Cancer Therapies

This blog is of course meant to be about autism, but today it is again more about cancer, since I keep coming across interesting potential therapies while researching Wnt/PAK/hedgehog therapies for autism.

On their way to visit a pharmacy?

It really looks like daily use of Mebendazole should be beneficial in some types of autism and perhaps a little short term bioavailability boost from cimetidine might help get things started. There are anecdotes on the internet of people with autism using it for its anti-parasite properties and showing a behavioral improvement.

Wnt signalling is highly complex and yet still only partially understood. One interesting role of Wnt signalling is in controlling the flow of calcium ions within cells. The non-canonical Wnt/calcium pathway helps to regulate calcium release from the endoplasmic reticulum (ER) in order to control intracellular calcium levels. Wnt ultimately causes the release of IP3 which then binds to the receptor IP3R which causes calcium to be released from the ER. Problems with this calcium release triggered by IP3R were put forward by Prof Gargus as a possible nexus where different genetic types of autism come together, but he does not translate this thinking into potential therapies. IP3R has been covered in earlier posts.  

Is dysregulated IP3R calcium signaling a nexus where genes altered in ASD converge to exert their deleterious effect?

The Excitatory/Inhibitory Imbalance – GABAA stabilization via IP3R

Wnt signalling also plays a role in dendritic spine morphology, which I wrote about at length previously. In autism the synaptic pruning process does not result in the optimal structure, but even after this process has been completed it is possible to fine tune brain function by changing the shape of the dendritic spines that remain. This dendritic spine morphology can be modulated by Wnt signalling. 

It appears that either a Wnt activator or a Wnt inhibitor may be required to improve dendritic spine morphology depending on the person and the nature of their dysfunction. In a bipolar mouse model, lithium was used as a Wnt activator to create a denser structure of dendritic spines and a more functional mouse. My assumption is that in my case I need a Wnt inhibitor. This is the same situation we have observed with the better known mTOR pathway, where some people are hypo while others are hyper.

Many drugs that have some effect in autism do play a role in Wnt signalling, even Atorvastatin, in my Polypill, has an inhibitory effect.

Wnt signalling is a conserved evolutionary pathway so it is present in everything from fruit flies to humans. It plays a role in many cancers, type 2 diabetes and it seems in neurological conditions such as autism, bipolar and schizophrenia.

My earlier posts on Wnt and PAK1 ended up with 3 options:-

·      Ivermectin

·      FRAX486

·      Bio30 Propolis

The Bio30 propolis is put forward as a PAK inhibitor, but I think it is too weak unless used in huge quantities. I did try BIO 30 and I think it may have had a marginal effect, but it is expensive and you need a lot of it.

So I think Mebendazole, as a Wnt inhibitor, looks like an alternative more practical route to achieve the same thing.

Roche do not seem to be commercializing FRAX486, whereas Mebendazole is sitting in the OTC part of most pharmacies across the world (excluding the USA). Under the brand name Vermox, pharmacies in New Zealand legally sell it worldwide.
If Mebendazole has potency to have an anti-cancer effect, like FRAX486, then it should have potency to give an autism effect.

Note that some people may need a Wnt activator.

You can read all about Wnt at this Stanford lab here.

Back to Cancer

Cancer appears to be more common among people with autism and so it was to be expected that some readers of this blog are treating both autism and some type of cancer.

It does seem that there is scope to repurpose some very common generic drugs to improve the prognosis of many cancers. As with autism, there is great resistance among mainstream clinicians to do this.

As with autism, there are hundreds of sub-types of cancer and so it is not easy to collect relevant evidence, even in the best circumstances, so often it is a case of anecdotes. It is hard to prove anything conclusively, but some very expensive cancer therapies are only minimally effective. As with autism, even a moderate chance of success is worth pursuing and none of the mentioned potentially “repurposable” drugs have more than trivial side effects. Many ultra-expensive dedicated cancer drugs have side effects that are far from trivial and some have very limited benefit.

It seems that while many clinicians are aware of the potential benefit of these off-label therapies, very few prescribe them. Some seem quite happy if you get them somewhere else, which in the case of Prof Williams (see below) from San Diego means regular trips across the border to a pharmacy in Tijuana, Mexico.

Cimetidine for cancer

I did mention cimetidine in my last post.

Cimetidine (Tagamet) is an H2 antihistamine that lowers acidity in your stomach, but cimetidine does much more, it even increases your level of estrogen, which may help some autism. The anti-cancer effects of cimetidine are well documented, they come in part from its own actions and in part from interfering with how the prescribed cancer drugs are metabolized. Cimetidine increases the plasma concentration of numerous drugs including some anticancer drugs.

There are various different theories to explain the anticancer effects of cimetidine itself, but what looks clear is that it improves the prognosis of many types of cancer.
You might expect it to have a negative effect on the types of cancers that have estrogen receptors.

Desloratadine for cancer

On the subject of antihistamines, the OTC second generation antihistamine Desloratadine (Clarinex, Aerius)  has been shown to improve outcomes in breast cancer. As usual drugs have multiple modes of action and so the anticancer effect may have nothing to do with histamine. The data to support this anticancer effect comes from Sweden and the data is presented in the patent application below.

Patent - Antihistamine for use in treatment of breast cancer

Perhaps one mode of anti-cancer action is the following one:-

The antihistamines clemastine anddesloratadine inhibit STAT3 and c-Myc activities and induce apoptosis incutaneous T-cell lymphoma cell lines.

Generic drugs with anti-cancer properties

So far we have covered in the last post and this one:

·      Ivermectin

·      Mebendazole (Vermox)

·      Albendazole

·      Cimetidine (Tagamet)

·      Statins (particularly Simvastatin, but also Atorvastatin)

·      Metformin

·      Desloratadine (Clarinex, Aerius)

·      Suramin (but use is limited by toxicity at high doses)

An antifungal treatment, Itraconazole, has an effect inhibiting hedgehog signaling, relevant to many cancers and has been shown to have some effect on prostate and breast cancer in particular. This might also have an effect in some autism where hedgehog signalling is elevated.

Repurposing Drugs in Oncology (ReDO)—itraconazole as an anti-cancer agent

Zinc, Hedgehog Signaling, Shank2/3, NMDA/AMPA Inactivation and Autism

Itraconazole does not work well with drugs that lower stomach acidity, like H2 antihistamines and PPIs.

The Polypill approach to cancer

I was looking for information to support the possible effect of Mebendazole in autism and I came across a great example of someone with my approach treating his brain tumor. With good sense he was seeking to follow mainstream therapy, but to supplement it with science based off-label therapies.

The professor who'cured' his cancer with a cocktail of everyday pills and 20 years on remains disease-free

The Drugs in Question: the evidence for and against

Metformin: Several studies suggest that tumors grow more slowly in cancer patients who take this anti-diabetic drug. Early-stage clinical trials are investigating its potential to prevent various cancers including prostate, breast, colorectal and endometrial.

Statins: Preclinical studies suggest these cholesterol-lowering heart drugs may prevent various cancers and stop them spreading. One recent meta-analysis associated a daily statin with a significant risk reduction of liver cancer.

Mebendazole: There is evidence this drug – usually prescribed to treat parasitical worm infections — may inhibit cancer cell growth and secondary tumors, though no clinical trials have been completed.

Cimetidine: This over-the-counter antacid has direct anti-proliferative effects on cancer cells, inhibits cell adhesion, reduces tumor angiogenesis (growth of blood vessels essential to a developing tumor) and also boosts anti-cancer immunity in various cancers.

Itraconazole: The common anti-fungal treatment is also thought to be anti-angiogenic and has shown promise as an agent for prostate cancer, non-small cell lung cancer and basal cell carcinoma, the most common kind of skin cancer.

Isotretinoin: This acne drug, marketed as Accutane, is occasionally used to treat certain skin cancers and neurological cancers as well as to prevent the recurrence of some brain tumors, although some studies suggest it is ineffective.

Professor Williams is not a doctor, but that did not stop him reading the research.

His choice of cheap generic off-label anti-cancer drugs looks pretty smart to me. He is still alive two decades after he “should” have been dead. It may all be a happy coincidence and perhaps he would have survived his orange-sized brain tumor without his own interventions. 

There are numerous alternative therapies for cancer and some people do even forgo conventional therapies to treat themselves, which looks very foolish to me.

Personally I would put my faith in science and that does not necessarily mean just medicine. Medicine is based on an evidence-based selective interpretation of often out of date science. So in some fields, medicine works just great, but in complex areas like cancer or anything to do with the brain, medicine lags decades behind science.

As Prof Williams learned, evidence is great as long as you are not going to die before someone collects it. If you have only a year to live what do you really care about any minor side effects metformin, simvastatin or cimetidine may have?

There are some apparently nutty therapies for cancer, just as there are for autism; I think someone should investigate them anyway, just in case someone has stumbled upon something effective by accident.

Modulating Wnt Signaling in Autism and Cancer

Source: LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: Arrows point the way

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.

Wnt signaling networks in autism spectrum disorder and intellectual disability

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: {"type":"clinical-trial","attrs":{"text":"NCT02586935","term_id":"NCT02586935"}}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)

As autism candidates emerge, cancer pathway rises to top

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.

Clinical Evaluation of a New Form of Cancer Therapy Based on the Principles of Atavistic Metamorphosis

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.

Brain Penetration and Efficacy of Different Mebendazole Polymorphs in a Mouse Brain Tumor Model  

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.

Broccoli sprouts for all Diabetes and some COPD

This blog is about translating existing medical research into therapy for autism, but quite often the same research has clear application to other conditions.

Very often those conditions include diabetes, a common severe form of asthma (COPD - Chronic obstructive pulmonary disease) and of course cancer.

Some readers of this blog are already applying some of these insights to improve their diabetes and indeed COPD. Type 2 diabetes is becoming very common and so more interest is being shown in better managing it. Sulforaphane from broccoli sprouts should benefit people with both Type1 and Type 2 diabetes, as more people are beginning to realize.

Cancer is a complex subject with many different molecular variants, but much of the science that needs to be applied is shared with autism. If you could master PAK1, RAS, PTEN, BCL2, P2X7, NRF2 etc you would be well placed to treat variants of both conditions. There is a surprising overlap between the existing drugs being repurposed for some autism and those being considered for some cancer (statins, metformin, propranolol, ivermectin etc.).

5 kilograms of broccoli in a pill slashes diabetics’ blood sugar

A chemical called sulforaphane, found in broccoli sprouts, has previously demonstrated an ability to reduce glucose levels in diabetic rats. Anders Rosengren of the University of Gothenburg in Sweden, and his colleagues wondered whether the same might be true for humans. To test the theory, his team gave 97 people with type 2 diabetes a concentrated dose of sulforaphane every day for three months, or a placebo. All but three people in the trial continued taking metformin. Those who didn’t take metformin were able to control their condition relatively well without it.

The concentration of sulforaphane given was around 100 times that found naturally in broccoli. “It was the same as eating around five kilograms of broccoli daily,” says Rosengren.

On average, those who received the broccoli extract saw their blood glucose reduce by 10 per cent more than those on the placebo. The extract was most effective in obese participants with “dysregulated” diabetes, whose baseline glucose levels were higher to start with.

Journal reference:

Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes

COPD is relevant to autism because it is epigenetic and features oxidative stress interfering in important biological processes, so there are some parallels with types of autism.

Broccoli helps clear damaged lungs

To ensure that the lungs function correctly, white blood cells called macrophages remove debris and bacteria that can build up in the lungs and cause infection.

This cleaning system is defective in smokers and people with chronic obstructive pulmonary disease (COPD) – a combination of emphysema and bronchitis – who suffer from frequent infections.

Now, researchers have figured out that a chemical pathway in the lungs called NRF2, involved in macrophage activation, is wiped out by smoking. They also found that sulforaphane, a plant chemical that is made by broccoli, cauliflower and other cruciferous vegetables when damaged, such as when chewed, can restore this pathway.

Journal reference:

Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model

Eosinophilic Esophagitis – another Granulocyte Disorder Associated with Autism

There are many comorbidities associated with autism.  I have long held the view that these comorbidities hold the key to understanding each particular case of autism.  In many cases this may be far more useful than genetic testing, which only seems to help in a minority of cases.

“Ringed esophagus” aka “Corrugated esophagus”


This then allows you to put people into sub-groups that may well respond to the same therapy.  This may all sound like common sense, but apparently is not.

Eosinophilic esophagitis (EoE) is a relatively new diagnosis and it is applies to a certain type of reflux/GERD/GORD that might be associated with a difficulty in swallowing and may not respond well to the standard stomach acid lowering therapies.

It is likely that most people with Eosinophilic esophagitis have never been correctly diagnosed. Many people have taken several years to get the correct diagnosis.

It is known that Eosinophilic esophagitis is much more common in autism than the general population. One study showed that EoE is four time more likely to be diagnosed in someone with autism. I suspect many people with autism never have their GI problems fully diagnosed.

We now have to add some new science to this blog

Granulocytes

There is a great deal already in this blog about mast cells.  Many readers have children who have allergies, mast cell activation, or even mastocytosis.  Mast cells are the ones (but not the only ones) that release histamine.

Mast cells are just one type of a class of cells called Granulocytes, that are produced in your bone marrow.

Granulocytes are a category of white blood cells characterized by the presence of granules, which release their contents when they degranulate.

The four types of granulocytes are:- 

·        mast cells

These have been well covered in the past. These are what cause problems for people with pollen allergy.

·        eosinophils

Eosinophils play a crucial part in the killing of parasites because their granules contain a unique, toxic basic protein and cationic protein. Eosinophils regulate other immune cell functions (e.g., CD4+ T cells, dendritic cells, B cells, mast cells, neutrophils, and basophils), they are involved in the destruction of tumor cells, and they promote the repair of damaged tissue. Interleukin-5 interacts with eosinophils and causes them to grow and differentiate; IL-5 is produced by basophils.

Note that some people with autism find that the TSO helminth parasites modify their immune system and improve their autism. This may relate to what is contained in the granules of eosinophils.  

·        basophils 

Basophils are similar to mast cells, in that they contain prestored histamine within their granules. Unlike mast cells they circulate in your blood . Basophils are the least common of the granulocytes, representing about 0.5 to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They can produce histamine and serotonin that induce inflammation, and heparin that prevents blood clotting.

There is research underway to try to develop basophil stabilizers.

·        neutrophils

Neutrophils are normally found in the bloodstream. During the beginning phase of inflammation, particularly as a result of bacterial infection, environmental exposure, and some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate towards the site of inflammation.

Neutrophils are recruited to the site of injury within minutes following trauma, and are the hallmark of acute inflammation; however, due to some pathogens being indigestible, they can be unable to resolve certain infections without the assistance of other types of immune cells.

Neutrophils also release an assortment of proteins in three types of granules by a process called degranulation. The contents of these granules have antimicrobial properties, and help combat infection.

An obvious question would be, if you know you have a problem with mast cells are you likely to have an issue with the other types of granulocytes?

One role of eosinophils is to regulate other immune cell functions (e.g., CD4+ T cells, dendritic cells, B cells, mast cells, neutrophils, and basophils).

The subject is highly complex and again not fully understood, but it is clear that granulocytes are all interrelated and so a problem with one may well be associated with a problem with others.

In the case of Eosinophilic esophagitis (EoE), both eosinophils and mast cell are directly involved.

Basophils, like mast cells, release histamine among other things when they degranulate.

Mast cells usually do not circulate in the blood stream, but instead are located in connective tissue.  Circulating granulocytes, like basophils can be recruited out of the blood into a tissue when needed.

So in addition to mast cell stabilizers perhaps, we might benefit from basophil and eosinophil stabilizers.

Surprisingly, the antihistamine cetirizine has Eosinophil-stabilizing properties, as does the asthma drug Montelukast. Both drugs are widely used in children.

Another substance, curine, also inhibits eosinophil influx and activation and is seen as a potential new treatment for asthma.  Interestingly the drug curine, is an alkaloid, that blocks L-type Ca²⁺ channels.

Regular readers may recall that I proposed the L-type calcium channel blocker Verapamil to control my son’s mast cell degranulation. Mast cells degranulate in a very complex fashion that involves the flow of Ca²⁺.

This may or may not be a coincidence. 

Fullerene nanomaterials are being developed as both mast cell and peripheral blood basophil stabilizers.

L-type calcium channels and GI disorders in Autism

There are many types of GI disorder in autism, however I suggest that a large group can be categorized as being broadly Granulocyte Disorders, which may well all respond to L-type calcium channel blockers, to some extent.

Indeed this may be a better solution than the widely used cromolyn sodium.

Perhaps people with autism, and their family members have certain calcium channels that are either overexpressed, or do not close fast enough, leading to a higher level of intracellular calcium.  This of course ties back in with Professor Gargus and his theories about IP3R and the calcium store inside the “endoplasmic reticulum”.

This all gets extremely complex.

My rather simple suggestion would be that if you have autism and any GI problem from the esophagus downwards, a three day trial of verapamil just might change your life.  As is almost always the case, there are some people who do not tolerate verapamil.

Interleukin 5

Interleukin 5 (IL-5) is an inflammatory cytokine produced by type-2 T helper cells  (Th2), mast cells, basophils and eosinophils.

IL-5 interacts with eosinophils and causes them to grow and differentiate.

IL-5 has long been associated with the cause of several allergic diseases including allergic rhinitis and asthma, where a large increase in the number of circulating, airway tissue, and induced sputum eosinophils have been observed.

You might expect high levels of IL-5 in people with Eosinophilic esophagitis (EoE)

Anti–IL-5 (mepolizumab) therapy for eosinophilic esophagitis 

Anti–IL-5 therapy is associated with marked decreases in peripheral blood and esophageal eosinophilia (including the number of CCR3⁺ blood cells) in patients with EE and improved clinical outcomes.

Not surprisingly the same anti-IL-5 therapy has been approved to treat severe asthma.

NICE recommends first-of-its kind asthma treatment mepolizumab  

Patients are given mepolizumab by injection every four weeks. It costs £840 per dose.

Mepolizumab for autism?

It is very expensive, so I doubt many people will think of Mepolizumab for autism.  If you have EoE, or severe asthma, you may be able to access this IL-5 therapy, my guess is that it would also reduce the severity of any comorbid autism.

Back to Eosinophilic Esophagitis

I was writing a while ago about food allergy in my book and came across the opinion that food allergy is no more common in autism than in typical people, but what is more common is Eosinophilic Esophagitis.

Eosinophilic esophagitis is a chronic immune system disease. It has been identified only in the past two decades, but is now considered a major cause of digestive system (gastrointestinal) illness.  In many cases it likely remains undiagnosed. If it continues, after a few years swallowing becomes difficult, in part because a “ringed esophagus” develops that impedes the passage of food.

As seems to be often the case there are plenty of contradictions in the diagnosis and treatment, as you will find as you read on.

The symptoms are broadly what would normally be diagnosed as reflux/GERD/GORD. This is very often found in people with autism and I expect in their relatives.

It is relevant to autism because it will be yet another comorbidity that when treated should improve autism, but it is also another marker of a particular sub-group of autism.

There are numerous other GI conditions comorbid with autism - colitis, IBD, IBS etc.  In the end I imagine that the molecular basis of some of these diagnoses is actually the same, so you will find the same therapies may be effective.

It looks like that one common factor is the mast cell and, just as in pollen allergy and asthma, stabilizing mast cells yields great benefit. Stabilizing mast cells is complex but involves the flow of calcium ions, Ca²⁺.  By modifying the flow of Ca²⁺ you can prevent mast cells degranulating.  This was one of my earlier discoveries, but there is now research showing the L type calcium channels “open” mast cells.  Keeping these channels closed is actually quite simple.

It would seem logical that the same approach could be therapeutic to other conditions that are, at least in part, mediated by mast cells.

According to the Mayo Clinic these are symptoms of eosinophilic-esophagitis

Adults:

·         Difficulty swallowing (dysphagia)

·         Food impaction

·         Chest pain that is often centrally located and does not respond to antacids

·         Persistent heartburn

·         Upper abdominal pain

·         No response to gastroesophageal reflux disease (GERD) medication

·         Backflow of undigested food (regurgitation)

Children:

·         Difficulty feeding

·         Vomiting

·         Abdominal pain

·         Difficulty swallowing (dysphagia)

·         Food impaction

·         No response to GERD medication

·         Failure to thrive (poor growth, malnutrition and weight loss)

The diagnosis of EoE is typically made on the combination of symptoms and findings of diagnostic testing.


Prior to the development of the EE Diagnostic Panel, EoE could only be diagnosed if gastroesophageal reflux did not respond to a six-week trial of twice-a-day high-dose proton-pump inhibitors (PPIs) or if a negative ambulatory pH study ruled out gastroesophageal reflux disease (GERD).

Treatment strategies include dietary modification to exclude food allergens, medical therapy, and mechanical dilatation of the esophagus.

The current recommendation for first line treatment is PPI in lieu of diet as a significant portion of EOE cases respond to this, and it is a low risk, low cost treatment.

The second and third line therapies are an elimination diet of either the 6 or 4 most common triggers, or topical corticosteroids, including both fluticasone, and topical viscous budesonide.

Elimination diets would be followed by re-introduction of foods under supervision if the first diet is successful. Allergy evaluation has not been found to be an effective means to determine what foods to eliminate.

  

Eosinophilic esophagitis in adults: An update

MAST CELL STABILIZERS

In a small case series, Cromolyn sodium failed to show any clinical or histologic improvement in EoE patients

LEUKOTRIENE INHIBITORS

Montelukast is an eosinophil stabilizing agent. It improved clinical symptoms in EoE but there was no histological improvement

PROGNOSIS

As mentioned earlier, EoE is a chronic inflammatory disease of the esophagus. The inflammation leads to remodeling, fibrosis and stricture. Fortunately, no case of esophageal malignancy has been reported in EoE. Patients are generally diagnosed after several years of their symptoms. Although symptomatic improvement occurs after treatment, recurrence is common after discontinuation of treatment. So maintenance therapy is needed to prevent recurrences. At the present time there is no head to head study to suggest the best maintenance treatment. Continuation of swallowed corticosteroid and/or dietary therapy should be done in all EoE patients particularly in those with history of food impaction, dysphagia, esophageal stricture, and in those with rapid symptomatic and histologic relapse following initial treatment

Eosinophilic esophagitis and Mast Cells

Eosinophilic esophagitis is called Eosinophilic because it is mediated by Eosinophils, however it has been established that mast cells also play a role. 

Involvement of mast cells in eosinophilic esophagitis

Whereas prior studies have primarily focused on the role of eosinophils in disease diagnosis and pathogenesis, this study investigates the involvement of mast cells.

Herein we have identified local mastocytosis and mast cell degranulation in the esophagus of EE patients; identified an esophageal mast cell associated transcriptome that is significantly divergent from the eosinophil-associated transcriptome with CPA3 mRNA levels serving as the best mast cell surrogate marker; and provide evidence for the involvement of KIT ligand in the pathogenesis of EE.

One possible explanation for eosinophilic esophagitis:

Expanding the paradigm of eosinophilic esophagitis: mast cells and IL-9

A potential immunological mechanism involved in the pathogenesis of EoE. An uncontrolled TH2 immune response initiated by an allergic insult results in the transition of the esophagus from a normal (NL) to EoE phenotype through enhanced IL-13 production that induces highly elevated CCL26 (eotaxin-3) expression by esophageal epithelium. Dysregulated TH2 immune response and enhanced CCL26 secretion together promote the infiltration of CD4⁺TH2 cells, eosinophils, and mast cells, and potentially, type-2 innate lymphoid cells (ILC2) and CD4⁺TH9 cells; into the esophagus. TGF-β and IL-4 produced by the activated mast cells and CD4⁺TH2 cells may induce eosinophils, ILC2, and/or CD4⁺TH9 cells to produce IL-9, which in turn, promotes esophageal mastocytosis that contributes to the development of EoE pathophysiology.

Possible Eosinophil stabilizers

An Open Label Add-On Trial of Cetirizine for Neuromyelitis Optica (P4.003)

CONCLUSIONS Eosinophil-stabilizing properties and favorable safety profile make cetirizine an attractive add-on therapy for NMO. Thus far it has been well-tolerated in our patient population, with incoming data about efficacy expected over the coming months

Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma

·        Curine is a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum.

·        Curine inhibits eosinophil influx and activation and airway hyper-responsiveness.

·        Curine mechanisms involve inhibition of Ca²⁺ influx, and IL-13 and eotaxin secretion.

·        No significant toxicity was observed in mice orally treated with curine for 7 days.

·         Curine has the potential for the development of anti-asthmatic drugs.

  

Conclusion

Non conventional therapies for eosinophilic esophagitis might include:-

·        Cetirizine

·        Verapamil

·        Montelukast

·        Curine

The very expensive therapy is Mepolizumab.

If you have one type granulocyte causing a disorder, is seems almost inevitable that the other types of granulocyte are also involved.

Treating granulocyte disorders should improve autism and left untreated they may mask the effect of otherwise useful autism therapies. 

One reader did previously suggest a bone marrow transplant for autism. A rather radical solution, but if someone with autism was given donor bone marrow as part of another therapy, you might well see their autism improve.