UA-45667900-1
Showing posts with label dendritic spine. Show all posts
Showing posts with label dendritic spine. Show all posts

Sunday 9 July 2017

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.


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



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.
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 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.




Wednesday 4 January 2017

Histidine for Allergy, but as an effective MTOR inhibitor?



Today’s post is likely to be of interest to those dealing with allergy and mast cell activation, but it may have broader implications for those with excess brain mTOR activity.
In the jargon, we are told that:
enhanced mammalian target of rapamycin (mTOR) signaling in the brain has been implicated in the pathogenesis of autism spectrum disorder”.
I have discussed mTOR and mTOR inhibitors previously on this blog.



Amino acids, not just for body builders?


mTOR plays a key role in aging and many human diseases ranging from cancer, diabetes and obesity to autism and Alzheimer’s.

The greatest interest in mTOR seems to be in cancer care.  Many cancer genes and pathways are also involved in autism, so we can benefit from the cancer research.  Another autism gene that is also a cancer gene is PTEN.  PTEN is a tumor suppressor and in the most common male cancer, prostate cancer (PCa), what happens is that PTEN gets turned off and so the cancer continues to grow.  If you upregulate PTEN you slow the cancer growth and if you upregulated this gene in those people at risk of Pca perhaps they would never develop this cancer in the first place?  PTEN is upregulated by statin-type drugs and people already on this type of drug have better PCa prognoses.   The beneficial of effect of statins on PCa is known, but the mechanism being PTEN upregulation does not seem to have been noticed. No surprise there.

Inhibiting mTOR using cancer drugs is very expensive.

Other substances affecting mTOR include amino acids, growth factors, insulin, and oxidative stress.

The amino acid Leucine is an mTOR activator, we don’t need that.  We actually want the opposite effect and, at least in mice, we can get it from some of the other amino acids. 


          Highlights 

·        Amino acids, his, lys and thr, inhibited mTOR pathway in antigen-activated mast cells



·        Amino acids, his, lys and thr inhibited degranulation and cytokine production of mast cells



·        Amino acid diet reversed mTOR activity in the brain and behavioral deficits in allergic and BTBR mice.



Neuroprotective and anti-inflammatory diet reduced behavioral deficits only in allergic mice.

              Abstract

Enhanced mammalian target of rapamycin (mTOR) signaling in the brain has been implicated in the pathogenesis of autism spectrum disorder (ASD). Inhibition of the mTOR pathway improves behavior and neuropathology in mouse models of ASD containing mTOR-associated single gene mutations. The current study demonstrated that the amino acids histidine, lysine, threonine inhibited mTOR signaling and IgE-mediated mast cell activation, while the amino acids leucine, isoleucine, valine had no effect on mTOR signaling in BMMCs. Based on these results, we designed an mTOR-targeting amino acid diet (Active 1 diet) and assessed the effects of dietary interventions with the amino acid diet or a multi-nutrient supplementation diet (Active 2 diet) on autistic-like behavior and mTOR signaling in food allergic mice and in inbred BTBR T + Itpr3tf/J mice. Cow’s milk allergic (CMA) or BTBR male mice were fed a Control, Active 1, or Active 2 diet for 7 consecutive weeks. CMA mice showed reduced social interaction and increased self-grooming behavior. Both diets reversed behavioral impairments and inhibited the mTOR activity in the prefrontal cortex and amygdala of CMA mice. In BTBR mice, only Active 1 diet reduced repetitive self-grooming behavior and attenuated the mTOR activity in the prefrontal and somatosensory cortices. The current results suggest that activated mTOR signaling pathway in the brain may be a convergent pathway in the pathogenesis of ASD bridging genetic background and environmental triggers (food allergy) and that mTOR over-activation could serve as a potential therapeutic target for the treatment of ASD.

  

So in mice a combination of the three amino acids Histidine, Lysine and Threonine reduced brain mTOR activity and improved autism.

I did look at all three of these amino acids and their other effects and I choose Histidine. 
Histidine can be produced in adult humans in very small amounts, but in young children they need to obtain some from other sources, usually dietary.

Histidine is the precursor of histamine.  Histamine has both good and bad effects.

Histidine decarboxylase (HDC) is the enzyme that catalyzes the reaction that produces histamine from histidine with the help of vitamin B6 as follows:



You can treat allergy by inhibiting HDC.

Tritoqualine, is an inhibitor of the enzyme histidine decarboxylase and therefore an atypical antihistamine,

You might think that having extra histidine would result in extra histamine, but this appears not to be the case.  There is a paradoxical reaction where increasing histadine actually seems to reduce the release of histamine from the mast cells that store it.  This may indeed be a case of feedback loops working in our favour.

So it seems that histidine may give two different benefits, it reduces IgE-mediated mast cell activation and it reduces mTOR signalling in the brain.

If the effect on mTOR is sufficient we would then benefit from an increase in autophagy, the cellular garbage disposal service that does not work well in autism.  We might eventually see a benefit from increased synaptic pruning which might be seen in improved cognition.  



Recap on mTOR and Synaptic Pruning

This has been covered in earlier posts.

In autism loss of mTOR-dependent macro-autophagy causes synaptic pruning deficits; this results in too many dendritic spines.









A dendritic spine (or spine) is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons.

A feature of autism is usually too many, but can be too few, dendritic spines.  In an earlier post we saw how the shape of individual spines affects their function.  The shape is constantly changing and can be influenced by external therapy. Wnt signaling affects dendritic spine morphology and so using this pathway you could fine-tune dendritic spine shape.  We did look at PAK1 inhibitors in connection with this.

Synaptic pruning is an ongoing process well into adolescence.

So it may be possible to improve synapse density and structure well after the onset of autism.

It should be noted that using Rapalogs, the usual mTOR inhibiting drugs, would have a negative effect in the minority of autism that feature hypo-active growth signalling.  That would be people born with small heads and small bodies.  So a child affected by the zika virus, might very likely exhibit autism and ID, but likely has too few dendritic spines and would then need more mTOR, rather than less.

Rapalog drugs like Everolimus are very expensive, but as in this recent paper do show effect in some autism. 



The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.

mTOR Complex 1 (mTORC1) is composed of MTOR, regulatory-associated protein of MTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the non-core components PRAS40 and DEPTOR. This complex functions as a nutrient/energy/redox sensor and controls protein synthesis. The activity of mTORC1 is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives (e.g., L-leucine and β-hydroxy β-methylbutyric acid), mechanical stimuli, and oxidative stress

Rapamycin inhibits mTORC1, and this appears to provide most of the beneficial effects of the drug (including life-span extension in animal studies). Rapamycin has a more complex effect on mTORC2.



How do amino acids affect mTOR?

This is not fully understood by anyone, but here is a relevant paper, for those interested.




Mammalian target of rapamycin (mTOR) controls cell growth and metabolism in response to nutrients, energy, and growth factors. Recent findings have placed the lysosome at the core of mTOR complex 1 (mTORC1) regulation by amino acids. Two parallel pathways, Rag GTPase-Ragulator and Vps34-phospholipase D1 (PLD1), regulate mTOR activation on the lysosome. This review describes the recent advances in understanding amino acid-induced mTOR signaling with a particular focus on the role of mTOR in insulin resistance.

We then discuss how mTORC1 activation by amino acids controls insulin signaling, a key aspect of body metabolism, and how deregulation of mTOR signaling can promote metabolic disease. 

Concluding remarks


Recent findings of new mediators and their regulatory mechanisms have broadened our understanding of amino acid-induced mTOR signaling. In addition to the role of the TSC1-TSC2-Rheb hub in transducing upstream signals from growth factors, stressors and energy to mTOR, the lysosomal regulation of mTOR functions as a platform to connect nutrient signals to the Rheb axis. Furthermore, two parallel pathways of amino acid signaling explain the diverse regulation of mTOR signaling. It is yet to be determined which regulators sense amino acids directly and whether the two pathways require separate amino acid sensing mechanisms. The identification of a direct amino acid sensor will shed light on these uncertainties.

A more integrated understanding of mTOR regulation in amino acid signaling will open the door for new therapeutic approaches for metabolic diseases, especially type 2 diabetes. Already, metformin, an antidiabetic drug, inhibits mTOR in an AMP-activated kinase (AMPK)-independent and Rag-dependent manner,64 providing further support for the idea that the regulation of amino acid sensing could be a therapeutic target for diabetes.



How typical is the level of amino acids in autism?



As regards essential amino acid levels, autistic children had significant lower plasma levels of leucine, isoleucine, phenylalanine, methionine and cystine than controls (P < 0.05),while there was no statistical difference in the level of tryptophan, valine, threonine, arginine, lysine and histidine (P > 0.05). In non-essential amino acid levels, phosphoserine was significantly raised in autistic children than in controls (P < 0.05). Autistic children had lower level of hydroxyproline, serine and tyrosine than controls (P < 0.05). On the other hand there was no significant difference in levels of taurin, asparagine, alanine, citrulline, GABA, glycine, glutamic acid, and ornithine (P > 0.05).

There was no significant difference between cases and controls as regards the levels of urea, ammonia, total proteins, albumin and globulins (alpha 1, alpha 2, beta and gamma) (P > 0.05).



  

Conclusion 

For the more common hyperactive pro growth signaling pathway types of autism, histidine should be a good amino acid, whereas for the hypoactive type, that might feature microcephaly, leucine should be a good choice.

Histidine is already used by some people to treat allergy.

Histidine does have numerous other functions and one relates to zinc, so it is suggested that people who supplement histidine add a little zinc. For this reason German histidine supplements thoughtfully all seem to include zinc.

Histidine also has some direct antioxidant effects and has an effect on Superoxide dismutase (SOD).

It is not clear how much histidine would be needed in humans to achieve the mTOR inhibiting effect found in mice.

The RDA for younger teenagers is histidine  850 mg and leucine 2450 mg.  What the therapeutic dose to affect mTOR in humans remains to be seen.

Histidine is also claimed to help ulcers, which is plausible.

For allergy some people are taking 1,500mg of histidine a day.






Monday 2 March 2015

CAPE-rich Propolis for Autism?

CAPE (caffeic acid phenethyl ester) is a substance known to be an inhibitor of PAK1.  PAK1 has been shown at MIT to be implicated in various disorders including Fragile X and schizophrenia.  PAK1 inhibitors are also effective in research models of various cancers, including leukemia.

There are currently no approved PAK1 inhibitor drugs, although several are in development.

PAK1 is also implicated in Neurofibromatosis, and clinicians have researched various alternative PAK1 inhibiting substances.  The two most interesting ones that I have already written posts about are:-

·        Ivermectin, an old anti-parasite drug (also shown effective in leukemia)
·        BIO 30 propolis, rich in CAPE

Ivermectin is already used as an autism treatment by “alternative” doctors who think autism is caused by parasites.  We saw in a recent post that a study looking for parasites in people with autism (in the US) found none.  Ivermectin reportedly does improve autism, according to one reader of this blog and other anecdotal evidence.

I think Ivermectin is likely to be more potent than BIO30, but Ivermectin cannot be safely used continuously, without long breaks.


BIO-30 Trial

Having discussed the idea with one of the Japanese Neurofibromatosis clinicians, it seemed worthwhile to see the effect in our kind of autism.

As you may have seen in previous posts the science behind PAK1 is complex.  It has numerous, mainly bad, effects.  It is involved in dendritic spine morphology; this might be one area where ongoing “damage” is still being done.  So when asked what kind of change I expected/hoped to see, I said “cognitive improvement”.

According to recent research:-

CAPE alone has never been used clinically, due to its poor bioavailability/water-solubility; Bio 30 contains plenty of lipids which solubilize CAPE, and also includes several other anticancer ingredients that seem to act synergistically with CAPE.

Propolis is widely used as a natural remedy, but this was my first experience with it.  The first problem was how to take it; it sticks to everything.

My solution is to cut a small piece of toast and then apply 20 drops of propolis.  Since propolis has a strong flavor, I try to mask it with a layer of Nutella spread on top.

I gave this “honey medicine” at breakfast and in early afternoon.  


Trial Conclusion

There is a cognitive enhancing effect, noticeable not just to me.  The effect is visible almost straight away, but was more noticeable with a dose of 2 x 20 drops than with my original 1 x 20 drops.

At this dosage, it is not revolutionary, but it does indeed provide a real “nootropic”/cognitive enhancing effect.


Propolis for All?

At the dose I am using, I would think this “therapy” is only worthwhile in people whose autism is well-controlled already; meaning no stimming/stereotypy/OCD, allergies/GI problems all resolved, no aggression or anxiety;  these behaviours will mask any benefit.

I actually think this is the first thing I have come across that looks ideally suited for Asperger’s and other HFA.

I did look on line for people trying BIO30 for schizophrenia, all I found was someone else asking the same question:-


Apparently FRAX486 treats schizophrenia in mice due to PAK1 inhibition. Why does no one try Bio 30 Propolis for schizophrenia, as it is a PAK1 inhibitor as well?


Propolis does have numerous other ingredients, including many very interesting flavonoids.

As long as you are not one of the one percent of people with a bee allergy, propolis seems a very safe product.

If you live in Australia or New Zealand you can buy the CAPE-rich propolis locally.  As we learnt in previous posts, only two types of propolis were found to be PAK1 inhibitors, an expensive one from Brazil and the CAPE-rich BIO30 Propolis from New Zealand.

If anyone tries it, please let me know the result.  You only need one bottle and a few days to see if it has an effect.






Monday 17 November 2014

Tuning Wnt Signaling for more/fewer hairs and to optimize Dendritic Spine Morphology in Autism




Today’s post is about another example of how evolution can play jokes on us.  It really is the case that a signaling pathway that controls hair growth is the same that determines the number and shape of dendritic spines in the brain.

This is good news not just for Homer Simpson but for people interesting in perking up behavior and cognitive function in autism.

The post also connects several subjects that we have previously encountered - dendritic spines which are abnormal in autism, Wnt signaling which is implicated in cancer (and autism), statins, Ivermectin, CAPE found in some propolis and verapamil.  There is plenty of research to back all these connections, but strangely nobody seems to be applying them to develop any practical therapies.

I introduced dendritic spines in an earlier post.  Each neuron in your brain has hundreds of protruding spines.
Dendritic Spines in Autism – Why, and potentially how, to modify them

In that post I reported that PAK1, the gene NrCAM and the protein MTOR were all implicated in the dysfunction in both shape and number of these spines.

It now seems that there may be one even more critical pathway involved – Wnt. There are links between Wnt and PAK1, that appeared in several earlier posts.

You may recall that dendritic spines are constantly changing shape.  Their shape affects their function.  In many disorders, both the number and shape of the spines is dysfunctional.  It appears that the morphology (shape) can be modified, which implies you could affect behavior, memory, and cognitive function.







My follow up post of dendritic spines has yet to materialize, but here is a sneak preview, showing the progression of autism, schizophrenia and Alzheimer’s in terms of the number of dendritic spines.









Dendritic Spines and Wnt Signaling

Dendritic spines are constantly changing their shape and certain psychiatric disorders are characterized by different morphologies (shapes) of these spines.  It is not just the number of spines, but their shape which affects cognitive function, memory and behavior.

The Wnt signaling pathway also lies behind hair growth.

What is more, we know that Wnt signaling is dysfunctional in autism and we even now which the genes are that likely trigger of this dysfunction.

Wnt dysfunction is also involved in many types of cancer and therefore has been subject of much research.

The surprise came when I read that attempts are underway to “tune” Wnt signaling to control hair growth.  Why not autism?

This post is about tuning Wnt signaling to improve cognitive function and behavior.  This appears just as plausible as controlling hair growth.



The Wnt Signaling Pathways

Here is the Wikipedia explanation.

Wnt signaling pathway



The Wnt signaling pathways are a group of signal transduction pathways made of proteins that pass signals from outside of a cell through cell surface receptors to the inside of the cell. Three Wnt signaling pathways have been characterized: the canonical Wnt pathway, the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway. All three Wnt signaling pathways are activated by the binding of a Wnt-protein ligand to a Frizzled family receptor, which passes the biological signal to the protein Dishevelled inside the cell. The canonical Wnt pathway leads to regulation of gene transcription, the noncanonical planar cell polarity pathway regulates the cytoskeleton that is responsible for the shape of the cell, and the noncanonical Wnt/calcium pathway regulates calcium inside the cell. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved, which means they are similar across many species from fruit flies to humans.[1][2]
Wnt signaling was first identified for its role in carcinogenesis, but has since been recognized for its function in embryonic development. The embryonic processes it controls include body axis patterning, cell fate specification, cell proliferation, and cell migration. These processes are necessary for proper formation of important tissues including bone, heart, and muscle. Its role in embryonic development was discovered when genetic mutations in proteins in the Wnt pathway produced abnormal fruit fly embryos. Later research found that the genes responsible for these abnormalities also influenced breast cancer development in mice.
The clinical importance of this pathway has been demonstrated by mutations that lead to a variety of diseases, including breast and prostate cancer, glioblastoma, type II diabetes, and others.[3][4]


The Canonical Wnt pathway is dysfunctional in Autism

It is the canonical Wnt pathway that is dysfunction in autism and it is this same pathway plays a role in dendrite growth and suboptimal Wnt activity negatively affects the dendritic arbor.

A very thorough review of all the genetic evidence is provided in the following study:



Notably, the available genetic information indicates that not only canonical Wnt pathway activation, but also inhibition seems to increase autism risk. The canonical Wnt pathway plays a role in dendrite growth and suboptimal activity negatively affects the dendritic arbor. In principle, this provides a logical explanation as to why both hypo- and hyperactivity may generate a similar set of behavioral and cognitive symptoms.


The review highlights that, as we have seen before, some people with autism are hypo and some people are hyper; this means some people need Wnt signaling to be inhibited and other people need the opposite therapy.  The author points out that you really need some test to check which way you need your Wnt “tuned”.  

It sounds a bit like tuning the timing of the sparks inside your car engine, in the days before it was all electronic and self-tuning.  In theory you needed to measure the timing of the sparks with a special strobe light; but if you knew what you were doing you could just use your ears.  So in the same vein, you could make a small change to inhibit Wnt and see the result, if it made matters worse you just stop and go the other way.  As you will see later in this post, some of us are already tuning Wnt without even realizing it.

We have exactly the same issue with mGluR5, where you might need a positive/negative allosteric modulator to optimize brain performance.  Different variants of “autism” would be located either left or right of “top dead center”.

In that post we learnt that at MIT they are suggesting that errors in synaptic protein synthesis are behind several types of autism and that these errors can be corrected using either positive or negative stimulators of the receptor mGluR5.









For a more detailed understanding of Wnt signaling, see the paper below:-





For Homer Simpson and others wanting more hair




Abnormal hair development and regeneration has been implicated in diseases of the skin (ie., hirsutism, alopecia, etc) or in open wounds when hair follicles are completely eliminated. To manage these clinical conditions, it is important to understand molecular pathways which regulate the number, size, growth and regeneration of hair follicles. Wnt signaling plays a fundamental role in this process. We need a deeper understanding so we can reliably adjust Wnt levels in existing follicles. This studies reviewed here have future translational value for skin regeneration following severe wound injuries or in the context of tissue engineering. Tuning the levels of Wnt ligands can directly modulate the number and growth of hairs. Using this new knowledge, we now know that Wnt activity can be modulated by adjusting the secretion of Wnt ligands, altering binding of ligands to receptors, inhibiting β-catenin translocation, or by regulating extra-follicular dermal Wnt and Wnt inhibitors.



How to tune Dendritic Spine Morphology

We have already encounter Brain-Derived Neurotropic Factor  (BDNF) in an earlier post.  You could think of BDNF as brain fertilizer.



“Older people and anyone with Retts Syndrome are likely to benefit from more NGF (Nerve Growth Factor).  In autism it appears possible that there was too much NGF and BDNF at a very early age, with levels then changing.  High levels of NGF and BDNF look a bad idea.  A lot more research is needed to understand what determines  NGF and BDNF levels.  It appears that BDNF may stay high in autism, but NGF levels.”

It has been shown that BDNF and Wnt signaling together regulate dendritic spine formation.

So, since in autism we have excess BDNF as the brain is developing, this might explain there are too many dendritic spines in autistic brains.  Too many spines and the wrong morphology (shape) would explain very many issues that have gone “wrong” in autistic brains.




Here, we show that Wnt signaling inhibition in cultured cortical neurons disrupts dendritic spine development, reduces dendritic arbor size and complexity, and blocks BDNF-induced dendritic spine formation and maturation. Additionally, we show that BDNF regulates expression of Wnt2, and that Wnt2 is sufficient to promote cortical dendrite growth and dendritic spine formation. Together, these data suggest that BDNF and Wnt signaling cooperatively regulate dendritic spine formation.
BDNF overexpression rapidly and robustly increases primary dendrite formation in cortical neurons (Horch et al., 1999; McAllister et al., 1997; Wirth et al., 2003). We reproduced this finding, and found that this increase was not blocked by overexpression of the Wnt inhibitors (Fig. S2), indicating that some aspects of BDNF modulation of dendrites remain intact in the presence of Wnt inhibitors. To further assess whether expression of the Wnt inhibitors impaired the signaling ability of BDNF, we analyzed autocrine induction of c-Fos expression by BDNF overexpression. c-Fos is an immediate early gene whose transcription is rapidly upregulated by BDNF (Calella et al., 2007; Gaiddon et al., 1996). We found that BDNF induced c-Fos expression was not reduced in neurons overexpressing any of the four Wnt inhibitors, suggesting that the ability of the inhibitors to interfere with BDNF-induced spine formation and spine head width expansion was not a result of decreased levels of BDNF signaling (Fig. S3).

Wnt2 overexpression is sufficient to increase cortical dendrite length. (A) Representative cortical neurons expressing either EV or Wnt2. Quantification of the total dendrite length per neuron (B) and the number of dendritic endpoints per neuron (C) for ...
Wnt2 overexpression increases dendritic protrusion density and influences spine shape on cortical neurons. (A) Representative dendritic segments of cortical neurons expressing either EV or Wnt2. (B) Quantification of dendritic protrusion density. (C) ...


Wnt inhibition and dendritic spine maturation

We found that a series of different Wnt signaling inhibitors were able to block BDNF-induced increases in dendritic spine density and dendritic spine head width


I think all this existing science really tells us a lot.


Back in the slow lane

In cancer research, decades have already been spent investigating Wnt signaling.




Drugs that Enhance Wnt Signaling

Back in my world, with a little help from Google scholar, I rapidly find that drugs already exist that affect Wnt signaling.  Some very familiar names pop up.




SummaryStatins improve recovery from traumatic brain injury and show promise in preventing Alzheimer disease. However, the mechanisms by which statins may be therapeutic for neurological conditions are not fully understood. In this study, we present the initial evidence that oral administration of simvastatin in mice enhances Wnt signaling in vivo. Concomitantly, simvastatin enhances neurogenesis in cultured adult neural progenitor cells as well as in the dentate gyrus of adult mice. Finally, we find that statins enhance Wnt signaling through regulation of isoprenoid synthesis and not through cholesterol. These findings provide direct evidence that Wnt signaling is enhanced in vivo by simvastatin and that this elevation of Wnt signaling is required for the neurogenic effects of simvastatin. Collectively, these data add to the growing body of evidence that statins may have therapeutic value for treating certain neurological disorders.Simvastatin rescues cerebrovascular and memory-related deficits in mouse models of Alzheimer disease (AD) (Li et al., 2006; Tong et al., 2009, 2012), and recent meta-analysis of clinical studies concluded that statins provide a slight benefit in the prevention of AD and all-type dementia (Wong et al., 2013). While these effects have been attributed to reduction of inflammation, reduced oxidative stress, upregulated PI3K/AKT signaling, and enhanced neurogenesis, the mechanisms by which statins are beneficial in neurological disorders are not fully understood.Simva is under investigation for its potential therapeutic effects outside of hyperlipidemia treatment. While statins have been reported to enhance Wnt signaling in vitro, it was heretofore not known whether statins can enhance this pathway in vivo and in the context of neurogenesis. Here we provide evidence that oral simva treatment enhances Wnt signaling in the mammalian adult hippocampus. This is significant in that aside from lithium, no other clinically approved compound has been demonstrated to enhance Wnt signaling in the brain


You will find the element Lithium in your smart phone battery, but it is also a drug.

Lithium is useful in the treatment of bipolar disorder. Lithium salts may also be helpful for related diagnoses, such as schizoaffective disorder and cyclic major depression. The active part of these salts is the lithium ion Li+.

But, not surprisingly, Lithium has other effects, like activating Wnt signaling.





Drugs that inhibit Wnt Signaling

There are drugs with the opposite effect, inhibiting Wnt signaling.


Abstract
In past years, the canonical Wnt/β-catenin signaling pathway has emerged as a critical regulator of cartilage development and homeostasis. FRZB, a soluble antagonist of Wnt signaling, has been studied in osteoarthritis (OA) animal models and OA patients as a modulator of Wnt signaling. We screened for FDA-approved drugs that induce FRZB expression and suppress Wnt/β-catenin signaling. We found that verapamil, a widely prescribed L-type calcium channel blocker, elevated FRZB expression and suppressed Wnt/β-catenin signaling in human OA chondrocytes. Expression and nuclear translocation of β-catenin was attenuated by verapamil in OA chondrocytes. Lack of the verapamil effects in LiCl-treated and FRZB-downregulated OA chondrocytes also suggested that verpamil suppressed Wnt signaling by inducing FRZB. Verapamil enhanced gene expressions of chondrogenic markers of ACAN encoding aggrecan, COL2A1 encoding collagen type II α1, and SOX9, and suppressed Wnt-responsive AXIN2 and MMP3 in human OA chondrocytes. Verapamil ameliorated Wnt3A-induced proteoglycan loss in chondrogenically differentiated ATDC5 cells. Verapamil inhibited hypertrophic differentiation of chondrocytes in the explant culture of mouse tibiae. Intraarticular injection of verapamil inhibited OA progression as well as nuclear localizations of β-catenin in a rat OA model. We propose that verapamil holds promise as a potent therapeutic agent for OA by upregulating FRZB and subsequently downregulating Wnt/β-catenin signaling.








AbstractConstitutive activation of canonical WNT-TCF signaling is implicated in multiple diseases, including intestine and lung cancers, but there are no WNT-TCF antagonists in clinical use. We have performed a repositioning screen for WNT-TCF response blockers aiming to recapitulate the genetic blockade afforded by dominant-negative TCF. We report that Ivermectin inhibits the expression of WNT-TCF targets, mimicking dnTCF, and that its low concentration effects are rescued by direct activation by TCFVP16. Ivermectin inhibits the proliferation and increases apoptosis of various human cancer types. It represses the levels of C-terminal β-CATENIN phosphoforms and of CYCLIN D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases. In vivo, Ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without obvious side effects. Analysis of single semi-synthetic derivatives highlights Selamectin, urging its clinical testing and the exploration of the macrocyclic lactone chemical space. Given that Ivermectin is a safe anti-parasitic agent used by > 200 million people against river blindness, our results suggest its additional use as a therapeutic WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases including multiple cancers.


Previous studies have revealed that its anti-tumor function could be attributed to its ability to suppress the abnormal Wnt/β-catenin signaling pathway


What about hair loss/gain?

To quote from  the previous study on hair loss gain:-

“Using this new knowledge, we now know that Wnt activity can be modulated by adjusting the secretion of Wnt ligands, altering binding of ligands to receptors, inhibiting β-catenin translocation, or by regulating extra-follicular dermal Wnt and Wnt inhibitors.”

We have now learnt that the drug Verapamil is thought to be a Wnt inhibitor.  So it would be fair to assume that hair loss would be reported as a side effect of using Verapamil.  Indeed it is.

Dermatologic side effects have included rash (up to 1.4%). Diaphoresis has been reported with intravenous verapamil. Arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, Stevens-Johnson syndrome, and erythema multiforme have been reported during open trials/postmarketing experience.


What about Statins and hair?

So many millions of people take statins, of course somebody would claim it causes hair loss (alopecia).  I think it should cause hair gain.  As with Verapamil the effect on the hair growth would be much greater if it was applied to the skin and not taken orally.  Maybe older people would not go to the doctor to complain about hair gain?




Summary

·        As hair loss is a generally accepted male characteristic, drug-induced alopecia may be mistaken as part of a natural process and therefore under reported.
·        There have been reports of alopecia associated with the use of all UK licensed statins but there is insufficient data to confidently attribute hair loss to statin use.
·        Case studies suggest an association but as yet there is insufficient information to suggest a mechanism, make comparisons of the individual incidence of alopecia between the various statins or propose a class effect.
·        The greatest number of reports of alopecia is for simvastatin but this may be related to a greater market share or length of time on market.


It would seem that enough people lose hair from Verapamil for it to be a published side effect.  The same is not true for statins and I think hair loss may be coincidental.


But, maybe too much and too little Wnt signaling cause hair loss ?

Recall earlier in this post that Hans Otto Kalkman suggested that both too much and too little Wnt might cause similar behavioral and cognitive symptoms.  Perhaps the same is true with hair growth.

The canonical Wnt pathway plays a role in dendrite growth and suboptimal activity negatively affects the dendritic arbor. In principle, this provides a logical explanation as to why both hypo- and hyperactivity may generate a similar set of behavioral and cognitive symptoms.

For optimal hair growth perhaps there is an optimal amount of Wnt signaling? 

That might explain why a small number of people find Wnt inhibitors (Verapamil) and drugs that enhance Wnt (statins) cause hair loss.

That might mean that people with very full hair have optimal Wnt signaling?

So advise Homer Simpson to find out whether his Wnt signaling is hyper or hypo.  Then he might find either simvastatin or verapamil brings back his full head of hair.



Wnt signaling and Diabetes

Yet again we find another connection between Diabetes and autism.

In the pancreas  β-cells produce insulin. In diabetics these β-cells get destroyed.  It appears that Wnt signaling is involved in controlling these β-cells.  It has been proposed that they could be protected via this pathway.


Role of Wnt signaling in the development of type 2 diabetes.

 

Abstract

Type 2 diabetes is characterized by insulin resistance, insulin deficiency, and hyperglycemia. Susceptibility to type 2 diabetes has been linked to Wnt signaling, which plays an important role in intestinal tumorigenesis. Carriers of variants of the transcription factor 7-like 2 gene, an important component of the Wnt pathway, are at enhanced risk for developing type 2 diabetes. The modulation of proglucagon expression by Wnt activity may partially explain the link between Wnt signaling and diabetes, and one of the transcriptional and processing products of the proglucagon gene, the glucagon-like peptide-1 (GLP-1), exhibits a wide variety of antidiabetogenic activities. GLP-1 stimulates Wnt signaling in pancreatic beta cells, enhancing cell proliferation; thus, positive feedback between GLP-1 and Wnt signaling may result in increased proliferation, and suppressed apoptosis, of pancreatic cells. Since beta-cell protection is a potential treatment for type 2 diabetes, stimulation of Wnt activity may represent a valid therapeutic approach.




Here, we review emerging new evidence that Wnt signaling influences endocrine pancreas development and modulates mature β-cell functions including insulin secretion, survival and proliferation. Alterations in Wnt signaling might also impact other metabolic tissues involved in the pathogenesis of diabetes, with TCF7L2 proposed to modulate adipogenesis and regulate GLP-1 production. Together, these studies point towards a role for Wnt signaling in the pathogenesis of type 2 diabetes, highlighting the importance of further investigation of this pathway to develop new therapies for this disease.





As with autism and cancer, the people with diabetes are also perhaps not benefiting from the latest science.



Oral verapamil administration prevents β-cell apoptosis and STZ-induced diabetes.





The End.