UA-45667900-1
Showing posts with label PAK1. Show all posts
Showing posts with label PAK1. Show all posts

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.





Thursday 2 October 2014

Dendritic Spines in Autism – Why, and potentially how, to modify them





This blog is getting rather more detailed than I had anticipated.  

Today’s post is about something very complex, but not fully understood by anyone, so I will be somewhat superficial in my coverage.  Just click on the links to learn more detail.

There are two words that may be new to you – Morphology and Dendritic Spines.





Morphology, in biology, the study of the size, shape, and structure of animals, plants, and microorganisms and of the relationships of the parts comprising them.

For today it is really could be thought of as the variability in size and shape of something.


A dendritic spine is a small protrusion from a neuron's dendrite that typically receives input from a single synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. Most spines have a bulbous head (the spine head), and a thin neck that connects the head of the spine to the shaft of the dendrite. 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.







Now we combine our two new words and have a better summary of what this post is about:

Morphology of dendritic spines and mental disease

It turns out that shape of dendritic spines may play a key role in mental disease, including autism.

The shape is not fixed and live imaging studies have revealed that spines are remarkably dynamic, changing size and shape over timescales of seconds to minutes and of hours to days.

The shape is important as it impacts on function, malformations lead to dysfunctions that can affect a myriad of brain functions.

Here are some variations in the shape of dendritic spines.









In case you are thinking this is all rather abstract, let’s jump forward to a patent for a possible new treatment for autism.


Afraxis Patent

  
SUMMARY OF THE INVENTION

Described herein are p21 -activated kinase (PA ) inhibitors that alleviate, ameliorate, delay onset of, inhibit progression of, or reduce the severity of at least one of the symptoms associated with autism.

Claims  

WHAT IS CLAIMED IS:

1. A method for treating autism comprising administering to an individual in need thereof a therapeutically effective amount of a p21 -activated kinase (PAK) inhibitor.
2. The method of claim 1, wherein the PAK inhibitor modulates dendritic spine morphology or synaptic function.
3. The method of claim 2, wherein the PAK inhibitor modulates dendritic spine density.
4. The method of claim 2 or 3, wherein the PAK inhibitor modulates dendritic spine length.
5. The method of any of claims 1-4, wherein the PAK inhibitor modulates dendritic spine neck diameter.
6. The method of any one of claims 1-5, wherein the PAK inhibitor modulates dendritic spine head volume.
7. The method of any one of claims 1-6, wherein the PAK inhibitor modulates dendritic spine head diameter.
8. The method of claim 1 or 2, wherein the PAK inhibitor modulates the ratio of the number of mature dendritic spines to the number of immature dendritic spines.
9. The method of claim 1 or 2, wherein the PAK inhibitor modulates the ratio of the dendritic spine head diameter to dendritic spine length.
10. The method of claim 1 or 2, wherein the PAK inhibitor modulates synaptic function.

Etc …

Of course, plenty of patents turn out to be worthless nonsense, but I think the people at Afraxis do know what they are doing; time will tell.



Morphology or Number of Dendritic Spines?

The PAK1 researchers and others believe the morphology (shape) of the dendritic spines is the problem, others believe the problem is that there are just too many of them.

Research has shown that a particular gene (NrCAM) can increase/decrease the number of dendritic spines.

Studies at University of North Carolina showed that knocking out the NrCAM gene caused mice to exhibit the same sorts of social behaviors associated with autism in humans.

Researchers from Columbia University found an overabundance of the protein MTOR in mice bred to develop a rare form of autism. By using a drug to limit MTOR in mice, the Columbia researchers were able to decrease the number of dendritic spines and thus prune the overabundance of synaptic connections during adolescence. As a result, the social behaviors associated with autism were decreased. However, the drug (Rapamycin) used to limit MTOR can cause serious side effects.



Dr. Tang measured synapse density in a small section of tissue in each brain by counting the number of tiny spines that branch from these cortical neurons; each spine connects with another neuron via a synapse.
By late childhood, she found, spine density had dropped by about half in the control brains, but by only 16 percent in the brains from autism patients.
“It’s the first time that anyone has looked for, and seen, a lack of pruning during development of children with autism,” Dr. Sulzer said, “although lower numbers of synapses in some brain areas have been detected in brains from older patients and in mice with autistic-like behaviors.”
Using mouse models of autism, the researchers traced the pruning defect to a protein called mTOR. When mTOR is overactive, they found, brain cells lose much of their “self-eating” ability. And without this ability, the brains of the mice were pruned poorly and contained excess synapses. “While people usually think of learning as requiring formation of new synapses, “Dr. Sulzer says, “the removal of inappropriate synapses may be just as important.”

“What’s remarkable about the findings,” said Dr. Sulzer, “is that hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning. This says that many, perhaps the majority, of genes may converge onto this mTOR/autophagy pathway, the same way that many tributaries all lead into the Mississippi River. Overactive mTOR and reduced autophagy, by blocking normal synaptic pruning that may underlie learning appropriate behavior, may be a unifying feature of autism.”


Maness, a member of the UNC Neuroscience Center and the Carolina Institute for Developmental Disabilities, also said that there are likely many other proteins downstream of NrCAM that depend on the protein to maintain the proper amount of dendritic spines. Decreasing NrCAM could allow for an increase in the levels of some of these proteins, thus kick starting the creation of dendritic spines.

Knocking out the gene NrCAM increases the number of dendritic spines  
   
Gene linked to increased dendritic spines -- asignpost of autism

  
The view from Japan

RIKEN is a large research institute in Japan, with an annual budget of US$760 million.  Their Brain Science Institute (BSI) has a mission to produce innovative research and technology leading to scientific discoveries of the brain.  So RIKEN  BSI is like MIT just for the brain.

Science does tend to stratify by geography.  Just as we saw that NGF (Nerve Growth Factor) is the preserve of the Italians, when it comes to PAK it is the Japanese.
As you can see below the Japanese are firmly behind PAK1. 

Abstract
The serine/threonine kinase p21-activated kinase 1 (Pak1) modulates actin and microtubule dynamics. The neuronal functions of Pak1, despite its abundant expression in the brain, have not yet been fully delineated. Previously, we reported that Pak1 mediates initiation of dendrite formation. In the present study, the role of Pak1 in dendritogenesis, spine formation and maintenance was examined in detail. Overexpression of constitutively active-Pak1 in immature cortical neurons increased not only the number of the primary branching on apical dendrites but also the number of basal dendrites. In contrast, introduction of dominant negative-Pak caused a reduction in both of these morphological features. The length and the number of secondary apical branch points of dendrites were not significantly different in cultured neurons expressing these mutant forms, suggesting that Pak1 plays a role in dendritogenesis. Pak1 also plays a role in the formation and maintenance of spines, as evidenced by the altered spine morphology, resulting from overexpression of mutant forms of Pak1 in immature and mature hippocampal neurons. Thus, our results provide further evidence of the key role of Pak1 in the regulation of dendritogenesis, dendritic arborization, the spine formation, and maintenance.


SHANK3 and Dendritic Spines

Mutations of the SHANK3 gene are known to cause autism. 

Researchers in France found that SHANK3 mutations lead to modification of dendritic spine morphology and they identified the mechanism.



You may recall in my earlier posts on growth factors that it was this type of autism that responded to treatment with IGF1.



If you take a broader look at today’s subject you will see that various growth factors are indeed closely involved.  Here is some comment from Wayman Lab at Washington State University:- 


"Not surprisingly, abnormalities in dendritic arborization and spinogenesis, which diminish neuronal connectivity, are a common feature of the cognitively compromised aging brain as well as numerous forms of mental retardation including Fragile X, Fetal alcohol, Downs and Retts syndromes.

It is clear that changes in synaptic activity and neurotropic factors (e.g., BDNF) are effective initiators of the remodeling process and result in long-term alterations in dendrite and spine structure. What is not known are the molecular mechanisms that underlie how they stimulate dendritic spine formation."


Take your pick

So it looks like three different methods may exist to potentially modify dendritic spine numbers and morphology:-


1.   PAK1

Much work is ongoing regarding PAK1.  It is my current favorite.
For those interested here is a recent study using FRAX486 on Fragile X mice.


Abnormal dendritic spines are a common feature in FXS, idiopathic autism, and intellectual disability. Thus, this neuroanatomical abnormality may contribute to disease symptoms and severity. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect may also ameliorate behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). In a healthy brain, PAK and FMRP - the protein product of fmr1 - antagonize one another to regulate spine number and shape. Inhibition of PAK with a strategy utilizing mouse genetics reverses spine abnormalities as well as cognitive and behavioral symptoms in fmr1 KO mice, as we demonstrated in our previous publication. This discovery highlights PAK as a potential target for drug discovery research. In this thesis work, we build on this finding to test whether the small molecule FRAX486 - selected for its ability to inhibit PAK - can rescue behavioral, morphological, and physiological phenotypes in fmr1 KO mice. Our results demonstrate that seizures and behavioral abnormalities such as hyperactivity, repetitive movements, and habituation to a novel environment can all be rescued by FRAX486. Moreover, FRAX486 reverses spine phenotypes in adult mice, thereby supporting the hypothesis that a drug treatment which reverses the spine abnormalities can also treat neurological and behavioral symptoms.


2. mTOR

In spite of its noted toxicity, Rapamycin, is about to be tested in a clinical trial on a rare type of autism called TSC:-



Funnily enough the trial is taking place at the Kennedy Krieger Institute.

When commenting on the use of Bumetanide for autism, I recall the President of the Institute was quoted as saying:-


"So many things cure cancer in mice and rats, and so many things cure all kinds of things and then when we give them to humans they have adverse effects and don't fix the problems we thought they could fix," says Gary Goldstein, president and CEO of the Kennedy Krieger Institute, a Baltimore-based clinic and research center. "I wouldn't give it to my child, I can tell you that."

I found it a little odd that he gave the green light to trialing Rapamycin in children, given the long list of very nasty side effects.

  
3.  NrCAM 

Manesslab at UNC is clearly the centre for research into finding therapeutic agents surrounding NrCAM.  It looks like this is still some way from trials in humans.

“Too many spines and too many excitatory connections that are not pruned between early childhood and adolescence could be one of the chief problems underlying autism. Our goal is to understand the molecular mechanisms involved in pruning and find promising targets for therapeutic agents.”



Conclusion

It should not be surprising that multiple pathways may have the same therapeutic benefit on dendritic spines.  We only need one to be safe and effective.

The link back to human growth factors is interesting since we know these are disturbed in autism and other mental conditions, but the dysfunction varies by sub-type.  In fact, Nerve Growth Factor (NGF) would likely be an effective therapy for dementia and perhaps even Retts syndrome.

In the next post we will learn some more interesting things about growth factor anomalies in autism.  It turns out that something called Akt, also known as protein kinase B (PKB), may be behind them all. A related protein called protein kinase C (PKC), is known to affect the morphology of dendritic spines. There is also protein kinase A (PKA).  Both PKA and PKB have been shown to have reduced activity in regressive autism, this will also be covered later.