Showing posts with label Bio30. Show all posts
Showing posts with label Bio30. Show all posts

Friday 19 August 2016

PAK inhibitors and potentially treating some Autism using Grandpa’s Medicine Cabinet

I wrote several posts about why PAK1 inhibitors should be beneficial in some autism and indeed some schizophrenia.

We also saw that PAK1-blocking drugs could be potentially useful for the treatment of neurofibromatosis type 2, in addition to RAS-induced cancers and neurofibromatosis type 1.

One problem with drugs developed for cancer is that, even if they finally get approved, they tend to be ultra-expensive.  Production volumes are low because even if they “work” they do not prolong life for so long and cancer has numerous sub-types.

Cheap drugs are ones used to treat common chronic conditions like high blood pressure, high cholesterol and indeed treatment of male lower urinary tract symptoms (LUTS), like benign prostatic hyperplasia (BPH).

A small number of readers of this blog have confirmed the beneficial effect of PAK inhibitors in their specific sub-types of autism.  The problem is that there are no potent PAK1 inhibitors suitable for long term use that are readily available.

The anti-parasite drug Ivermectin is an extremely cheap PAK1 inhibitor, but cannot be used long term, due to its other effects.

Propolis containing CAPE (Caffeic Acid Phenethyl Ester) is a natural PAK1 inhibitor, but may not be sufficiently potent as is reported by people with neurofibromatosis.

You would think somebody would just synthesize CAPE (Caffeic Acid Phenethyl Ester) artificially and then higher doses could be achieved.

PAK Inhibitors and Treatment of Prostate Enlargement

I was rather surprised that research has recently been published suggesting that PAK inhibitors could be used to treat the prostate enlargement, common in most older men. 


Prostate smooth muscle tone and hyperplastic growth are involved in the pathophysiology and treatment of male lower urinary tract symptoms (LUTS). Available drugs are characterized by limited efficacy. Patients’ adherence is particularly low to combination therapies of 5α-reductase inhibitors and α1-adrenoceptor antagonists, which are supposed to target contraction and growth simultaneously. Consequently, molecular etiology of benign prostatic hyperplasia (BPH) and new compounds interfering with smooth muscle contraction or growth in the prostate are of high interest. Here, we studied effects of p21-activated kinase (PAK) inhibitors (FRAX486, IPA3) in hyperplastic human prostate tissues, and in stromal cells (WPMY-1). In hyperplastic prostate tissues, PAK1, -2, -4, and -6 may be constitutively expressed in catecholaminergic neurons, while PAK1 was detected in smooth muscle and WPMY-1 cells. Neurogenic contractions of prostate strips by electric field stimulation were significantly inhibited by high concentrations of FRAX486 (30 μM) or IPA3 (300 μM), while noradrenaline- and phenylephrine-induced contractions were not affected. FRAX486 (30 μM) inhibited endothelin-1- and -2-induced contractions. In WPMY-1 cells, FRAX486 or IPA3 (24 h) induced concentration-dependent (1–10 μM) degeneration of actin filaments. This was paralleled by attenuation of proliferation rate, being observed from 1 to 10 μM FRAX486 or IPA3. Cytotoxicity of FRAX486 and IPA3 in WPMY-1 cells was time- and concentration-dependent. Stimulation of WPMY-1 cells with endothelin-1 or dihydrotestosterone, but not noradrenaline induced PAK phosphorylation, indicating PAK activation by endothelin-1. Thus, PAK inhibitors may inhibit neurogenic and endothelin-induced smooth muscle contractions in the hyperplastic human prostate, and growth of stromal cells. Targeting prostate smooth muscle contraction and stromal growth at once by a single compound is principally possible, at least under experimental conditions.

It looks like a PAK inhibitor could potentially solve both the key problems in BPH and so replace the current therapies.

Existing Drugs for LUTS/BPH

Undoubtedly someone is going to wonder whether existing drugs for LUTS/BPH might improve autism.  This is actually possible, but totally unrelated to PAK1 inhibition and RASopathies.

Existing drugs are in two classes, 5α-reductase inhibitors and α1-adrenoceptor antagonists.

α-adrenoceptor antagonists

Alpha blockers relax certain muscles and help small blood vessels remain open. They work by keeping the hormone norepinephrine (noradrenaline) from tightening the muscles in the walls of smaller arteries and veins, which causes the vessels to remain open and relaxed. This improves blood flow and lowers blood pressure.
Because alpha blockers also relax other muscles throughout the body, these medications can help improve urine flow in older men with prostate problems.

Selective α1-adrenergic receptor antagonists are often used in BPH because it is the α1-adrenergic receptor that is present in the prostate.

 α 2-adrenergic receptors are present elsewhere in the body

Alpha-2 blockers are used to treat anxiety and post-traumatic stress disorder (PTSD). They decrease sympathetic outflow from the central nervous system. Post-traumatic stress disorder is an anxiety disorder that is theorized to be related to a hyperactive sympathetic nervous system.

Alpha-2 receptor agonists for the treatment of post-traumatic stress disorder

So a nonselective alpha blocker, like one given to an older man with high blood pressure and BPH, might well have an effect on some kinds of anxiety.

You would think that a selective alpha 2 blocker might be interesting, how about Idazoxan?

Idazoxan is a drug which is used in research. It acts as both a selective α2 adrenergic receptor antagonist, and an antagonist for the imidazoline receptor. Idazoxan has been under investigation as an antidepressant, but it did not reach the market as such. More recently, it is under investigation as an adjunctive treatment in schizophrenia. Due to its alpha-2 receptor antagonism it is capable of enhancing therapeutic effects of antipsychotics, possibly by enhancing dopamine neurotransmission in the prefrontal cortex of the brain, a brain area thought to be involved in the pathogenesis of schizophrenia.

Mirtazapine is a cheap generic drug used at high doses for depression.  It happens to be a selective alpha 2 blocker, but it has numerous other effects as well.  One reader of this blog does respond very well to Mirtazapine.

So realistically in Grandpa’s medicine cabinet there might a selective alpha 1 agonist or a non-selective alpha agonist, it is the latter type that might have an effect on some kinds of autism.

5α-reductase inhibitors

The pharmacology of 5α-reductase inhibition involves the binding of NADPH to the enzyme followed by the substrate. Specific substrates include testosterone, progesterone, androstenedione, epitestosterone, cortisol, aldosterone, and deoxycorticosterone.

Beyond being a catalyst in testosterone reduction, 5α-reductase isoforms I and II reduce progesterone to 5α-dihydroprogesterone (5α-DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC).

In vitro and animal models suggest subsequent 3α-reduction of DHT, 5α-DHP and DHDOC lead to neurosteroid metabolites with effect on cerebral function.

These neurosteroids, which include allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 5α-androstanediol, act as potent positive allosteric modulators of GABAA receptors, and have anticonvulsant, antidepressant, anxiolytic, prosexual, and anticonvulsant effects.

Inhibition of 5α-reductase results in decreased conversion of testosterone to DHT.

This, in turn, results in slight elevations in testosterone and estradiol levels. 

In BPH, DHT acts as a potent cellular androgen and promotes prostate growth; therefore, it inhibits and alleviates symptoms of BPH. In alopecia, male and female-pattern baldness is an effect of androgenic receptor activation, so reducing levels of DHT also reduces hair loss.

A new look at the 5alpha-reductase inhibitor finasteride

Finasteride is the first 5alpha-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to inhibit the Type II isoform of the 5alpha-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihydrotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms of the 5alpha-reductase enzyme are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC), respectively. Recent preclinical data indicate that the subsequent 3alpha-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of gamma-aminobutyric acid (GABA)ergic inhibitory neurotransmission. Consistent with their ability to enhance the action of GABA at GABA(A) receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual- and alcohol-related behaviors. Thus, finasteride, which inhibits both isoforms of 5alpha-reductase in rodents, has been used as a tool to manipulate neuroactive steroid levels and determine the impact on behavior. Results of some preclinical studies and clinical observations with finasteride are described in this review article. The data suggest that endogenous neuroactive steroid levels may be inversely related to symptoms of premenstrual and postpartum dysphoric disorder, catamenial epilepsy, depression, and alcohol withdrawal.

This would suggest that a 5α-reductase inhibitor, like finasteride, that might be among Grandpa’s tablets might very well have an effect on someone with GABAa dysfunction, this includes very many people with autism, schizophrenia and Down Syndrome.

Whether the effect will be good or bad is hard to say, and may well depend on whether other drugs that target GABA or NMDA receptors are being used. Due to their other effects, 5α-reductase inhibitors are usually only used in adults.

Merck developed a lower dose form of finasteride, called Prospecia to treat baldness, usually in men.  It is 20% the normal potency used for BPH.

Side effects

The current BPH drugs cause side effects in some people.  PAK1 inhibitors may also have some side effects.


Going back in the days of living with your extended family might make treating many people’s autism much simpler.  It looks like many older people’s drugs can be repurposed for some types of autism (ion channel modifying diuretics, calcium channel blockers, statins, even potentially intranasal insulin in some).  Because older people’s drugs are so widely used they are well understood and inexpensive.  

Clearly the research on PAK inhibitors for LUTS/BPH is at an early stage, but there is a huge potential market.   A widely available PAK1 inhibitor might be a big help to some people with autism, neurofibromatosis, other RASopathies, not just Grandpa’s prostate.

In addition to FRAX486 and IPA3, why doesn’t someone try synthetic CAPE, i.e. without the bees, as a PAK inhibitor?

Bioactivity and chemical synthesis of caffeic acid phenethyl ester and its derivatives.

There is far more chance of a PAK1 inhibitor coming to market for LUTS/BPH, or certain cancers than for autism.  That is a fact of life.

As for 5α-reductase inhibitors, like finasteride, we know from Hardan’s study on Pregnenolone at Stanford that this hormone can have a positive effect and we know that various natural steroid metabolites will modulate GABA subunits.  So it is quite likely that finasteride is going have a behavioral effect.  Perhaps Hardan would like to trial finasteride 5mg and 1mg (Prospecia) in some adults with autism. I suspect it will make some people “worse” and others somewhat “better”; so please do not report the “average” response, highlight the nature of the positive responders.

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.

Friday 6 June 2014

PAK1 Therapy for Autism – All packed and ready to go!

Following up on recent posts about PAK1, whose presence is required for 70% of cancers to grow and MIT have implicated in several types of autism, I have collected all the data I can find to make trials of PAK1 inhibition in autism.
I contacted the leading Japanese researcher who has developed PAK1 therapies for various kinds of tumor, mainly found in neurofibromatosis, but also brain tumors and even epilepsy.  He suggested the dosage of the CAPE-rich propolis from New Zealand and also suggested another drug called Fingolimod/Gilenya.  

This drug is an immunomodulating drug, approved for treating multiple sclerosis, but it is also a PAK1 inhibitor.  It appears to cross the blood brain barrier.  The downside it that Gilenya is hugely expensive, costing around $50,000 a year.
While Tonegawa's group at MIT continue to develop their new PAK1 inhibitors, I am concerned that they will end up with a drug costing as much as Gilenya, which will put it out of reach of most people, even if it was effective.

So that brings me back to the trials I propose.

Trial 1   -  BIO 30 Propolis

This is a natural product and as such will appeal to many of this blogs readers.  It needs no prescription from your doctor.  You can buy it over the internet from numerous pharmacies in New Zealand.

The dosage proposed for autism by the Japanese Researcher is 1-2 ml per 10 kg of body weight.

It appears that about 1% of people have an allergy to bee products.  If you are in the 99%, it is reported that even very much larger doses of BIO 30 have no side effects.

Trial 2   -  Ivermectin/Stromectol

This is the cheap drug that is used to treat parasites, but turns out to be a PAK1 inhibitor.  It was also recently shown to kill leukemia cells.

Here I will draw on the autism worm-dosage used by Dr Wu, who prescribes Ivermectin in the belief that the autistic kids’ behaviours are driven by worms.

Dr Yu is combining Ivermectin with other anti-parasite drugs.  I am assuming he “got it right for the wrong reason”, in other words the worms are not the issue, PAK1 is the issue.

Below is the dosage Dr Yu suggests in his autism presentation and one case report where there was a before and after evaluation.  Here the ATEC was used, which is a scale designed by Bernard Rimland and Stephen M.Edelson of the Autism Research Institute (the DAN people).


From what I could find, a single dose of Ivermectin (Stromectol) should kill the parasites.  Pets are given the same drug on a regular basis, some preventatively.

In low doses it appears to be very safe, but not in high doses.

Strongyloidiasis is a human parasitic disease caused by the nematode (roundworm).  On the site the dosage for Strongyloidiasis is:-

The above is for a single dose therapy.  Dr Wu’s worms are either much more resilient, or his much higher and multiple dose therapy is actually working for entirely different reasons.

Trial 3   -   Fingolimod/Gilenya

Given the huge cost of Gilenya, I cannot imagine anybody trying it for autism.  Perhaps Novartis would like to donate some?

We did cover immunomodulatory therapy in earlier posts and it was Dr Chez who likes to write about this subject, in relation to autism.  He has published several trials and a good book.

Perhaps he should do the Gilenya trial?

The Blood Brain Barrier

I did ask the Japanese researcher if CAPE, the anti-PAK1 ingredient of the New Zealand propolis can cross the blood brain barrier, since it is claimed that Ivermectin does not.  He says that BIO30 and Fingolimod/Gilenya cross the BBB.

This brings me to a slight diversion.

In this research the aim was to confirm the mechanism behind why inflammation causes the blood brain barrier (BBB) to leak.  It has been suggested that the leaky BBB is a key part of autism.  The less leaky it is the better for autism.  Since pro-inflammatory agents like histamine and IL-6 really do make autism worse, it is highly relevant that the research shows that pro-inflammatory agents cause the BBB to let through more of the substances that it is supposed to keep out.

Perhaps the ever-present pro-inflammatory cytokines found in autism, mean that the BBB is always partially compromised.  A drug like Ivermectin might therefore pass more freely across the BBB, than would be expected in other people.

So Ivermectin might remain a cheap alternative to Gilenya.  Dr Yu’s case studies perhaps warrant some more serious attention.

Will it work?

There are good reasons why PAK1 inhibition should have a positive effect.  It is definitely not quack science, it is the serious MIT kind.

In treating Neurofibromatosis NF-1 tumors, it does seem to be more effective at stopping new tumors, rather than shrinking existing ones.   This perhaps should not be surprising, since PAK1 is needed for a tumor to grow and may not be needed for it to live.  At much higher doses, it is reported that existing tumors shrink. So with autism, maybe PAK1 is needed early on, before birth; blocking PAK1 in a 10 year old may be pointless.

The only way to find out for sure if it works in your type of autism is to try it.

If it does not work for Monty, aged 10 with ASD, we cannot say it will not work in somebody’s two year old with a different type of autism.

Also, in Monty, the PAK1 effect might already be being mitigated by his existing drugs.

It would be helpful if there was a clinical trial, but there is not.


Trial 1 is easy to do at home, and if you do it for a month, you would need two bottles of propolis, costing $50 including shipping from New Zealand.

Since the Nobel Laureate from MIT tells us that autism requires PAK1 and that, in mouse models of autism, PAK1 inhibitors are effective treatments, it seems odd nobody has tried it.  In PAK1-driven Neurofibromatosis, there are now many people claiming BIO30 to be effective.  In this condition you can measure/count the tumors, so I guess they should know if it works.

The MIT-inspired drugs, like Tonegawa’s FRAX486 will not be available for many years, and who knows how much they will cost.

In the case of Ivermectin, somebody really should look at the toxicology data and see how safe regular usage would be in humans.  The Leukemia researchers proposed this drug be actively developed, but nothing seems to have happened.  Just for a few days, Trial 2 would not seem to be too risky.

We agree to leave trial 3 to Dr Chez, in Sacramento.

Wednesday 21 May 2014

PAK inhibitors not just for Cancer, Alzheimer’s and Neurofibromatosis, but also for Autism, Schizophrenia, Fragile X and Shank 3

You might be wondering, what does a time bomb have to do with all the above conditions.  The answer is a substance in the human body called PAK1.  PAK1 appears to have no useful bodily function, after birth, but it appears to be behind very many dysfunctions in the body.  One scientist suggested that it is there to ensure that we do not live forever.

PAK1 is at the centre of a very expensive effort to develop effective cancer drugs; since the majority of cancers, for males or females, involve PAK1.  If you can block or inhibit PAK1, you can stop tumour growth in many types of cancer.  It turns out that PAK1 is also involved in Alzheimer’s, Huntington's Disease, Neurofibromatosis, Autism, Schizophrenia, Fragile X and Shank 3.

Cancer drugs are big business and budgets seem to be almost limitless.  The good thing is that as long as the PAK1 inhibitor can cross the blood brain barrier (BBB), what works for cancer, is likely to have an effect in all the mentioned brain conditions, including autism.

What is odd, is that in the rare condition of Neurofibromatosis Type 1, which in mild cases might be considered autism with spots, families with the condition are widely aware of PAK1 and are not waiting for drugs to be commercialized.  They are using naturally available PAK inhibitors, like a particular kind of Propolis from New Zealand.  It seems that NF-1, along with PANDAS and PANS, is thought of as a disease to be treated, whereas the much more common, autism, still is not.  Odd isn’t it?

Many of the researchers looking at PAK are Japanese and this in itself is interesting.  Japanese medicine, like Russian medicine, is a world of its own; indeed Russian researchers are also heavily involved in PAK research.   So many clever minds are engaged in this effort.

There are as yet no commercially available PAK1 drugs, but there are many experimental ones.

One problem I have observed is that there are three very similar types of PAK - PAK1, PAK2 and PAK3.  The new drugs seem to inhibit all the three, to greater or lesser extents.  The problem I have seen is that PAK2 is actually good for you.  Blocking PAK1 and PAK2 in mice might work wonders, but in humans this might not be true.  It appears we need PAK1-specific drugs, that do not affect PAK2.

PAK Research in Detail

Since even Wikipedia does not cover the science of PAK in any depth, neither will I.  I have found an excellent collection of research from 2013 that will tell the scientists among you, everything there is to know.  It is available as book or electronically, if you look on google for a minute or two you may find a free ebook version.

PAKs, RAC/CDC42 (p21)-activated Kinases, 1st Edition

Towards the Cure of Cancer and Other PAK-dependent Diseases

 It is very readable and if you are interested in cancer or Alzheimer’s it should also be of interest.

In my post I will just look at the treatment possibilities and research that shows it should be effective.

I will look at a wide range of conditions related to autism, namely:-
  • Schizophrenia  (adult-onset autism)
  • Neurofibromatosis Type 1 (autism with spots)
  • Fragile X (autism with low muscle tone and MR)
  • Shank 3
  • Mental Retardation (MR)
 Mast cells will also make another guest appearance.  

I have already suggested in early posts that following rare genetic conditions may not lead us anywhere in our search for effective autism therapies;  however, when you have three of them, plus schizophrenia, then we have to take note.

As a bonus we have another Nobel Laureate, this time Susumu Tonegawa from MIT.  He works at MIT’s Picower Center for Learning and Memory, along with Mike Bear, who we have previously covered in relation to both Arbaclofen and mGluR5.  Tonegawa suffered his own tragedy when his teenage son committed suicide in his dorm room at MIT.

p21 activated kinases (PAKs) and PAK inhibitors

PAKs are not somethings you are likely to heard of, even the ever up to date Wikipedia has virtually nothing to say on the subject; I guess we must be at the cutting edge.

PAKs are a family of enzymes in the body.  They are implicated in many biological processes, one of which is cancer.  The chemicals that reduce the activity of these enzymes are called PAK inhibitors 

We are interested in Group 1 PAKs that is to say PAK1, PAK2 and PAK3; in particular we want to find PAK1 inhibitors.

To date a lot of money has been spent looking for drugs that are effective PAK inhibitors, but also safe for humans 

The Role of PAK1 in Brain Dysfunction

PAK1 appears to play a central role in lost brain cell function in  Schizophrenia, Fragile X, Shank 3 and  Neurofibromatosis Type 1 (NF-1).  Different scientists are involved in these different areas and their explanation of what is going on does vary.  But in effect they all found (in their mouse models) that by inhibiting PAK, they could restore lost brain function.

There is now a research drug called FRAX486 that looks particularly effective and this is the drug used in the trials I will detail later.

The problem is that research drugs take decades to become approved human drugs and I do not want to wait decades.  So the choice is either to use the research drug or find another PAK-inhibitor.  I opt for the latter.

Note on Mast Cells

Regular readers will have noticed how I believe mast cells play a surprisingly important role in autism.  Here is a link and a summary from a paper showing how PAK2 plays a role in stabilizing mast cells, whereas PAK1 plays an opposing role in making them degranulate.  When this happens histamines, IL-6 and other inflammatory agents are released.  So PAK2 does some good.


 The Research Studies

Susumu Tonegawa at MIT is one of the clever scientists pursuing PAK inhibitors;  he is looking at Fragile-X and now, it appears autism.  I think he is the clear expert in this field.
Having established its role in many cancers,  next came its role NF-1, Shank-3, Fragile-X and most recently schizophrenia.  Since schizophrenia is very common and clearly overlaps mainstream autism, we will start there.

Experimental Drug FRAX486 Reverses Schizophrenia In Mice

"A new study shows that one of a class of compounds known as PAK inhibitors, appears to have reversed behaviors associated with schizophrenia and restored some lost brain cell function in adolescent mice with a rodent version of the mental illness. The researchers at Johns Hopkins found that the compound FRAX486 appears to halt an out-of-control biological “pruning” process in the schizophrenic brain during which important neural connections are unnecessarily destroyed."

Moreover, this PAK inhibitor—which we call FRAX486—also rescues seizures and behavioral abnormalities such as hyperactivity and repetitive movements, thereby supporting the hypothesis that a drug treatment that reverses the spine abnormalities can also treat neurological and behavioral symptoms. Finally, a single administration of FRAX486 is sufficient to rescue all of these phenotypes in adult Fmr1 KO mice, demonstrating the potential for rapid, postdiagnostic therapy in adults with FXS.

Drug discovery in psychiatry has been limited to chemical modifications of compounds originally discovered serendipitously. Therefore, more mechanism-oriented strategies of drug discovery for mental disorders are awaited. Schizophrenia is a devastating mental disorder with synaptic disconnectivity involved in its pathophysiology. In this study, we studied a biological pathway underlying synaptic disturbance and examined whether p21-activated kinase inhibitors ameliorate the pathology in vitro and in vivo. The beneficial effects of these inhibitors reported here may provide us with an opportunity for drug discovery in major mental illnesses with synaptic disturbance.
Drug discovery in psychiatry has been limited to chemical modifications of compounds originally discovered serendipitously. Therefore, more mechanism-oriented strategies of drug discovery for mental disorders are awaited. Schizophrenia is a devastating mental disorder with synaptic disconnectivity involved in its pathophysiology. Reduction in the dendritic spine density is a major alteration that has been reproducibly reported in the cerebral cortex of patients with schizophrenia. Disrupted-in-Schizophrenia-1 (DISC1), a factor that influences endophenotypes underlying schizophrenia and several other neuropsychiatric disorders, has a regulatory role in the postsynaptic density in association with the NMDA-type glutamate receptor, Kalirin-7, and Rac1. Prolonged knockdown of DISC1 leads to synaptic deterioration, reminiscent of the synaptic pathology of schizophrenia. Thus, we tested the effects of novel inhibitors to p21-activated kinases (PAKs), major targets of Rac1, on synaptic deterioration elicited by knockdown expression of DISC1. These compounds not only significantly ameliorated the synaptic deterioration triggered by DISC1 knockdown but also partially reversed the size of deteriorated synapses in culture. One of these PAK inhibitors prevented progressive synaptic deterioration in adolescence as shown by in vivo two-photon imaging and ameliorated a behavioral deficit in prepulse inhibition in adulthood in a DISC1 knockdown mouse model. The efficacy of PAK inhibitors may have implications in drug discovery for schizophrenia and related neuropsychiatric disorders in general.
There are many other neuropsychiatric disorders with synaptic changes that might benefit from these compounds. The Tonegawa laboratory previously published that PAK inhibition and knockout are protective against synaptic deterioration in an animal model for Fragile X syndrome (38, 39). In addition, several lines of evidence have suggested the involvement of PAKs in Alzheimer’s disease and mental retardation (4043). Studies that aim to identify rare variants associated with neuropsychiatric disorders may further reveal PAK family genes as genetic factors. Thus, consideration of these compounds in many other neuropsychiatric disorders may also be an important subject in future studies.
As far as we are aware, PAKs are regarded as therapeutic targets in cancer and immune/allergy-related conditions. Although this question requires careful consideration, we expect minimal adverse effects of PAK inhibitors when we target neuropsychiatric disorders.

This is an interesting patent that was granted on the basis of using PAK1 inhibitors to treat social learning disorders

The use of Pak1 inhibitors to treat social or learning disabilities is disclosed. In one embodiment patients exhibiting social or learning disabilities as well as abnormally low NF1 activity are administered PAK inhibitors to treat the social or learning disabilities. Reductions in PAK activity have been found to ameliorate the effects of aberrant neurofibromatosis type 1 activity.

Applicants have demonstrated that defects in NF1 gene leads to deficiencies in learning including for example, deficiencies in social learning. The NF1 gene encodes neurofibromin, which negatively regulates Ras GTPase activation, and thereby reduces the strength and duration of Ras signal transduction. P21-activated kinase (Pak1) is a downstream effector regulated by the Rho family of GTPases that mediate diverse cellular functions including cytoskeletal dynamics, vesicular transport, and gene expression.

Applicants have discovered that the deficit in social learning associated with Nf1+/− mice is rescued by deletion of the Pak1 gene. Accordingly, applicants anticipate that patients having defective NF1 activity can be treated with PAK inhibitors (e.g., a Pak1 inhibitor) to treat learning disabilities and other symptoms or conditions resulting from deficient Nf1 activity. In accordance with one embodiment a method for treating an NF1 deficiency (i.e., decreased NF1 gene expression, decreased NF1 protein product, or decreases functionality of the NF1 protein product relative to the native NF1 gene product) associated learning disability is provided. In one embodiment the method comprises the steps of identifying a patient with defective NF1 activity and administering to said patient a pharmaceutical composition comprising an effective amount of a PAK inhibitor


In case you do not know, neurofibromatosis (NF1) is one of the most common single gene disorders.  It is associated with skin conditions of widely varying magnitude, but surprisingly many autistic-like neurobehavioral developmental disorders are present.  It seems that NF1 is highly comorbid with autism and ADHD.  A recent survey showed half of parents reported autistic behaviours, far higher than the literature had suggested.  Since only 20% of cases have physical complications, it would seem highly likely that many cases are misdiagnosed as autism.


Neurofibromatosis is considered a treatable medical condition, even in countries that do not regard autism as treatable.  In the United Kingdom there are two clinical centres for the condition, and in Germany it seems that Hamburg is the clinical centre of excellence.

Mental Retardation (MR)

I have already mentioned in previous posts that some types of mental retardation may indeed by treatable, this was based on my observation that certain drugs can produce cognitive improvement in autism.
So it was a nice surprise to find in the literature that PAK3 has been shown to be involved in some types of MR.  That would imply PAK3 inhibitors might have some effect on MR.
Since MR is highly comorbid with autism, perhaps PAK3 is also involved in autism. 

Importance of the field

P21-activated kinases (PAKs) are involved in multiple signal transduction pathways in mammalian cells. PAKs, and PAK1 in particular, play a role in such disorders as cancer, mental retardation and allergy. Cell motility, survival and proliferation, the organization and function of cytoskeleton and extracellular matrix, transcription and translation are among the processes affected by PAK1.

8. PAK1 in neurological and mental disorders

PAK3 in clearly involved in some neurodegenerative disorders and variants of mental retardation and plays a special role in synapse formation and plasticity in hippocampus. However, the involvement of PAK1 in these processes is less clear-cut. For example, both PAK1 and PAK3 were reduced in the hippocampus affected by Alzheimer disease, yet only PAK3 was affected in some other areas of the diseased brain. However, this reported loss of the PAKs from the cytosol appears to be accompanied by re-localization of PAKs to the membrano-cytoskeletal fractions, where they appear to be active. Using staining for drebnin and reduction in dendrites as indicators, Dr. Cole’s group has observed that a dominant-negative form of PAK1 sensitizes, while the wild type form protects from some effects of beta-amyloid oligomers in cultured primary neurons. However, in both cases it is hard to rule out that ectopically expressed PAK1 in some of these experiments acted as a surrogate for the highly homologous PAK3.
Dominant-negative PAK1, which, potentially, inhibits other PAK isoforms as well, upon expression in mouse forebrain affected synapse morphology and consolidation of long-term memory, but rescued some defects of a mouse model of Fragile X syndrome.
In case of Huntington’s disease, PAK1 specifically co-localizes with huntingtin inclusions in the affected brain146. In tissue culture models, interference with PAK1 function modestly decrease the formation of aggregates by mutant huntingtin, while the constitutively active PAK1 enhances the aggregation. Accordingly, similar activity was reported for PAK1 regulator α-PIX. The matter is complicated, however, by the observation that kinase activity of PAK1 is dispensable for this phenomenon. Overall, it appears that pathological changes in the brain could be associated both with elevated and reduced function of PAKs and the specific role of PAK1 in these processes may be variable as well.

Group I p21-activated kinases are a family of key effectors of Rac1 and Cdc42 and they regulate many aspects of cellular function, such as cytoskeleton dynamics, cell movement and cell migration, cell proliferation and differentiation, and gene expression. The three genes PAK1/2/3 are expressed in brain and recent evidence indicates their crucial roles in neuronal cell fate, in axonal guidance and neuronal polarisation, and in neuronal migration. Moreover they are implicated in neurodegenerative diseases and play an important role in synaptic plasticity, with PAK3 being specifically involved in mental retardation. The main goal of this review is to describe the molecular mechanisms that govern the different functions of group I PAK in neuronal signalling and to discuss the specific functions of each isoform.


The SHANK3 gene is a member of the Shank gene family. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways.  Mutations of the SHANK3 gene are known to be associated with autism.  

It is complex, but it appears that the reducing effect of Shank3 knockdown on NMDARs and F-actin is blocked by PAK1 inhibitors

Shank3, which encodes a scaffolding protein at glutamatergic synapses, is a genetic risk factor for autism. In this study, we examined the impact of Shank3 deficiency on the NMDA-type glutamate receptor, a key player in cognition and mental illnesses. We found that knockdown of Shank3 with a small interfering RNA (siRNA) caused a significant reduction of NMDAR-mediated ionic or synaptic current, as well as the surface expression of NR1 subunits, in rat cortical cultures. The effect of Shank3 siRNA on NMDAR currents was blocked by an actin stabilizer, and was occluded by an actin destabilizer, suggesting the involvement of actin cytoskeleton. Since actin dynamics is regulated by the GTPase Rac1 and downstream effector p21-activated kinase (PAK), we further examined Shank3 regulation of NMDARs when Rac1 or PAK was manipulated. We found that the reducing effect of Shank3 siRNA on NMDAR currents was mimicked and occluded by specific inhibitors for Rac1 or PAK, and was blocked by constitutively active Rac1 or PAK. Immuno cytochemical data showed a strong reduction of F-actin clusters after Shank3 knockdown, which was occluded by a PAK inhibitor. Inhibiting cofilin, the primary downstream target of PAK and a major actin depolymerizing factor, prevented Shank3 siRNA from reducing NMDAR currents and F-actin clusters. Together, these results suggest that Shank3 deficiency induces NMDAR hypofunction by interfering with the Rac1/PAK/cofilin/actin signaling, leading to the loss of NMDARmembrane delivery or stability. It provides a potential mechanism for the role of Shank3 in cognitive deficit in autism.

PAK, p21-activated kinase, is the key downstream effector of Rac1, which stimulates spine synapse formation and neurite outgrowth by facilitating actin filament assembly. Different mutations in the PAK genes have been identified in mental retardation cases. Mice expressing a forebrain-specific dominantnegative form of PAK show fewer dendritic spines, altered spine morphology, and changes in synaptic strength.  Shank proteins have been shown to form a complex with PAK and overexpression of Shank in cultured neurons promotes synaptic accumulation of PAK. Consistently, we have found that Shank3 knockdown leads to reduced PAK1 activity. Moreover, inhibiting PAK1 decreases the basal NMDAR current, and the reducing effect of Shank3 knockdown on NMDARs and F-actin is occluded by PAK1 inhibitors and blocked by constitutively active PAK1. These data suggest that Rac1/PAK1- mediated actin dynamics is important for NMDAR membrane delivery/maintenance and its regulation by Shank3.

Mast Cells

Mast cells are the cells that react will allergens and lead to the release of histamine and many other inflammatory agents like the cytokine IL-6.  It is shown that PAK1 plays a key role in mast cell degranulation and could therefore play a key role in treating allergies and asthma.

APak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells.


Mast cells coordinate allergy and allergic asthma and are crucial cellular targets in therapeutic approaches to inflammatory disease. Allergens cross-link immunoglobulin E bound at high-affinity receptors on the mast cell's surface, causing release of preformed cytoplasmic granules containing inflammatory molecules, including histamine, a principal effector of fatal septic shock. Both p21 activated kinase 1 (Pak1) and protein phosphatase 2A (PP2A) modulate mast cell degranulation, but the molecular mechanisms underpinning these observations and their potential interactions in common or disparate pathways are unknown. In this study, we use genetic and other approaches to show that Pak1's kinase-dependent interaction with PP2A potentiates PP2A's subunit assembly and activation. PP2A then dephosphorylates threonine 567 of Ezrin/Radixin/Moesin (ERM) molecules that have been shown to couple F-actin to the plasma membrane in other cell systems. In our study, the activity of this Pak1-PP2A-ERM axis correlates with impaired systemic histamine release in Pak1(-/-) mice and defective F-actin rearrangement and impaired degranulation in Ezrin disrupted (Mx1Cre(+)Ezrin(flox/flox)) primary mast cells. This heretofore unknown mechanism of mast cell degranulation provides novel therapeutic targets in allergy and asthma and may inform studies of kinase regulation of cytoskeletal dynamics in other cell lineages.

Where to find your PAK-inhibitor?

In the literature you will find that there are various different PAK inhibitors

Not surprising if you want to want to inhibit PAK1, PAK2 and PAK3, then FRAX486 is a good choice.

But where do you get FRAX486 from?

Susumu Tonegawa, Afraxis and Roche

It looks like in about 2007 Tonegawa has created a start-up company called Afraxis to develop FRAX 486.  Having done further research and raised some venture capital they licensed their drug portfolio to the drug major, Roche, in 2013.
I hope this works out better for Tonegawa that Roche’s deal with his MIT colleague Mark Bear who also linked up his start-up Seaside Therapeutics with Roche.  That one did not end so well.
Avalon Ventures’ Afraxis Licenses Entire Drug Portfolio to Genentech
Roche’s Genentech has licensed global rights to develop and commercialise Afraxis’ entire portfolio of CNS compounds in a deal worth up to US$187.5 M. Afraxis’ lead programme targets PAK (p21-activated kinase) and has initially been focused on developing disease-modifying therapies for Fragile X syndrome, the most common inherited cause of mental retardation. Although not a sale, the deal will still provide an exit for Avalon Ventures, Afraxis’ sole shareholder, and follows the acquisition of Avalon-backed Zacharon Pharmaceuticals by BioMarin Pharmaceutical earlier in January 2013. For Roche, the deal supplements an already robust neuroscience pipeline.

Any other alternatives?

Fortunately another Japanese scientist, Hiroshi Maruta, has written a paper on all the possible PAK inhibitors available today for humans.

If you read his paper, he is pointing in the direction of the natural world and a special kind of propolis rich in CAPE (caffeic acid phenethyl ester) produced by bees in New Zealand.  His fall back is an old drug for humans and pets called ivermectin, which was found by chance to have a secondary affect as a PAK-inhibitor.

It is a substance, CAPE, specific to the New Zealand bees that makes their propolis act as a PAK-inhibitor.  Regular propolis from your health food store is most likely made by the wrong type of bees.

So if you do not fancy waiting 15 years for Roche to commercialize Susumu Tonegawa’s clever discoveries from MIT which may or may not be effective in humans, you could stick with the clever Japanese and follow Hiroshi Maruta’s thinking and go down under to New Zealand.  During its long isolation, New Zealand developed a distinctive biodiversity of animal, fungal and plant life; most notable are the large number of unique bird species and by the sound of it some pretty special bees.
Can a bee product really be an effective drug? I definitely start as a sceptic, but the natural flavonoid Quercetin really does work, so why not Propolis?  Propolis has been used medicinally for more than a thousand years, but only the New Zealand one and one Brazil variety contain PAK inhibiting compounds. 

There is also an odd saying from Germany, that "bee keepers do not get cancer". Maybe there is something in this?

The problem with many of the other natural PAK-inhibitors is their bioavailability.  They may work in the test tube, but the human body does not absorb them enough for them to be effective.  Curcumin, Resveratrol, Honokiol (from Magnolia bark) all appear, but unless you can absorb them and they can cross the blood brain barrier (BBB) they will not work.

The NF-1 and NF-2 sufferers have zeroed in on the BIO30 Propolis as the realistic alternative.  I think they made the right choice.


The logical conclusion is to buy some BIO30 Propolis and give it a try.  I hope Susumu Tonegawa and Roche eventually make a commercially available drug, but  new drugs seem to take 15 years to bring to the market.  The existing drug, Ivermectin, really should be given a clinical trial in NF-1 or Fragile-X.