Repurposing Anti-parasite drugs to treat Cancer and Autism?

 

I should start this post by highlighting that generally cancer and autism are not caused by parasites.

I have to be a little careful because we now know that certain types of virus and bacteria are involved in the initial trigger to initiate some types of cancer. This is why many females are now offered human papillomavirus (HPV) vaccines to minimize the chance of several different cancers. I noticed recently that in the US this vaccine is advertised on TV.  I used to know a woman who like most people had the HPV virus as a child, but did not have this vaccine.  She developed a rare oral cancer that the vaccine would have protected against and died very young. We saw in a previous post how a specific gut bacteria blocks the initiation of childhood leukemia.

The pharmaceutical industry does not seem to like the idea of repurposing existing drugs to treat a different disease.  There are some exceptions; it is OK to treat females with acne, using the diuretic drug Spironolactone.  Nobody seems to object to the treatment of intractable headaches with drugs actually approved to lower blood pressure (Verapamil, Amlodipine etc).

When investigating cancers you have to look at the specific underlying mechanisms, just as you do with autism.

As we saw long ago in this blog, it has been suggested to classify autism as either over-active pro-growth signaling pathways, or under-active pro-growth signaling pathways. Most is the over-active type.

Cancer is very clearly another example of over-active pro-growth signaling pathways, so it is not surprising that there is an overlap between therapies for autism and cancer.  The difference is that they are far more likely to be effective in autism. 

So, a cheap anti-parasite drug for kids like Mebendazole, which just happens to also be a Wnt inhibitor,  may slow down the growth of some cancers, but it is sadly not curative.  In an autistic brain where Wnt signalling might be overactive, a lower dose of Mebendazole, might well provide a long-term benefit.   

My old posts that mention Wnt signaling are here:-

https://www.epiphanyasd.com/search/label/Wnt 

Wnt signaling interestingly plays a role in how your hair will go gray/grey. If you reduce Wnt signaling, your hair will go gray and so this is an inevitable side effect of a potent Wnt inhibitor. 

Premature graying might indeed indicate reduced Wnt activity.

 

Pyrantel pamoate

Our reader Dragos recently fined tuned his adult son’s anti-aggression therapy and he recently shared his latest innovation:-

 

"you have to give him 20mg of propranolol 2-3 times a day, pyrantel pamoate 750mg in the evening for 2-3 days, and you will see that his anger will disappear, stay on propranolol. After 3 weeks repeat with antiparasitic, you will see that I was right, you don't use psychotropic drugs"

 

Propranolol is a normally used to lower blood pressure, but it does this in a way that also reduces anxiety.  At the low doses used by Dragos, it has been used to treat actors with stage fright. It can be used before exams or driving tests, to calm the person down.

Propranolol has been trialed in autism. Some people use a low dose and some use a higher dose.

Pyrantel pamoate is used to treat hookworms and other parasites that can be picked up by young children. It works by paralyzing the worms. This is achieved by blocking certain acetylcholine receptors in the worm.

As is very often the case, pyrantel pamoate likely has other modes of action that are entirely different. Is it a Wnt inhibitor like the other hookworm treatment Mebendazole?

I did a  quick search on google and it gave me the wrong pamoate. 

Pyrvinium pamoate is able to kill various cancer cells, especially CSC. The drug functions through the reduction of WNT- and Hedgehog-dependent signaling pathways (Dattilo et al., 2020). 

Pyrvinium pamoate is yet another anti-parasitic drug, but not the one Dragos is using.

So pyrantel pamoate may not be a Wnt inhibitor, unlike many anthelmintic drugs, but it is used by the “anti-parasitic re-purposer in chief” Dr Simon Wu.  He publishes his findings/thoughts, which is good to see.  He likes to combine different anti-parasitic drugs.

I did look up the effect of pyrantel pamoate on gene expression.  There is data, but you really need to see the source material to know whether anything is valid.

Inhibiting GSTP1 (glutathione S-transferase pi 1) is suggested and that is a feature in common with an anti-parasite drug class called Thiazolides (e.g.  Nitazoxanide).  That would make pyrantel pamoate a potential therapy for triple-negative breast cancer, where the cancer cells rely on vigorous activity by the enzyme glutathione-S-transferase Pi1 (GSTP1).  Cancer cells are highly vulnerable to oxidative stress, and as we know glutathione is the main way the body extinguishes it. Glutathione S-transferases P1 protects breast cancer cell from cell death.  So you want to inhibit GSTP1.

Pyrantel has many other suggested effects even reducing expression of the gene FXR2 (fragile X mental retardation,2) and increasing expression of the gene MTSS1 (metastasis suppressor 1).

Pyrantel is even suggested as an epilepsy drug.

 

Drug repositioning in epilepsy reveals novel antiseizure candidates

Epilepsy treatment falls short in ~30% of cases. A better understanding of epilepsy pathophysiology can guide rational drug development in this difficult to treat condition. We tested a low-cost, drug-repositioning strategy to identify candidate epilepsy drugs that are already FDA-approved and might be immediately tested in epilepsy patients who require new therapies.

Expanding on these analyses of epilepsy gene expression signatures, this study generated a list of 184 candidate anti-epilepsy compounds. This list of possible seizure suppressing compounds includes 129 drugs that have been previously studied in some model of seizures and 55 that have never been studied in the context of seizures. 91 of these 184 compounds are already FDA approved for human use, but not for treating seizures or epilepsy. We selected four of these drugs (doxycycline, metformin, nifedipine, and pyrantel tartrate) to test for seizure suppression in vivo.

Pyrantel tartrate is an antiparasitic agent that acts by inhibiting fumarate reductase, and by directly acting on acetylcholine receptors at the neuromuscular junction of infecting helminths. Pyrantel tartrate is FDA approved for use in domestic animals and has been used to treat human parasitic infections.73 Unlike nifedipine and metformin (for which some rodent studies and human reports relate to seizures), a March 2018 PubMed search for “pyrantel and epilepsy” and “pyrantel and seizure” found no manuscripts that studied pyrantel in seizures. Thus, pyrantel tartrate represents a truly novel antiseizure drug candidate yielded by our screen.

 

All in all it is not surprising that Dr Yu is prescribing pyrantel pamoate.

Digging any deeper is beyond the scope of a blog post.

What is clear is that pyrantel pamoate and mebendazole are unlikely to be equally effective in Dragos’ son.

Other anti-parasite drugs work very differently.

In the chart the mode of action of some common drugs  is presented.

 

Anthelminticsfor drug repurposing: Opportunities and challenges

 

Mode of action of albendazole (ABZ), ivermectin (IVM), levamisole (LV), mebendazole (MBZ), niclosamide (NIC), flubendazole (FLU), rafoxanide (RAF), nitazoxanide (NTZ), pyrvinium pamoate (PP), and eprinomectin (EP).

  

Suramin is now quite well known as a potential autism therapy and two different groups are trying to commercialize it.  Suramin is the original anti-purinergic drug (APD), it blocks purinergic receptors that have names like P2Y2.

When I looked at PAK1 a long time ago, which was put forward as a treatment pathway for neurofibromatosis, some schizophrenia and some autism I came across Ivermectin as an existing alternative to the research drug FRAX486, or the expensive BIO 30 propolis from New Zealand.

A decade later and the world goes crazy when the idea of using Ivermectin to treat COVID 19 gets well publicized.  The good news is that now we know that regular use of Ivermectin is not as dangerous as people thought it would be.  Many people have been using the veterinary version in the US, Brazil and elsewhere. 

The supporting research:- 

Effect of Pyrantel on gene expression.

 https://maayanlab.cloud/Harmonizome/gene_set/pyrantel-5513/CMAP+Signatures+of+Differentially+Expressed+Genes+for+Small+Molecules

 

decreases expression of:-

FXR2   fragile X mental retardation, autosomal homolog 2

(and many more)

 

Increases expression of

MTSS1 metastasis suppressor 1

BNIP1 BCL2/adenovirus E1B 19kDa interacting protein 1

BRAF B-Raf proto-oncogene, serine/threonine kinase

(and many more)

 

https://maayanlab.cloud/Harmonizome/gene_set/Pyrantel+Pamoate/CTD+Gene-Chemical+Interactions

Glutathione S-transferase P is an enzyme that in humans is encoded by the GSTP1 gene.

Pyrantel Pamoate Gene Set

Dataset          CTD Gene-Chemical Interactions

2 genes/proteins interacting with the chemical Pyrantel Pamoate from the curated CTD Gene-Chemical Interactions dataset.

GPR35    G protein-coupled receptor 35

GSTP1   glutathione S-transferase pi 1

 

Triple-negative breast cancer target is found

They discovered that cells from triple-negative breast cancer cells rely on vigorous activity by an enzyme called glutathione-S-transferase Pi1 (GSTP1). They showed that in cancer cells, GSTP1 regulates a type of metabolism called glycolysis, and that inhibition of GSTP1 impairs glycolytic metabolism in triple-negative cancer cells, starving them of energy, nutrients and signaling capability. Normal cells do not rely as much on this particular metabolic pathway to obtain usable chemical energy, but cells within many tumors heavily favor glycolysis.

  

"Inhibiting GSTP1 impairs glycolytic metabolism," Nomura said. "More broadly, this inhibition starves triple-negative breast cancer cells, preventing them from making the macromolecules they need, including the lipids they need to make membranes and the nucleic acids they need to make DNA. It also prevents these cells from making enough ATP, the molecule that is the basic energy fuel for cells." 

 

Anthelmintics for drug repurposing: Opportunities and challenges 

It has been demonstrated that some of the anthelmintics are able to inhibit critical oncogenic pathways, such as Wnt/β-catenin, signal transducer and activator of transcription proteins 3 (STAT3), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB; therefore, their application for cancer treatment has been considered.

 

Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System

 

Anthelmintics for drug repurposing: Opportunities and challenges

 

Mode of action of albendazole (ABZ), ivermectin (IVM), levamisole (LV), mebendazole (MBZ), niclosamide (NIC), flubendazole (FLU), rafoxanide (RAF), nitazoxanide (NTZ), pyrvinium pamoate (PP), and eprinomectin (EP).

 

Thiazolides inhibit growth and induce glutathione-S-transferase Pi (GSTP1)-dependent cell death in human colon cancer cells

More research on the repurposing anti-parasite drugs: 

Antiparasitic and Antifungal Medications for Targeting Cancer Cells Literature Review and Case Studies Frederick T. Guilford, MD; Simon Yu, MD

Chronic inflammation is a new catch phrase for the explanation of all chronic degenerative diseases, from asthma, arthritis, heart disease, auto-immune disease, and irritable bowel disease to cancer. Occult infections from oncovirus, bacterial, and fungal infections as well as from lesser known parasitic infections are driving forces in the cellular evolution and degeneration of cancer cells. An approach using currently available medications that target both fungal and parasitic metabolism appears to interfere with the metabolic synergy that is associated with tumor growth and aggressiveness 

 

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs 

 

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

 

Anti-Parasite drug Ivermectin shows promise against cancer 

A Pinworm Medication Is Being Tested As A Potential Anti-Cancer Drug

 Conclusion

I did suggest long ago that Mebendazole, as a Wnt inhibitor, might be a cheap and effective treatment for some autism.  I had envisaged that it would need to be given daily, as it is in the cancer trials.

Dragos’ use of pyrantel pamoate, for an average of 4 days a month is interesting.  It is cheap, safe and practical.

One key issue with antiparasitic drugs is how much is absorbed into the blood stream.  If 100% of the drug stays in the gut, its benefit will be limited.

About 20% of Mebendazole ends up in the blood stream and if you take it often this figure is reported to increase.

The combo of propranolol + pyrantel pamoate is an interesting option to treat self-injury and aggressive behavior.  It works for Dragos and undoubtedly will for some others.

Is the inhibition of Wnt signalling the reason why pyrantel pamoate is effective for Dragos’ son?  There is no evidence to support that.

Are antiparasitic drugs going to be widely adopted to treat any unrelated conditions, cancer included, I very much doubt it.

Cancer is better avoided, than treated.  It is a much more achievable objective.

The Fragile X researcher Randi Hagerman takes metformin, as her chemoprevention therapy. She is the medical director of MIND Institute at the University of California, Davis.

You can raise IQ in people with Fragile X by 10-15% using Metformin.  I guess Randi had been reading up on Metformin and came across the anti-cancer effects.

If I had to suggest an anti-parasite drug for Randi to try in Fragile X, I would suggest the PAK inhibitor Ivermectin, made (in)famous by Donald Trump and Jair Bolsonaro during Covid. The research drug FRAX 486 is called FRAX for Fragile X. It is a PAK inhibitor that never made it to market.  Ivermectin is an existing drug that is also a PAK inhibitor.  Worth a try, Randi?

I expect Dr Yu might try and increases his chances and make a combo with a second anti-parasitic drug.

Metformin is one of several anti-cancer choices, it depends which type of cancer is of concern. For RAS-dependent cancer I think Atorvastatin is the best choice. 

If you read the research, like me and Randi, chemoprevention is the obvious choice for older adults. Dementia prevention is equally obvious.

Parkinson’s prevention may be achieved by blocking Cav1.3 (amlodipine etc)

Alzheimer’s prevention may be achieved using low dose fenamates (Ponstan etc).

For vascular dementia and Alzheimer’s prevention/treatment spermidine (in the form of modified wheatgerm) is promising.

Anti-parasite drugs for cancer and autism? Yes, it sounds mad. But is it?

What is for sure is that your pediatrician will think you have gone mad!

Our reader MG in Hong Kong will have got some new ideas to think about.

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. 

P21-Activated Kinase Inhibitors FRAX486 and IPA3: Inhibition of Prostate Stromal Cell Growth and Effects on Smooth Muscle Contraction in the Human Prostate

Abstract

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 GABA_A 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.

Conclusion

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.

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.

Mounting Evidence Regarding Autism, Neurofibromatosis and PAK1

When I google “autism” and “PAK1”, I keep seeing my own posts come up.  This is beginning to be a regular occurrence, when I research an idea.  Google “verapamil autism”, “clonazepam autism” “bumetanide autism” and even “NAC autism”, the same thing happens.

So it is nice to have some further studies that also show the possible importance of PAK1 in treating autism.  This time it is from the University of Indiana and more precisely, Anantha Shekhar, Professor of Psychiatry at the School of Medicine.

We have the study’s abstract and the more people-friendly press release.

Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase (PAK1)

Abstract

Children with neurofibromatosis type 1 (NF1) are increasingly recognized as having a high prevalence of social difficulties and autism spectrum disorders (ASDs). We demonstrated a selective social learning deficit in mice with deletion of a single Nf1 allele (Nf1^+/−), along with greater activation of the mitogen-activated protein kinase pathway in neurons from the amygdala and frontal cortex, structures that are relevant to social behaviors. The Nf1^+/− mice showed aberrant amygdala glutamate and GABA neurotransmission, deficits in long-term potentiation and specific disruptions in the expression of two proteins that are associated with glutamate and GABA neurotransmission: a disintegrin and metalloprotease domain 22 (Adam22) and heat shock protein 70 (Hsp70), respectively. All of these amygdala disruptions were normalized by the additional deletion of the p21 protein-activated kinase (Pak1) gene. We also rescued the social behavior deficits in Nf1^+/− mice with pharmacological blockade of Pak1 directly in the amygdala. These findings provide insights and therapeutic targets for patients with NF1 and ASDs.

Here is the very informative and readable press release.

 

Blocking one gene could aid social behavior in some forms of autism, IU scientists report

INDIANAPOLIS -- Blocking a single gene that is active in the brain could provide a means to lessen behavioral problems among children with a common genetic disease, many of whom are also diagnosed with an autism disorder, according to researchers at the Indiana University School of Medicine.

The genetic disorder, neurofibromatosis type 1, is one of the most common single-gene diseases, affecting about 1 in 3,000 children worldwide. Symptoms can range from café-au-lait spots on the skin to tumors that are disfiguring or that can press dangerously against internal organs.

"Physicians are increasingly recognizing that many children with the disorder have social and behavioral difficulties, and as many as one in five cases of autism may be associated with the same biochemical defects seen in neurofibromatosis type 1," said Anantha Shekhar, M.D., Ph.D., Raymond E. Houk Professor of Psychiatry at the IU School of Medicine.

The researchers used a mouse model of neurofibromatosis, examining both behavioral differences from normal mice and biochemical differences in the animals' brains, particularly in the amygdala, a brain structure associated with social behavior and emotional regulation.

Reporting their work in the journal Nature Neuroscience, the researchers found that the neurofibromatosis model mice had problems with long term social learning -- remembering important social cues involving interactions with other mice. Tests also showed that neurochemical pathways between structures of the brain involved with social behavior were disrupted by the neurofibromatosis mutation.

However, blocking the activity of another gene -- called Pak1, which is involved with those neurochemical pathways -- improved the social behaviors of the mice. Mice bred to have both the neurofibromatosis mutation and the deletion of the Pak1 gene engaged in social behavior similar to normal mice. In addition, mice with the neurofibromatosis mutation that were injected with a compound known to block Pak1 gene activity had normal social behavior restored.

"These findings could lead to novel approaches to treating behavioral problems that are seen in NF1 patients and some patients with autism spectrum disorders," said D. Wade Clapp, M.D., Richard L. Schreiner Professor of Pediatrics at the IU School of Medicine.

Implications

The researchers from Indiana are suggesting that 20% of people with autism may have the same dysfunction as the very much rarer condition of neurofibromatosis type 1.  Those 20% are likely to benefit from treatments shown to be effective in NF-1.

How do you know whether you are in the 20%?  A little genetic testing might tell you, or maybe not (see below).

In the absence of such testing, you could possibly deduce something from looking at the comorbidities.

It might seem odd that NF-1, a rare disorder affecting 1 in 3,000 children could share its underpinnings with 20% of children with autism, which would roughly equate to 6 in 3,000 children.

This reminds me of a question I raised earlier:-

Just How Rare are the Known Genetic Causes of Autism?

In that post it became clear that you can have a partial dysfunction of a “rare” genetic disorder.  I wonder if that partial dysfunction will show up on today’s genetic tests.

Comorbidities

The comorbidities of autism that most intrigue me are asthma, allergies and ulcerative colitis.  I have a suspicion that they are all linked by mast cell degranulation and further, that what is underlying autism is promoting mast cells to degranulate.

A recent study showed how PAK1 is involved in modulating mast cell degranulation:-

A Pak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells

 

And another one:- 

PAK1 AS A THERAPEUTIC TARGET

Fortunately, the effects of PAK1-deficiency on the immune system have a very encouraging up-side. As demonstrated by otherwise relatively healthy PAK1-/- mice, Pak1 is critical for disassembly of cortical F-actin upon allergen stimulation, and PAK1 deficiency prevents the release of pro-inflammatory molecules from the granules of mast cells during the IgE-associated allergic responses

I have already shown the effectiveness of Verapamil as a therapy for autism and mast cell degranulation.  I suspect that a further improvement may follow with a potent PAK1 inhibitor.

I think the Indiana research also points in the same direction.

There is also the issue of malformed dendritic spines, which will be fully addressed in a later post.  This appears in autism and schizophrenia and may explain much of why autistic brains function differently to other peoples.  It is thought that this malformation is also linked to PAK1.

So while treating mast cell degranulation will help some people’s autism, you could also go one step backwards up the chain and address the signal that was prompting them to degranulate.  This same signal may trigger an unrelated damaging cascade of events elsewhere in the brain.

Which PAK1 inhibitor?

In earlier post we saw that the choices of PAK1 inhibitor are:-

1.     Experimental drugs still under development by Afraxis, the MIT spin-off  

2.     Ivermectin, an old anti-parasite drug, used with some success by fringe alternative doctors in the US.  At least one reader of this blog is a fan of Ivermectin for autism.
 
3.     Certain types of Propolis, like the one containing CAPE (Caffeic Acid Phenethyl Ester) that comes from New Zealand
 

The question remains whether the Propolis is potent enough to have the same effect as Ivermectin.  In the NF-1 and NF-2 community, opinion is split as to whether Propolis can shrink existing tumours.  This issue of stopping new tumours developing, versus shrinking existing ones does seem to crop up quite often in cancer research as well.  Drugs are, not surprisingly, most effective when used very early on.

Ivermectin cannot be used long term continuously, since it is toxic.  It can be used “on and off” for decades as an anti-parasite therapy.

Crossing the Blood Brain Barrier

Once question arose in an earlier post as to how Ivermectin could be effective in autism, since it does not readily cross the blood brain barrier.  According to the experts it does not have to, see below:-

PAK1 AS A THERAPEUTIC TARGET

11. Expert opinion: Is PAK1 a suitable target for therapy?

As discussed above, there is growing evidence that PAKs are involved in the phenomena that are clinically significant for various cardio-vascular disorders, but the specificity of PAK1 involvement is still uncertain. Studies indicate that even closely related PAKs (e.g. PAK1 and PAK2) have non-identical sets of substrates. The issue is further complicated because of the multiple and sometimes opposing roles of PAKs in these processes and certainly merits further investigation.

The reports on the involvement of PAK1 in various diseases of the brain indicate that both up- and down-regulation of this enzyme may be associated with pathological changes. This, along with the uncertainty about the relative contribution of other isoforms, clouds the prospect of targeting PAK1 for therapeutic intervention in these conditions. Furthermore, these observations necessitate a close attention to the affects that any anti-PAK therapy targeted at other organs might have on the nervous system, including the cognitive functions and the memory. In this regard, failure of an anti-PAK1 agent to penetrate the blood-brain barrier may not be a detriment to its therapeutic utility. Similarly complicated is the question of PAK1 targeting in infections: while it may partially attenuate certain viruses, it would also negatively impact some functions of the immune system. In fact, the recent report of PAK1-deficient animals having IgE-mediated responses to allergens may indicate that, at least, for such acute life-threatening conditions as anaphylaxis the benefits of suppressing PAK1 may outweigh the risks.

My PAK-1 inhibitor Trial

I am practicing what I preach, so to speak.  Only once the pollen allergy season is well and truly over, will I trial my PAK-1 inhibitor.  I want a genuine result, free from external effects, like degranulating mast cells.

Since Ivermectin is known to react with other drugs in my PolyPill, I will be using the Propolis from New Zealand.