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Showing posts with label PAK inhibitor. Show all posts
Showing posts with label PAK inhibitor. 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. 



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 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.


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.






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, 29 September 2014

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.


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.

 


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:-


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:-

 

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. 












Saturday, 6 September 2014

Tics, Ticks, Autism - Wnt signaling & PAK1

I was interested to receive a comment from a reader of this blog who finds that the anti-parasite drug Ivermectin has a major impact on her child’s  autism, debilitating tics and OCD (Obsessive Compulsive Disorder).

Regular readers may recall that when looking at so-called PAK1 inhibitors, which look like the Holy Grail for both common cancers and autism, it turned out that two already exist.  One is an old anti-parasitic drug called Ivermectin and the other is a substance found in certain types of bee propolis from Brazil and New Zealand.

It then turned out that a handful of “alternative” practitioners in the US are already using Ivermectin for autism, but for entirely different reasons.  They believe that various parasites exist inside the children and cause/exacerbate autism.

I thought this was intriguing and quite likely another case of “the right therapy, for the wrong reason”.


Tics and Ticks

Tics are those sudden, repetitive involuntary actions that can vary from annoying to debilitating.

Ticks are tiny parasites that like to attach themselves to your skin, they can fall from trees/bushes or attach themselves to skin as you pass through long grass. Some ticks carry Lyme Disease.

Tics are common in autism, PANDAS, PANS and many forms of OCD (Obsessive Compulsive Disorder).

It seems that some “alternative” practitioners in the US are treating PANDAS and PANS on the assumption that it is caused by Lyme Disease.  Others are recommending “de-worming” for autism, on the assumption that intestinal parasites are to blame.

Here is a link to somebody writing about these alternative practitioners, for those who are curious.


My take

This all sound highly odd to me, partly because it seems that you have to keep taking the de-worming tablets for the long term.  With regular mild parasites found in developed countries, drugs therapy can eliminate the parasites.  In some tropical climates more aggressive parasites exist that are almost impossible to eradicate 100%.

So regular de-worming of humans in the United States, in 2014, sounds bizarre.

On the other hand, you cannot dispute when somebody finds their child’s tics and OCD have disappeared with the de-worming therapy and that they return when the therapy stops.

Is it, as I suggested in the early posts, that the PAK1 inhibiting properties of Ivermectin are behind its effect?  Hopefully yes, but I am not sure.  So I will take a look at Ivermectin and see if it has any other properties that could impact autism, tics and OCD.


Ivermectin - not just for your dog

Most people would only come across Ivermectin at the vet, but there is much more to it.



Discovered in the late-1970s, originating solely from a single microorganism isolated at the Kitasato Institute, Tokyo, Japan from Japanese soil, Ivermectin has had an immeasurably beneficial impact in improving the lives and welfare of billions of people throughout the world. Originally introduced as a veterinary drug, it kills a wide range of internal and external parasites in commercial livestock and companion animals. It was quickly discovered to be ideal in combating two of the world’s most devastating and disfiguring diseases which have plagued the world’s poor throughout the tropics for centuries. It is now being used free-of-charge as the sole tool in campaigns to eliminate both diseases globally. It has also been used to successfully overcome several other human diseases and new uses for it are continually being found.

The origins of ivermectin as a human drug are inextricably linked with Onchocerciasis (or River Blindness), a chronic human filarial disease caused by infection with Onchocerca volvulus worms. The disease causes visual damage for some 1–2 million people, around half of who will become blind.

Lymphatic Filariasis, also known as Elephantiasis, is another devastating, highly debilitating disease that threatens over 1 billion people in more than 80 countries. Over 120 million people are infected, 40 million of whom are seriously incapacitated and disfigured. The disease results from infection with filarial worms


Modes of Action

Let us look at the various modes of action proposed for Ivermectin.

1.     GABA

Initially, researchers believed that Ivermectin blocked neurotransmitters, acting on GABA-gated Cl channels, exhibiting potent disruption at GABA receptors in invertebrates and mammals.

In mammals the GABA receptors occur only in the central nervous system (CNS), i.e. in the brain and the spinal cord. But mammals have a so-called blood-brain barrier (BBB) that prevents microscopic objects and large molecules to get into the brain. Ivermectin, while paralyzing body-wall and pharyngeal muscle in nematodes has no such impact in mammals.  Consequently Ivermectin is much less toxic to mammals than to parasites without such a barrier, which allows quite high safety margins for use on livestock, pets and humans.


2.     Glutamate

Subsequently, researchers discovered that it was in fact glutamate-gated Cl channels (GUCl) that were the target of Ivermectin and related drugs.


3.     Reversing Immunosuppression

The growing body of evidence supports the theory that the rapid parasite clearance following Ivermectin treatment results not from the direct impact of the drug but via suppression of the ability of the parasite to secrete proteins that enable it to evade the host’s natural immune defence mechanism.


In a major breakthrough that comes after decades of research and nearly half a billion treatments in humans, scientists have finally unlocked how a key anti-parasitic drug kills the worms brought on by the filarial diseases river blindness and elephantitis

Regular readers will recall that a beneficial parasite therapy in inflammatory diseases is the TSO worm.  This worm also modulates the host’s immune system so as not to be ejected.  This calming of the over activated immune system appears to be beneficial in several conditions and possibly autism.


4.     Inhibitor of Wnt-TCF Pathway

Recent cancer research has shown the Ivermectin has a highly unexpected property; it can block a pathway called Wnt-TCF on which many cancers are dependent.



Wnt signaling is also a strong activator of mitochondrial biogenesis. This leads to increased production of reactive oxygen species (ROS), in other words oxidative stress, known to cause DNA and cellular damage.

Perhaps aberrant Wnt signaling is involved in the mechanism of autism?

Well it appears to be the case.




 Mounting attention is being focused on the canonical Wnt signaling pathway which has been implicated in the pathogenesis of autism in some our and other recent studies. The canonical Wnt pathway is involved in cell proliferation, differentiation and migration, especially during nervous system development. Given its various functions, dysfunction of the canonical Wnt pathway may exert adverse effects on neurodevelopment and therefore leads to the pathogenesis of autism.


5.     Inhibitor of PAK1

We already know from earlier in this blog, that Ivermectin is a PAK1 inhibitor.  Blocking PAK1 should prevent several common cancers, according to researchers at MIT, who also suggest that autism cannot occur without PAK1.\

Not entirely surprisingly, if you look into the cancer research you will see that PAK and WNT are interrelated.

p21-Activated kinase (PAK) interactswith Wnt signaling to regulate tissue polarity and gene expression

Wnt signaling is mediated by three classes of receptors, Frizzled, Ryk, and Ror. In Caenorhabditis elegans, Wnt signaling regulates the anterior/posterior polarity of the P7.p vulval lineage, and mutations in lin-17/Frizzled cause loss or reversal of P7.p lineage polarity. We found that pak-1/Pak (p21-activated kinase), along with putative activators of Pak, nck-1/Nck, and ced-10/Rac, regulates P7.p polarity. Mutations in these genes suppress the polarity defect of lin-17 mutants. Furthermore, mutations in pak-1, nck-1, and ced-10 cause constitutive dauer formation at 27 °C, a phenotype also observed in egl-20/Wnt and cam-1/Ror mutants. In HEK293T cells, Pak1 can antagonize canonical Wnt signaling. Moreover, overexpression of Ror2 leads to phosphorylation of Pak1. Together, these results indicate that Pak interacts with Wnt signaling to regulate tissue polarity and gene expression.


So there at least five possible effects that Ivermectin can have.


Too much Ivermectin is not good

According to the literature in the developing world, there are 200 million people (http://onlinelibrary.wiley.com/doi/10.15252/emmm.201404084/abstract) currently taking Ivermectin, which is provided free for river blindness; some of those have been using the drug for over 20 years - so much is known about it.

It is suggested that at excessive doses, Ivermectin starts to cross the BBB and then affects the neurotransmitter GABA.  Ivermectin stimulates the release of the GABA in the presynaptic neurons and enhances its postsynaptic binding to its receptors. This increases the flow of chloride ions in the neurons, which causes hyperpolarization of the cell membranes. This on its turn disturbs normal nervous functions and causes a general blockage of the stimulus mechanisms in the CNS. The resulting cerebral and cortical deficits include mainly:
    • Ataxia (uncoordinated movements)
    • Hypermetria (excessive or disproportionate movements)
    • Disorientation
    • Hyperesthesia (excessive reaction to tactile stimuli)
    • Tremor (uncoordinated trembling or shaking movements)
    • Mydriasis (dilatation of the pupils); in cattle and cats also myosis (contraction of the pupils)
    • Recumbency (inability to rise)
    • Depression
    • Blindness
    • Coma
So, too much Ivermectin is not a good idea.


So why is Ivermectin good for Tics, OCD and Autism?

At low doses Ivermectin does not cross the BBB (blood brain barrier), but in autism it appears that the BBB can be more permeable than it should be.  So possibly Ivermectin produces an increase in GABA, like that caused by Valproic Acid.  Some people with autism find Valproic Acid very beneficial.

Perhaps those glutamate-gated Cl channels (GUCl) play a, yet unidentified, role in autism.

Or, perhaps we got it right and PAK inhibiting property is what matters. 

Perhaps being an PAK1 inhibitor will also make it a Wnt inhibitor, or maybe not, worth checking though?

Perhaps the MIT guys got it wrong and it is Wnt rather than PAK that we should be focused on? 

I hope the blog reader that prompted this post does indeed give the bee propolis a go and see if it has the same effect as Ivermectin.


Cancer

Having said in an earlier post that I will not try and out-smart the cancer researchers, I will just say that the extremely cheap drug Ivermectin does seem to have some potent anti-cancer properties.  

I know that cancer drugs are supposed to be hugely expensive.

An earlier post mentioned Ivermectin’s positive effect on Leukemia, but it seems that the WNT-TCF Pathway is involved in very many cancers.  This is not to mention that just being a PAK1 inhibitor should be enough to prompt further interest.


Conclusion

Well it looks like Dr Wu and Dr Klinghardt have indeed got the therapy right, but I believe for entirely the wrong reasons. By promoting themselves via organisations like Autism One, they are almost guaranteed to be ignored by mainstream doctors and researchers. The therapy will therefore remain on the fringe, with the quacks and cranks.


From my perspective, what really matters is whether a therapy works.  We can always later on figure out why it works.  So thank you Dr Wu and Dr Klinghardt.