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.

Wandering & Forever Young

Today’s post is rather light on the usual science.

One reader recently suggested a post on wandering. Wandering off and getting lost is a common event for many with more severe autism and while for some it may be an issue only in childhood, for many it will continue to adulthood.  US news reports frequently feature this kind of wandering, but it occurs everywhere.

Minions like to wander too

The broader issue here is that many people with severe autism remain child-like their entire lives.  So they continue to face many of the same risks as a neuro-typical toddler. If you do not pay great attention to your typical two year they also may have all kinds of accidents, but they soon figure out that roads are dangerous and falling from a window is going to hurt.

There are lots of clever high tech tracking solutions to help find your child, but the ideal solution must be not to lose him in the first place.

We have a high fence around our garden; we have a cover on our pool that even an adult cannot fall through and a number coded lock on the way out to the garage. So it would be hard for any toddler to wander off from our house and hard to fall from an upper window.

I think we have reached a developmental age where wandering is not likely, this is likely in part due to pharmacological intervention.

Many years ago I used to travel on business to Warsaw, in Poland, and we were fortunate to stay in a very upmarket hotel in the reconstructed old town called the Bristol.  You would think this would be a very safe place.  Some years later a friend was telling me how our former colleague was staying there over one weekend with his wife and their typical toddler son.  The boy was left unattended and somehow fell to his death from an upper window.

We do not electronically tag all two year olds, the idea is that they are given near constant supervision and hopefully things work out well. 

The big risks for kids with autism are drowning and seizures; in some cases it is a seizure while in the bath unattended that causes drowning.  Drowning should be preventable.  I think that with the appropriate treatment the onset of seizures in many people with autism might be prevented.

In the US on average 10 people drown each day, of whom two will be under 14 years old. Another 10 children receive emergency department care each day for nonfatal submersion injuries.

Life is a risky business.

Tracking Devices

There are numerous types of tracking device, but most have the drawback that they are removable.  To be genuinely effective the device would have to some kind of bracelet that cannot be removed.

In some countries by law all pet dogs have to be microchipped. If the dog gets lost a small inexpensive scanner reads the number on the chip which is looked up on an online database revealing the owner's details.

Our neighbour’s dog wanders off on regular basis, but thanks to his chip he has made it home so far.

It would be possible to microchip non-verbal people.  The problem here is that who would have a scanner?  Who would know that the person was chipped?  If you have to have a mark saying “I’m chipped” you might as well just write the person’s name and address indelibly on their forearm.  Better still don’t lose them.

Sense of Danger

Some people say that their child with autism has no sense of danger, but is that because he has not yet developed one, or he will never have one?  I remember being in an outdoor green market with Monty when we met an older boy who was in our mainstream school for a year or two.  He was non-verbal, autistic and had seizures. We usually saw him strapped into an oversized pushchair.  He could walk, but clearly it was deemed preferable to keep him strapped in.

Monty was used to exploring the stalls in the market and often he would be given something to taste.  The other boy was there with his mother and his assistant. I started talking to the mother, Monty started to move the next stall and then the assistant “pounced”, like Monty was about to walk in front of a bus.  I explained that is was OK, he was not about to run away; he had already learned a sense of danger from experience.

Clearly people are very different, but you do have to give people some space to develop and explore, if you expect them to learn.

Monty likes fire, but rather than hide him from it he is one who lights our open fire at home.  He is now fully aware that you can burn yourself (and your house). We do have several smoke detectors.

So I think some people may be over protective and not allowing the child to develop a sense of danger, while some others let their moderately autistic young child roam the street in front of their home and are surprised when trouble occurs.

Dressed to Kill

Many people like to be snappy dressers; I think people should be equally attentive to how they dress their adult-sized offspring with severe autism.

I recall a news article a while back when a mother let her adult son with severe non-verbal autism wander from home.  He was dressed in green military attire, like a big version of Rambo.  He wandered into a neighbour’s garden and the occupant saw the intruder and called the police.  The police arrived and tackled the non-responsive, threateningly-dressed, intruder to the ground.  The mother turned up and was upset that the officer had man handled her child.  I think this was in Canada, a little further south and the officer might have shot him.

Had the youth been dressed in shorts and a Mickey Mouse sweatshirt I doubt the home owner would have called the police in the first place, rather “it’s just that boy Jimmy from down the street wandering again, I must call his mother, she did tell me that he wanders”.

It does matter how you are dressed and how you behave.  I recall another parent commenting that adults with autism are not cute, that sounded odd to me.  An 8 year old with autism banging his head against the wall certainly is not cute.  A well behaved adult-sized person with classic autism can be cute, more than likely he is just a big kid, or a gentle giant.  If he is a permanent “big kid”, dress him like one and nobody is going to feel threatened by any unexpected behaviours.

Conclusion

Wandering can be deadly; if someone with non-verbal autism is prone to wander technology can only be of limited help.

The tendency to wander has to be matched by the level of supervision.

This blog is usually about pharmacological therapies and in many cases these should be able to improve cognition and self-awareness so that wandering is much less likely.

There will always be curious or adventurous types that will find a way over the fence and out into the wider world. Better make sure they know how to cross roads and know how to swim.  Even if they are only minimally verbal, from a very early age they need to know their name and address.  If they are totally non-verbal, you need a better fence, a tracking device that cannot be removed, or that permanent marker.