The Role of Microglia in the Puzzle of Neuro-inflammation in Autism

Regular readers of this and similar blogs will have noticed that the human body functions in quite irrational ways.  We know why this is; we are the product of a very slow evolutionary process, rather than being a clean-sheet design like your smart phone or iPad.

As a result, nothing is ever quite as simple as it seems and at times the cleverer you are, the less likely you are to find a medical therapy effective in humans.

Such is the case with autism, inflammation and microglia.

It might seem that you can track back inflammation in autism to its “root cause”, which could appear to be those immune cells in the brain, called microglia.  We know they are “activated” in autism and we know that autism is typified by an “over-activated” immune response.

Working with the assumption that autism is a brain dysfunction, you would assume that the effective therapy should be inside the so-called blood brain barrier (BBB).

You would then just look for a potent drug that could “stabilize” the microglia/immune cells in the brain, to calm things down.  Having achieved this, you would sit back and marvel at the behavioral change and improvement in cognitive function.

This was exactly the thought process a few years ago when the US  National Institute of Mental Health (NIMH) got together with the Johns Hopkins researchers to follow up on their findings of chronic inflammation in the brains of people with autism.  Subsequent, third party, research has also confirmed that the microglial cells are “activated” in autism

Trial Description

Minocycline to Treat Childhood Regressive Autism

There is a subgroup of children with autism that appear to develop typically for a period of time, and then lose skills, or regress. A recent study by Vargas and co-workers at Johns Hopkins has demonstrated that the regressive subtype of autism is associated with chronic brain neuroinflammation as exemplified by activation of microglia and astroglia and the abnormal production of inflammatory cytokines and growth factors assayed in both tissue samples (brain banks) and CS. The authors remarked that these responses were similar to those seen in some neurodegenerative disorders such as amyotrophic lateral sclerosis, and that chronic microglia activation appears to be responsible for a sustained neuroinflammatory response that facilitates the production of multiple neurotoxic mediators. Chronic neuroglial activation could be the result of an abnormal persistence of a fetal development pattern. In this scenario neuroglial activation could play a role in initiating and in maintaining the pathology. Alternatively, neuroglial activation may only be a secondary response to the initiating causal factor(s) and not a direct effector of injury. Since neuroglial activation requires the nuclear translocation of the pro-inflammatory transcription factor NF-kappa B, and since inhibitors of NF-kappa-B with good CNS penetrance are available, the role of neuroinflammation in initiating and sustaining the autistic condition can be probed.

The antibiotic minocycline is a powerful inhibitor of microglial activation, apparently through blockade of NF-kappa-B nuclear translocation. Minocycline is neuroprotective in mouse models of amyotrophic lateral sclerosis (ALS) and Huntington's disease and has been recently shown to stabilize the course of Huntington's disease in humans over a 2-year period.

To evaluate the possibility of benefit in autistic children, we propose to conduct an open-label trial of the anti-inflammatory antibiotic minocycline, an agent that reduces inflammation by blocking the nuclear translocation of the proinflammatory transcription factor NF-kappa-B. Minocycline is Food and Drug Administration (FDA)-approved for treatment of a variety of infections and has been widely used for the treatment of adolescent acne. Minocycline is currently in phase III trials for the treatment of Huntington's disease and amyotrophic lateral sclerosis.

This proposal is for an initial 6-month, single-arm, off label, open-label study (with a 3 month extension phase offered to responders) that will evaluate dose safety and efficacy of minocycline in 10 children, ages 3 to 12 years, with a primary diagnosis of autism and a history of developmental regression. The subjects will be evaluated by a diagnostic/behavioral assessment, and the extent of neuroinflammation judged by CSF cytokine/chemokine profiles before and after the 6-month treatment. Subjects will also be given 0.6 mg/kg vitamin B6 twice a day as a prophylactic for possible minocycline induced nausea and vomiting. If the results of this feasibility study are encouraging, we expect to conduct a double-blind, placebo-controlled trial of minocycline therapy.

Nothing happens fast in the world of autism and so this six month study of 10 people (who completed the actual trial) was conceived in 2006, was actually concluded in 2013.  Here is the resulting paper:-

  

A pilot open-label trial of minocycline in patients with autism andregressive features

Conclusions

Changes in the pre- and post-treatment profiles of BDNF in CSF and blood, HGF in CSF and CXCL8 (IL-8) in serum, suggest that minocycline may have effects in the CNS by modulating the production of neurotrophic growth factors. However, in this small group of children, no clinical improvements were observed during or after the six months of minocycline administration.

Unfortunately, this study showed that a treatment, known to effectively stabilize microglial cells, had no positive effect on autism and actually seemed in some cases to make it worse.

We can conclude from this that stabilizing the microglia will not be the “holy grail” for treating autism.  Rather, the activated microglia is just one part of a complex, and only partially understood process.

Microglia as the Immunostat 

In a recent post we saw how Rodney Johnson referred to the microglia as the “immunostat” of the body.  Like the thermostat on the wall in your home central heating system.

Inflammation Leading to Cognitive Dysfunction

This is indeed an interesting analogy and might explain some of what is going on.

We saw in Johnson’s paper all the ways that the immune system outside the blood brain barrier (BBB) was able to communicate with the microglia.  We should assume that this communication works both ways; something that is usually overlooked.

In a perfectly functioning body, as in a perfectly functioning house, the immunostat/thermostat gives a good indication of the actual state/temperature, as well as the one you intended.  So if you set your room thermostat to 72 Fahrenheit / 22 Celsius  you expect the actual temperature to be 72 Fahrenheit / 22 Celsius.

However, in the real world things do not work like this.

We live in a house with very large south facing windows, a big fireplace, underfloor heating in some places and European-style hot water radiators (in the US they do have them).  So we have at least four sources of heat.  In spite of having clever German electronics to control our heating system, the thermostat in the centre of the house, by itself, is not adequate.

Something similar is happening in body and brain of people with autism, just replace temperature with inflammation.

Just as my house has multiple systems resulting in heating, the human body has numerous processes leading to “inflammation”.  Some of these inflammatory processes are interconnected and some are not.  The net result at any one time can be measured by looking at various cytokine levels, gene expression, microglial activation and numerous other things; there is no single measurable thing called “inflammation”.

There will never be a single wonder anti-inflammatory treatment.

The activated state of the microglia rather than being the ultimate target for intervention may just be a reflection of inflammation elsewhere in the body, or alternatively it may be just the result of oxidative stress in the brain.

Just like after a few years you may need to replace your wall thermostat, because it is giving false data, the clever immunostat, that may be the microglia, could have been disrupted by all that oxidative stress in the brain.  It might even be sending its proinflammatory signal in reverse, back across the BBB, to the rest of the body. Not such a crazy idea?

The future of anti-inflammatory interventions

The NIMH and Johns Hopkins would naturally be disappointed by the results of their study; but it was a study well worth doing.  Hopefully they will pursue other avenues of thought.

We already know that there are numerous ways to achieve a degree of immuno-modulatory change and that in some types of autism there can be a profound behavioral impact.

These range from simple Ibuprofen, to steroids like Prednisone; not to mention those Kv1.3 blockers and ShK-peptides.  These will likely all affect the microglia, but it is not their main mode of action.

Insights

As is often the case, there are useful insights that you can learn from a “failed” trial.

I would imagine that an autistic person with ulcerative colitis would also have activated microglia. Treating that person with minocycline should have some stabilizing influence on the microglia, but without resolving the ulcerative colitis, the pro-inflammatory signals continue to be sent around the body.

Turning down the thermostat in my house, when I have a big log fire blazing, has no effect on the temperature. 

The microglia in the brain of people with autism probably should not be activated; we really need to know why they are activated.

If you can work on the numerous processes/pathways leading to “inflammation” you would most likely also achieve some deactivation of the microglia.

Therefore we should look at things like PPAR gamma which are directly relevant to the pathology of autism, and agonists of PPAR gamma also happen to be “anti-inflammatory” and indeed, in the test tube, some can stabilize microglia.

One, far away, day they will bring those ShK-peptides to the market. 

In the meantime, my current targets are Tangeretin and Nobiletin, flavonoids found in tangerines.

For the scientists among you:-

In addition to being a PPAR gamma agonist, Tangeretin is also a known P2Y₂ receptor antagonist.  Both properties are potentially useful.

PPAR gamma has been covered in this blog already.  P2 receptors are a class of Purinergic receptor.  Within the field of purinergic signalling, these receptors have been implicated in learning and memory, locomotor and feeding behavior, and sleep. 

Suramin is used in research as a broad-spectrum antagonist of P2 receptors.

It is Suramin that Robert Naviaux, at UC San Diego, has been researching as a potent autism therapy.  He has shown it effective in mouse models, but the problem is that it is not safe for long term use in humans.  Regular readers should note that, yet again, an anti-parasite drug has been found to have an effect in autism.  Parasites do not cause autism, but understanding them better would be a potential advantage.

Why Suramin, a Century-Old, Anti-Parasitic Drug May Hold the Key to Understanding Autism

Dr. Robert Naviaux's recent finding suggests reversible metabolic syndrome could be at core of autism

The full paper is below:-

Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy

In particular, P2Y₁₁ is a regulator of immune response.  There are big gaps in the science and I have no idea if tangeretin affects P2Y_11.

Bumetanide and/or low-dose Clonazepam for Autism

Today’s post answers a question left un-answered in earlier posts about the best way to treat the imbalance (excitatory vs inhibitory or just E/I) that exists in the function of the key neurotransmitter GABA in many types of autism.

I first started this blog after the pleasant shock of seeing the positive behavioral and cognitive effect caused by Bumetanide.

This was just copying a recent French clinical trial on humans.

Later on in this blog we came across Professor Catterall who made two experiments in mice to show that the same E/I imbalance could be treated using tiny doses of a drug called Clonazepam.  At doses a hundred time higher, Clonazepam is used to treat seizures and anxiety, but at those doses it dose have side effects.

The mechanism is different to Bumetanide, by the effect was claimed to be the same.

Since Bumetanide has actually been shown effective in a human trial, most readers of this blog have this as their first choice.

I commented that in Monty, aged 11 with ASD, there was indeed an additional positive effect of adding clonazepam to existing bumetanide therapy.  Now having several effective treatments, it is harder to quantify the effect of new ones.  

It remained unknown what would be  the effect of low dose Clonazepam without the Bumetanide. 

Since Bumetanide is known to reduce potassium levels, albeit in a minority of cases, to the extent that supplementation is required, it is necessary to monitor blood levels of potassium.  This is a drawback of the therapy, although the majority of people will not actually need supplementation.  So one regular reader of this blog has tried Clonazepam; and I assume, Maja, without Bumetanide.

Here is her feedback.

Tried Clonazepam 0.025mg in one dose, in the evening, before sleep. After whole 3 days, as you predicted, change was amazing - she become self confident, a bit naughty, but in some joyful, playful way. Started to play more often with friends (by report of teacher end assistant in school). They both reported that she is different, but in good way, even she is harder to manage with (i didn't tell them about new therapy in that time)

Started to play differently, not in pattern she's developed over the years (she has great imaginations, wich is a plus, but has stereotype of ideas in the play).

First of all, we noticed that she is capable to sense odors (she had some kind of anosmia before), than she managed to catch a rhythm to dance (that was a real wow!).

She was speaking with people in the shop (briefly, but adequately)...
There is much more...

Change is still present, but after three weeks are slightly paler . There are not so intense. I'm still overwhelmed, just wont to know if I am missing something.

Thank you Maja for sharing.

In Monty, the effect was not this profound, but then he was already on Bumetanide, and so I was rather expecting no effect.

So, bumetanide and/or low-dose clonazepam for Autism?  

I suggest both, for maximum effect.

P.S.  For the scientists among you

There is another drug, Diamox/Acetazolamide, that I think may also have the same effect as Bumetanide and Low dose Clonazepam.  It is a so-called carbonic anhydrase inhibitor, meaning it forces the kidneys to excrete bicarbonate (HCO3-) and thus makes the blood more acidic.  This has the side benefit of increasing the amount of oxygen in the blood, and hence its use off-label to prevent altitude sickness.  In the brain this change in HCO3- should affect Anion exchanger 3 (AE3) and Sodium dependent anion exchanger (NDAE) which sit alongside the GABAa receptors. By reducing Cl- levels within the cell, the effect would be the same as Bumetanide, which affects the NKCC1 transporter.  This might explain why Diamox, a diuretic, is also used to treat some epilepsy and periodic paralysis.  Note Bumetanide is also used to treat periodic paralysis and some seizures.

This was all covered in a very complicated post:-

GABA A Receptors in Autism – How and Why to Modulate Them

If you are one of those who believe that there is mild hypoxia in some cases of autism, then you could also consider Diamox as an alternative to hyperbaric oxygen therapy.

  

  

Wombles and Music Therapy for Autism

Apple users may have to click here

Instead of giving you my rather heavy post about epigenetics and autism, today’s post is much more down to earth.

Medical opinion in North America has long been very much in favour of ABA (Applied Behavioural Analysis) as the only “scientifically proven” therapy for the core symptoms of autism.

This evidence is actually quite flaky, so much so that in the very "evidence driven" United Kingdom, their highly regarded National Institute for Health and Care Excellence (NICE) does not even mention ABA, let alone endorse it, in their guidance note in how to manage autism.

The management and support of children and young people on the autism spectrum

ABA is a potent tool to manage autism and provides a flexible framework to teach people who do not respond to traditional teaching methods.  However, it is no cure for autism and the old studies suggesting that almost 50% of kids going to an intensive ABA program will lose their autism diagnosis after two years are nonsense.  They just serve to over-extend the expectations of parents entering ABA therapy and increase guilt among those not able to afford it.

All of our ABA consultants to date have agreed with this view.  In highly intelligent kids with mild autism, maybe 50% can improve so far to lose their diagnosis; but maybe they would have done so after two years without ABA?

Selective interpretation of evidence

A therapy that is sometimes included alongside swimming with the dolphins, as being non-evidence based, is music therapy.

Music and dance is used extensively with many typical kids of kindergarten age, mainly as a fun activity.

I myself would have previously thought that was all there was to it.  But after several years of observing the effect of lots of music on Monty, aged 11 with ASD, there really is much more to it.  

Monty’s original assistant was (and remains) really into music, and so he had lots of music and dance from a very young age.  A few years later we bought a piano and he started piano lessons.

It appears that for some people, singing is easier than talking, or perhaps it is that music encourages communication.  We saw in a post long ago that singing lowers your level of cortisol, the stress hormone. 

Music (and dance) appear to unlock something deep within. (Perhaps the music gene)

Who are the Wombles

The Wombles are furry inhabitants of a burrow on Wimbledon Common in London, England.  They live by collecting up and reusing all the rubbish humans leave behind.

The Wombles were created by British author Elisabeth Beresford, and originally appeared in a series of children's novels from 1968. A stop motion animated series of five minute episodes was made between 1973 and 1975.  A new TV series, with CGI animation, is in production, along with a movie.

Wombles on Sunday Morning

Last Sunday morning, when half the house was sleeping, Monty was sitting in the kitchen with his iPad; then he selected his Wombling song on Youtube.  He then started singing his own mixture of the original lyrics and his creation, at full volume.  Listen a bit harder and he was singing in two languages.

Given most kids with classic autism really struggle to communicate, this is quite remarkable and light years ahead of where he used to be.

I am a convert to both ABA and music therapy, but I do not think you can prove the effectiveness of either.  Anecdotal evidence, but lots of it, is as good as it can realistically get.

The moral of the story is that if you set the bar too high, you will reject valid therapies alongside all the quack therapies. 

Also, you may have to persevere for a long time to kindle that interest in music; but as our ABA consultant commented recently, the biggest problem her older clients have, is that they have nothing to do – no hobbies, no interests.  Keep up with those lessons.

  

Gingerols and Statins (as Farnesyltransferase inhibitors) for RASopathies and Some Autism

Today’s post was driven by another attempt not to take a statin.

Statins are among the world’s most prescribed, and yet most maligned, drugs.  Hundreds of millions of people take a statin drug every day to lower their cholesterol, but a small, vocal minority complain about muscle pains, memory loss and even type 2 diabetes.

Since my Polypill is evidently a therapy, and not a cure, for autism, the odds are that it will be needed life-long.  Regardless of the apparent lack of side-effects, nobody should be taking drugs/supplements that are not really needed.  Atorvastatin (Lipitor/Sortis) is part of my Polypill for the type of autism affecting Monty, aged 11, with ASD.

Every time I stop the statin part of my Polypill therapy, I end up starting it again after only a one day break.  I notice all sorts of little behavioral changes that I really do not want to see.   

These changes involve loss of initiative, flexibility and motivation.  I really do not see how these would be measured in any existing behavioral assessment of autism.  These little changes make a big difference in daily life, so-called adaptive behavior.

In case you are wondering, the types of people with autism that I think might benefit from statins, have high cholesterol and some of the following:-

·        Non-verbal, or people who are slightly verbal, but choose not to speak

·        Poor ability to generalize skills already mastered in 1:1 therapy

·        Great difficulty in separating

·        Great difficulty in coping with change

As with some other elements of the Polypill, there are numerous reasons why statins could/should help in autism.  Today I found yet another one and an interesting non-drug alternative.

Why Statins?

I originally choose statins as a possible therapy, based on their ability to control pro-inflammatory cytokines (e.g. cytokine storms), and their known neuro-protective properties (e.g. reduce mortality after a traumatic brain injury).

I then noted they also affect some autism target genes, such as PTEN and BCL-2.

I did also note that statins were being researched to treat Neurofibromatosis, a single gene condition that is frequently comorbid with an “autism” diagnosis.

Today’s post is really about why statins should help in Neurofibromatosis and what else shares the same mechanism of action. 

Putting aside cytokines, PTEN and BCL-2, this new mechanism (excessive RAS/ERK signaling) might also be active in broader autism and Intellectual Disability / MR.

The other recent development was a study at UCLA that looked at a rare condition called Noonan Syndrome.  Noonan Syndrome and Neurofibromatosis are members of a group of conditions called RASopathies.

The RASopathies are developmental syndromes caused by mutations in genes that alter the Ras subfamily and Mitogen-activated protein kinases that control signal transduction.

Statins reverse learning disabilities caused by genetic disorder

Drawing upon Silva’s previous research on neurofibromatosis 1, another Ras-influenced disease, the UCLA team treated the mice with lovastatin, an FDA-approved statin drug currently in wide clinical use.

When adult mice with Noonan were treated with lovastatin in the UCLA study, the drop in Ras activity dramatically improved their memory and ability to remember objects and navigate mazes.

“We were amazed to see that statin treatment restored the adult animals’ cognitive functions to normal. Traditionally, science assumes that therapy needs to start in the fetal stage to be effective,” explained Silva. “Our research suggests that the leading gene mutation responsible for Noonan syndrome plays critical roles not only in fetal development, but also in how well the adult brain functions.”

According to Silva, UCLA’s approach could help the estimated 35 million Americans who struggle with learning disabilities

The paper itself:-

Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome

RAS/ERK Inhibitors

For those of you more interested in the implications, rather than the science, here they are.

Known RAS inhibitors include:-

·        Statins, the popular cholesterol reducing drugs.  The “lipophilic” statins (Simvastatin, Lovastatin, Atorvastatin) can cross the blood brain barrier

·        Farnesyltransferase inhibitors, these are mainly anti-cancer research compounds, but one is the flavonoid Gingerol

Gingerol, is the active constituent of fresh ginger.  It is normally found as a pungent yellow oil, but also can form a low-melting crystalline solid.

Cooking ginger transforms gingerol into zingerone, which is less pungent and has a spicy-sweet aroma. When ginger is dried, gingerol undergoes a dehydration reaction forming shogaols, which are about twice as pungent as gingerol. This explains why dried ginger is more pungent than fresh ginger.

Ginger also contains 8-gingerol, 10-gingerol, and 12-gingerol.

Physiological effects

Gingerol seems to be effective in an animal model of rheumatoid arthritis.

Gingerol has been investigated for its effect on cancerous tumors in the bowel, breast tissue, ovaries, the pancreas, among other tissues, with positive results.

Neurofibromatosis, Behavioral dysfunction and RAS signaling

Neurofibromatosis Type 1: Modeling CNS Dysfunction

Neurofibromatosis type 1 (NF1) is the most common monogenic disorder in which individuals manifest CNS abnormalities. Affected individuals develop glial neoplasms (optic gliomas, malignant astrocytomas) and neuronal dysfunction (learning disabilities, attention deficits). Nf1 genetically engineered mouse models have revealed the molecular and cellular underpinnings of gliomagenesis, attention deficit, and learning problems with relevance to basic neurobiology. Using NF1 as a model system, these studies have revealed critical roles for the NF1 gene in non-neoplastic cells in the tumor microenvironment, the importance of brain region heterogeneity, novel mechanisms of glial growth regulation, the neurochemical bases for attention deficit and learning abnormalities, and new insights into neural stem cell function. Here we review recent studies, presented at a symposium at the 2012 Society for Neuroscience annual meeting, that highlight unexpected cell biology insights into RAS and cAMP pathway effects on neural progenitor signaling, neuronal function, and oligodendrocyte lineage differentiation.

Working memory, which, like attention, depends on intact prefrontal circuitry, is also impaired in both Nf1^+/− mice and in individuals with NF1. Functional imaging studies showed that the working memory impairments of NF1 subjects correlated with hypoactivation in the prefrontal cortex, which may reflect increased GABA-mediated inhibition in prefrontal cortical circuits of Nf1^+/− mice. Remarkably, a dose of a GABA receptor inhibitor (picrotoxin), which caused deficits in working memory in control mice, rescued the working memory deficits of Nf1^+/− mice, a result consistent with the hypothesis that increased inhibition is at the root of the working memory deficits associated with NF1.

Increases in RAS/ERK signaling in Nf1^+/− mice have been implicated in the working memory, attention, and spatial learning deficits of these mice. Genetic and pharmacological manipulations that target the RAS/ERK signaling pathway were shown to rescue the physiological and behavioral deficits of Nf1^+/− mice. Importantly, pharmacological manipulations that impair the isoprenylation of RAS (statins, farnesyl transferase inhibitors), and therefore decrease the levels of RAS/ERK signaling, also rescue key electrophysiological and behavioral phenotypes of Nf1^+/− mice. Indeed, at concentrations that do not affect signaling, physiology, or behavior of wild-type controls, statins reverse the signaling, electrophysiological, attention, and spatial learning deficits of Nf1^+/− mice. Prompted by these findings, clinical studies are currently underway to test the efficacy of statins as a treatment for the behavioral and cognitive deficits in individuals with NF1.

Similar to individuals with NF1, Nf1 mutant mice also show attention deficits. These deficits are thought to be key contributors to academic and social problems in children with NF1. Using an additional Nf1 GEM strain to study attention, in which the Nf1^+/− mutation is combined with Cre-driven homozygous Nf1 gene deletion in GFAP-expressing cells (Nf1 OPG mouse), it was found that reduced striatal dopamine was responsible for the observed attention deficits. Treatment with methylphenidate (but not with drugs that affect RAS) reversed the attention deficits of these Nf1 OPG mutants, suggesting that defects in brain catecholamine homeostasis contribute to the attention deficits observed. These results suggest that, in addition to drugs that affect RAS/ERK signaling, drugs that manipulate dopaminergic function could also be used to treat the cognitive deficits associated with NF1.

Treatments and future directions

With the availability of genetically engineered mouse models for NF1-associated CNS pathology, it now becomes possible to envision a pipeline in which fundamental basic science discoveries lead to the identification of new cellular and molecular targets for therapeutic drug design, culminating in preclinical evaluation before testing in patients with NF1. First, the success of Nf1 mouse model implementation has already resulted in the clinical evaluation of lovastatin in children with NF1-associated learning deficits and rapamycin analogs for the treatment of glioma. Second, mouse models afford an opportunity to envision specific features of NF1 as distinct diseases defined by the timing of NF1 gene inactivation or the particular cell of origin. Similar to other cancers, the identification of molecular or cellular subtypes of NF1-associated nervous system tumors or learning/behavioral problems may result in more individualized treatments with a higher likelihood of success. Third, as we further exploit these powerful preclinical models, additional cellular and molecular targets may emerge as candidates for future therapeutic drug design. In this regard, one could envision more effective therapies resulting from the combined use of targeted inhibition of multiple growth control pathways regulated by neurofibromin in the neoplastic cell (NF1-deficient neuroglial precursor) or dual targeting of non-neoplastic (microglia) and neoplastic cells within NF1-associated CNS tumors.

RASopathies & Autism

Autism traits in the RASopathies

Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.

This systematic study offers empirical support that autism traits are associated with developmental Ras/MAPK pathway dysregulation. It suggests that individuals affected by RASopathies should be evaluated for social communication challenges and offered treatment in these areas. This is the first strong evidence that multiple members of a well-defined biochemical pathway can contribute to autism traits. Future studies could explore potential modifying or epistatic factors contributing to variation within the RASopathies and the role of Ras/MAPK activation in idiopathic ASDs.

RAS/ERK Inhibitors

Inhibition of Ras for cancer treatment: the search continues

Discussion

Despite intensive effort, to date no effective anti-Ras strategies have successfully made it to the clinic. We present an overview of past and ongoing strategies to inhibit oncogenic Ras in cancer.

Conclusions

Since approaches to directly target mutant Ras have not been successful, most efforts have focused on indirect approaches to block Ras membrane association or downstream effector signaling. While inhibitors of effector signaling are currently under clinical evaluation, genome-wide unbiased genetic screens have identified novel directions for future anti-Ras drug discovery.

Conclusion

In some people with “autism” statins are an effective therapy.  Higher doses of statin are associated with side effects.  By knowing the principal mode of action of statins in autism, we might be able to develop a more potent therapy – STATIN PLUS.

On the basis of today’s post, investigating Farnesyltransferase inhibitors, as inhibitors of RAS signalling, looks an interesting option.

Gingerol is available as an inexpensive, supposedly standardized, product.  Ginger itself has been safely used in traditional medicine for thousands of years.

Perhaps Gingerol is the PLUS and for people unwilling to use a statin, perhaps Gingerol could be the statin?

The current medical view on ginger:-

According to the America Cancer Society

Recent preliminary results in animals show some effect in slowing or preventing tumor growth. While these results are not well understood, they deserve further study. Still, it is too early in the research process to say whether ginger will have the same effect in humans.

Anti-Oxidative and Anti-Inflammatory Effects of Ginger in Health and Physical Activity: Review of Current Evidence

  

Note on Intellectual Disability / MR

Regular readers may recall, I have commented that not only are many types of autism partially treatable, but so should be some types of Intellectual Disability / MR.  This same theme about treating cognitive dysfunction is raised in the paper below.

In the days when most readers of this blog were at school, 30-50% of people with an autism diagnosis were also diagnosed with Intellectual Disability / MR.  This is no longer the case; as autism diagnoses have skyrocketed in Western countries, diagnosis of Intellectual Disability / MR has not followed it.

People born today with what used to be called autism, often suffer from epilepsy and impaired cognitive function.  They do now tend to get rather sidelined by the much wider scope of the “autism” diagnosis used today, mainly in Anglo-Saxon countries (where most research is carried out).

The point where this matters is in clinical trials, since many of the milder autisms (now even being called “quirky autism”) may be caused by entirely different dysfunctions.  The observational diagnosis of “autism” is enough to enter most trials, but as we have seen in this blog, autism is not a true diagnosis; it is merely a description of symptoms.  It is like going to the doctor and saying “I think I might have a head ache” and after some questions, the doctors sits back and says “yes, you have a headache”.  You want to know why you have a head ache and how to make it go away.

Understanding Intellectual Disability through RASopathies

A fraction of the cases of intellectual disability is caused by point mutations or deletions in genes that encode for proteins of the RAS/MAP Kinase signaling pathway known as RASopathies. Here we examined the current understanding of the molecular mechanisms involved in this group of

genetic disorders focusing in studies which provide evidence that intellectual disability is potentially treatable and curable. The evidence presented supports the idea that with the appropriate understanding of the molecular mechanisms involved, intellectual disability could be treated pharmacologically and perhaps through specific mechanistic-based teaching strategies.

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.