Dr Dolittle, Autism and the Broccoli Sprouts

In the Dr Dolittle books and subsequent films, a man develops the power to communicate with animals.  It seems that one effect of broccoli sprout powder (and we assume Sulforaphane), in autism,  is an urge to talk, not only to humans, but also to animals.

Monty, aged 11 with ASD, took his first dose of 2.5ml of broccoli powder (Supersprouts brand from Australia) and after about half an hour developed euphoria.  The laughter later subsided and throughout the day he was very talkative.  This was relevant speech and not repeating things he had heard previously.  Other than the euphoria, which is the word chosen by elder brother Ted, a nice development was the desire to communicate with the animal world.

After a visit to his favourite ice cream shop, he looked up and saw the big railway bridge. “Bye bye railway station” commented Monty.  Walking up the hill we first passed a kitten, playing by the verge, “Hello baby kitten! Bye bye baby kitten!”  Then a big dog appeared “Hello big white dog and a woman! Bye bye big white dog and woman!”.  This was all rather unexpected.

The next day, another 2.5ml of broccoli powder and the same result.  Euphoria and lots of talking.

Then I decided to start experimenting with the dose.  I gave 1.25ml three times a day.

After the breakfast dose, no euphoria but still plenty of speech.  After lunch, the second dose and the return of mild euphoria.  After the evening dose, more euphoria.  The half-life of Sulforaphane in people is claimed to be about two hours.

Based on this limited experience, I think 2.5ml is about right.  There is no need for more.

  

Cost

I paid AU$ 110 (US$ 95 or GBP 60) for 300g of broccoli powder including shipping.

2.5ml of powder weighs 1.1g.  So using that daily dose of 2.5ml the cost would be 35 US cents (22 UK pence).

My earlier assumption was that a dose of about 18 g of fresh sprouts would produce the required level of Sulforaphane.  In theory, this would be 3 ml of broccoli powder, if it had 100% of the right enzymes in it and none of the bad stuff (called ESP, from the last post).  I was quite surprised at the effect of 2.5ml.  Johns Hopkins told me that most broccoli powders are no good; that is why I looked around before choosing the Australian product.

As a dosage comparison, this supplement is sold in Australia with a suggested daily dose of 5g, which equates to about 11 ml. 

So my “autism dose" looks quite conservative.  I think even half the suggested adult dose would make Monty completely hyper.

Note that the dose of the anti-oxidant NAC used in autism trials is 4X the usual adult dose of NAC and 2X the adult dose for adults with COPD (severe asthma).

The effect on an adult

I tried a scaled up dose myself, but sadly no euphoria followed.

  

Note

Monty is already taking a potent anti-oxidant called NAC, which has been investigated in an autism trial at Stanford.

The broccoli sprouts produce a substance called Sulforaphane (SFN).  This substance activates Nrf2 which upregulates “phase II enzymes”; they increase the body’s antioxidant response.  SFN is also an inhibitor of HDAC (Histone Deacetylase) and this may give SFN the ability to target aberrant epigenetic patterns.

SFN is therefore a secondary anti-oxidant.  It has been shown to improve the body’s response to cancer and environmental toxins.  The chemoprotective properties may result from SFN’s epigenetic properties or the anti-oxidant properties.

SFN was shown in a recent study at Johns Hopkins to improve autism in young adults.  It is not known definitively why it was effective.

Conclusion

My experiment indicates that, in classic autism, Sulforaphane (SFN) does provide a marked and immediate benefit over NAC alone, which is what I set out to determine.

Australian broccoli sprout powder appears to be a relatively cheap and effective way to make SFN at home. 

Sulforaphane, Epithiospecifier Proteins (ESP) or just Sulforadex for Autism

  

One reader of the last post on Sulforaphane raised the issue of whether she should cook her broccoli sprouts, to optimize her autism therapy.

This seemed a bit strange, since even the researchers at Johns Hopkins are eating their sprouts raw.  She does have a valid point.  It seems that while sprouts have large amounts of glucoraphanin and the required enzyme myrosinase, they also have something called Epithiospecifier Protein (ESP).  If there is much ESP present, instead of Sulforaphane you get a very similar compound called Sulforaphane Nitrile.  You can see that the “S” has been replaced by an “N”.

All is not lost, for those of you with sprouts growing in the kitchen.

Further research showed that the concentration of ESP in the sprouts peaks on the second day and that by day 5 has dropped dramatically.

It was also showed that raising the temperature of the sprouts to 60 degrees Celsius deactivated the ESP.  Heating Broccoli florets much beyond this then reduced the Sulforaphane produced, but not heating the sprouts.

Heating decreases epithiospecifier protein activity and increases sulforaphane formation in broccoli.

Abstract

Sulforaphane, an isothiocyanate from broccoli, is one of the most potent food-derived anticarcinogens. This compound is not present in the intact vegetable, rather it is formed from its glucosinolate precursor, glucoraphanin, by the action of myrosinase, a thioglucosidase enzyme, when broccoli tissue is crushed or chewed. However, a number of studies have demonstrated that sulforaphane yield from glucoraphanin is low, and that a non-bioactive nitrile analog, sulforaphane nitrile, is the primary hydrolysis product when plant tissue is crushed at room temperature. Recent evidence suggests that in Arabidopsis, nitrile formation from glucosinolates is controlled by a heat-sensitive protein, epithiospecifier protein (ESP), a non-catalytic cofactor of myrosinase. Our objectives were to examine the effects of heating broccoli florets and sprouts on sulforaphane and sulforaphane nitrile formation, to determine if broccoli contains ESP activity, then to correlate heat-dependent changes in ESP activity, sulforaphane content and bioactivity, as measured by induction of the phase II detoxification enzyme quinone reductase (QR) in cell culture. Heating fresh broccoli florets or broccoli sprouts to 60 degrees C prior to homogenization simultaneously increased sulforaphane formation and decreased sulforaphane nitrile formation. A significant loss of ESP activity paralleled the decrease in sulforaphane nitrile formation. Heating to 70 degrees C and above decreased the formation of both products in broccoli florets, but not in broccoli sprouts. The induction of QR in cultured mouse hepatoma Hepa lclc7 cells paralleled increases in sulforaphane formation.

So it would seem that if you want to eat the sprouts raw, you need to wait for five days before consuming them.  Not good to eat them when two days old.

If you cook them, you do risk affecting the myrosinase and then you might need to add back some more from another source, just as Nicole mentioned in her comment.  But some research implies the sprouts are heat stable.

This all starts to get rather complicated.

Personally I decided to buy freeze dried broccoli sprout powder from Australia.  They claim to measure for ESP, and there is very little.  Their myrosinase has not been deactivated in processing.

If true, their product is near ideal.  Is say near ideal, because one spoonful also has the taste of a plateful of broccoli.

Mine has now arrived and so I will serve one level teaspoonful a day.

Other research actually suggested that Daikon radish may be event better than broccoli.  Johns Hopkins chose to patent the broccoli.  In their research compound, they reacted broccoli sprouts with daikon radish sprouts to make a standardized Sulforaphane which is then freeze dried and kept frozen.

RADISH SPROUTS VERSUS BROCCOLI SPROUTS: A COMPARISON OF ANTI-CANCER POTENTIAL BASED ON GLUCOSINOLATE BREAKDOWN PRODUCTS

Comparison of bioactive phytochemical content and releaseof isothiocyanates in selected brassica sprouts

Daikon powder is readily available and is a potent source of heat stable myrosinase.

So I will seek to get the optimal output from my Australian sprout powder by adding a dash of Daikon powder.

A better way?  Sulforadex

This kitchen chemistry may all seem rather haphazard and indeed it is.

Rather than try and make 8 mg of Sulforaphane in your kitchen, would it not be better to buy 8 mg of standardized heat stable Sulforaphane in the pharmacy?

Sulforadex is potentially exactly that; it is an analog of Sulforaphane.  Trials have started in humans and at very much higher doses to check for toxicity and side effects.

Here is a link to the Phase 1 trial:-

http://www.richmondpharmacology.com/downloads/Publications/Evgen-BPS-poster-tiny-web.pdf

The only questions I have are:- is anyone 100% certain that Sulforaphane is the only beneficial compound produced by eating broccoli?  Is Sulforaphane the only compound present in Johns Hopkin’s frozen capsules?  When they react their broccoli sprouts with daikon sprouts in the lab, there are other compounds produced.

Monty, aged 11 with ASD, is by now remarkably accommodating when it comes to downing unappetizing potions.  NAC tastes pretty bad, unless you use the more expensive effervescent variety.  But this pales in comparison to what a spoonful of broccoli sprout powder tastes like (and looks like).

They also make this powder in capsule form, for those who can swallow them. 

The more appetising anti-oxidant would be a bar of high flavanol dark chocolate, as we discovered in the previous post.  As well as tasting better, it may quite possibly be just as effective.

Why not Cocoa Flavanols for Autism?

Why not Cocoa Flavanols for Autism?

  

Judging by my blog statistics, lots of people are interested in broccoli (Sulforaphane) to treat autism.  Thanks to the patents held by Johns Hopkins, you can expect to hear much more about Sulforaphane in the coming years.

Meanwhile, Columbia University and Mars, the chocolate people, have released a study showing that “flavanoids” in cocoa can do wonders for memory loss in older people.  In effect, they can restore memory in 60 years olds to where it was 20 or 30 years earlier.

If you take a step back and look at what is known by science about oxidative stress and antioxidants, all will become much clearer.

Oxidative Stress Pioneers

In an earlier post we met Paul Talalay, a German-American, who worked at Johns Hopkins.  He specializes in foods that protect you from cancer.  He is Mr Broccoli. 

It turns out that perhaps the real pioneer in this field is a 100% German, called Helmut Sies, who also studies foods that act as antioxidants and nutrients that provide protection from cancer.  We have his very detailed diagram below, that explains the relationship between many of the factors involved in oxidative stress.  I wish I had found it earlier.  I added the six outer boxes.

If you want to read clever studies about this subject, just include Helmut Sies in your search; for example “selenium Helmut Sies”.

Redox Pioneer: Professor Helmut Sies

On this graphic you will see GSH (Glutathione).  When you take NAC (N-acetylcysteine) you directly raise the level of GSH.  When eat broccoli you activate Nrf2, which is a Redox switch, just under the traffic light in the graphic.

When you eat certain flavonoids, like Cocoa, or carotenoids like lycopene (found in tomatoes), you again promote the anti-oxidative free radical scavenger effect.  Look in the blue boxes under diet.

Not on the diagram, we also have flavonolignans which are natural phenols composed of a part flavonoid and a part lignan. As pointed out in a comment in the last post by Seth Bittker, one interesting  flavonolignan is Silibinin, which has anti-oxidant and chemoprotective effects

Note the presence of (Coenzyme) Q10 in the yellow box.  This is part of the mitochondrial cocktail suggested by Dr Kelley from Johns Hopkins for regressive autism.  Q10 is depleted by statins.

Glutathione peroxidases, in the yellow box, are also very interesting.  These are selenium-containing enzymes.  GPx (x goes from 1 to 8)  catalyze the reduction of H₂O₂ and organic hydroperoxides to harmless products. This function helps to maintain membrane integrity and to reduce further oxidative damage to molecules such as lipids and lipoproteins with the associated increased risk of conditions such as atherosclerosis.  It appears GP₁ may be defective in autism and this is contributes to increased oxidative stress.  This area has been well studied due to its impact on heart disease.  You appear to be able to counter the lack of GPx with yeast-bound selenium, other forms of selenium do not work, due to a lack of bioavailability. A post will appear just on Selenium.

There are several other potent (exogenous) antioxidants that we have come across:-

• Alpha lipoic acid also known as ALA or Tioctic acid (found  in Dr Kelley’s cocktail)
•   L-Carnosine (studied by Dr Chez )
•  Vitamin C (suggested by many, including Dr Kelley)

Another day, another anti-oxidant

In human health, two well used anti-oxidant drugs are Alpha lipoic Acid (ALA,  also known as Tioctic acid) and N-acetyl cysteine (NAC).  They share many similar effects.

•       Potent antioxidant
•       Increase insulin sensitivity
•       Improve memory in those with mild cognitive          impairment
•       May lower blood pressure
•       Improve behavior in autism

NAC is widely used to treat Chronic obstructive pulmonary disease (COPD) and ALA is used to treat diabetic neuropathy. Perhaps they could be interchanged

·        NAC has a chemoprotective effect
·        ALA has been shown to induce cell cycle arrest in  human breast cancers      cells

Back to Cocoa Flavanols and Mars

This flurry of activity was driven by a well publicized study done at Columbia University Medical Center (CUMC), using a high cocoa flavanol concentration drink provided by Mars.

Dietary cocoa flavanols reverse age-related memory decline

   

In the CUMC study, 37 healthy volunteers, ages 50 to 69, were randomized to receive either a high-flavanol diet (900 mg of flavanols a day) or a low-flavanol diet (10 mg of flavanols a day) for three months. Brain imaging and memory tests were administered to each participant before and after the study. The brain imaging measured blood volume in the dentate gyrus, a measure of metabolism, and the memory test involved a 20-minute pattern-recognition exercise designed to evaluate a type of memory controlled by the dentate gyrus.
The high-flavanol group also performed significantly better on the memory test. “If a participant had the memory of a typical 60-year-old at the beginning of the study, after three months that person on average had the memory of a typical 30- or 40-year-old,” said Dr. Small. He cautioned, however, that the findings need to be replicated in a larger study—which he and his team plan to do.

This is very impressive.  But how do the other anti-oxidants compare?

Well, without funding from Mars, researchers only managed the money to test ALA and NAC on mice; but as you might expect, the result was similar.

The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice

Chronic administration of either LA or NAC improved cognition of 12-month-old SAMP8 mice in both the T-maze footshock avoidance paradigm and the lever press appetitive task without inducing non-specific effects on motor activity, motivation to avoid shock, or body weight. These effects probably occurred directly within the brain, as NAC crossed the blood-brain barrier and accumulated in the brain. Furthermore, treatment of 12-month-old SAMP8 mice with LA reversed all three indexes of oxidative stress. These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants.

Cocoa Flavanols are good for your heart

This is also good news, but it does seem that antioxidants are generally very good for your heart.

First cocoa.

In this study blood pressure, glucose, insulin and cholesterol were all markedly affected for the better by the cocoa as was cognitive function.

This is great;  but it is what Helmut Sies has been telling the world for many years.

Benefits in Cognitive Function, Blood Pressure, and Insulin Resistance Through Cocoa Flavanol Consumption in Elderly Subjects With Mild Cognitive Impairment

The Cocoa, Cognition, and Aging (CoCoA) Study

Abstract—Flavanol consumption is favorably associated with cognitive function. We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment. We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing _990 mg (high flavanols), _520 mg (intermediate flavanols), or _45 mg (low flavanols) of cocoa flavanols per day. Cognitive function was assessed by Mini Mental State Examination, Trail Making Test A and B, and verbal fluency test. At the end of the follow-up period, Mini Mental State Examination was similar in the 3 treatment groups (P_0.13). The time required to complete Trail Making Test A and Trail Making Test B was significantly (P_0.05) lower in subjects assigned to high flavanols (38.10_10.94 and 104.10_28.73 seconds, respectively) and intermediate flavanols (40.20_11.35 and 115.97_28.35 seconds, respectively) in comparison with those assigned to low flavanols (52.60_17.97 and 139.23_43.02 seconds, respectively). Similarly, verbal fluency test score was significantly (P_0.05) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols (27.50_6.75 versus 22.30_8.09 words per 60 seconds). Insulin resistance, blood pressure, and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups. Changes of insulin resistance explained _40% of composite z score variability through the study period (partial r2_0.4013; P_0.0001). To the best of our knowledge, this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment. This effect appears mediated in part by an improvement in insulin sensitivity.

There are more cocoa studies:-

Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults  The effect of acute consumption of a flavonol-rich cocoa drink on cerebral vasomotor reactivity in African Americans

Mars Cocoa Science website

Cocoa Flavanols as a therapy for Autism

Based on the work of Helmut Sies and the trials funded by Mars, it is pretty obvious that 1,000mg of cocoa flavanols a day would very likely have a marked effect on someone with autism, assuming that is they were not already taking NAC, ALA, Carnosine, Broccoli, Sulforaphane or Selenium.  500 mg should also have an effect.

Choice of antioxidant

The question is what is the ultimate treatment for oxidative stress in autism?

I guess this will depend on exactly what type of autism you have (regressive or not), to what extent you have a mitochondrial dysfunction and whether you have any genetic dysfunction related to oxidative stress.

What works best in Billy, may be suboptimal in Charlie, but still much better than nothing at all.

It looks to me that NAC and ALA will likely be the most potent antioxidants.

If you live in the US, you can buy cocoa flavanols in standardized doses from Mars.  One capsule = 125mg of cocoa flavanols.   I have to add that I am far more inclined to believe Mars, than those supplement companies out there.  You can buy tablets saying they contain 50 mcg of Selenium, but what do they really contain? 

You can also buy “high flavanol” raw (non-alkalized) cocoa powder in big bags.  This lighter brown cocoa has lost far less of the flavonoids in the processing process.  In theory, a 5g teaspoon of the very best one will contain (on a good day) 415 mg of flavavols.

Mars are only supplying their CocoaVia products in North America, so if you want to try cocoa flavanols you have a few options:-

·        8.5 teaspoons of standard raw cocoa  (content will vary widely)

                or

·        1.2 teaspoons of “Chococru” upmarket raw cocoa

                or

·        4 capsules of CocoaVia from Mars  

Each of the above should give you 500mg of cocoa flavanols, which would look like a good starting point.  As with NAC, the studies show that the benefit increases the more you take, but the extra benefit drops off.

If somebody in the US tries CocoaVia, do let us know the result.

Not surprising, Mars tell us on the label that the product is not intended for children.  I do not suppose they ever thought of it being an autism therapy either.

I do like the idea of the redox switch, Nrf2, which Sulforaphane is known to activate.  I also like the idea of the enzyme GP₁ that acts as catalyst in the oxidation/reduction process.

The science is around 20 years old and nobody has yet figured it all out;  they probably will not conclusively do so in the next 20 years either.

Food for thought!

Statins for Cancer and Autism? Another case for PTEN?

When I first started this blog and my investigation into the biology of autism, I did shy away from the more complex areas like genetics.  I assumed that this would be best left to the “experts” and be beyond the powers of those without fancy laboratory tools.

My literature review took me early on to oxidative stress and then neuroinflammation.  I deduced that in the case of neuroinflammation, it might be possible to control inflammatory cytokines using statins.  I also noted the use of statins in TBI (Traumatic Brain Injury). I thought it would be harmless to do a quick trial, not really expecting anything to happen; but it did, and from the very first dose.

The literature is full of references to lipid dysfunction in autism and one large sub-group in autism is known to have high cholesterol.  Cholesterol and inflammation are now known to go hand in hand.  When inflammation is present, the body can react by laying down a protective layer of cholesterol.  The problem is that too much cholesterol is not good for you either.  The real culprit is not the cholesterol, it is the inflammation.

If you are in the high cholesterol autism group, a cholesterol lowering drug that is also anti-inflammatory may be “just what the doctor ordered”.

Be warned that another subgroup in autism has very low cholesterol.  In a study at the Kennedy Krieger Institute, 19% of children had extremely low cholesterol, meaning lower than 99% of typical children.

Autism: New Study Discovers Statistically Significant Link Between Abnormally Low Cholesterol Levels And Autism Spectrum Disorders

There is a rare condition, leading to autism called Smith-Lemli Opitz syndrome (SLOS).  SLOS is caused by a mutation in an enzyme involved in cholesterol synthesis; the resulting biochemical characteristics may be predictable. Most patients have lowered plasma cholesterol levels.

Since cholesterol testing is cheap and widely available, you can easily determine which group you are in.

This post is for the high cholesterol cohort.

Note well how meaningless a figure for the "average cholesterol level" in autism would be. In the autism literature they frequently take the mean average for all data, thus missing the point. 

Why Statins for Autism?

My initial logic was that since inflammatory markers are often elevated in autism and that oxidative stress and inflammation are self-reinforcing, it would be logical to find an effective anti-inflammatory agent.  Steroids might fit the bill, but they cause plenty of side effects in long term use; their short term use in autism can be remarkably effective.  So I looked further, and having screened the literature, ended up convincing myself of the potential of statins.  Read all about cytokine storms in the old posts, if you are interested.

I choose  Atorvastatin (also known as Lipitor or Sortis), since it freely crosses the blood brain barrier (BBB) and is safely used my tens of millions of people around the world.

It worked.

Explaining Statin Therapy to others.

The most important thing is to have a therapy that works;  but then you have to explain it to others.

I was recently explaining it again to a doctor relative, who was asking how I could be sure it works.  I explained that every time I stop using it, within a day behaviour changes in the same predictable way.  It is as if people with autism have an inhibitory barrier; there are things they can do, want to do, but something is blocking them from doing them.

Examples are numerous.  Speech being one.  Plenty of kids with autism are non-verbal, everything is physically functional, yet they do not talk, even when they want to communicate.

At the age Monty, now aged 11 with ASD, tried the statin he was relatively verbal.  The immediate change in him was that he suddenly started to play the piano, by himself.  Odd it may sound.

In his earlier years he would often get “stuck”.  He would be upstairs and unable to come downstairs, somebody had to go up and get him.

When I now stop the statin, he will again get “stuck”.  He will stand in the kitchen and want to leave and just say “go that way”, but not move.  You have to take his hand, so that he can “go that way”.

A Better Explanation?

Now I have another explanation of why statins may be effective in one large sub-group of autism.

Statins up-regulate a known key dysfunctional autism gene, and protein, called PTEN.  I mentioned PTEN in a previous post, since one chemical released by eating broccoli also up-regulates PTEN.

Science has already shown that things that down-regulate PTEN (like seizures) make autism worse.

The full science behind PTEN will come in a later post.

Statins and Cancer

Regular readers will recall that PTEN is also a tumor suppressor gene and is therefore a target for cancer research.

Thinking the way I do, I know that statins increase PTEN and that this should slow cancer growth.  Hundreds of millions of people take statins and many millions get cancer, so what about people on statins getting cancer?

A quick check on google and there we have studies showing that people on statins get less cancer and that in common cancers like that of the prostate, the outcome is better when statins are taken.

Now this is not a cancer blog, but you do not have to dig very deep to uncover a wealth of supporting evidence.

Statins and Prostate Cancer: Novel, Encouraging Study

Postoperative statin use and risk of biochemical recurrence following radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

Conclusion

In this retrospective cohort of men undergoing RP, post-RP statin use was significantly associated with reduced risk of BCR. Whether the association between post-RP statin use and BCR differs by race requires further study. Given these findings, coupled with other studies suggesting that statins may reduce risk of advanced prostate cancer, randomized controlled trials are warranted to formally test the hypothesis that statins slow prostate cancer progression.

Statins and prostate cancer (Harvard Medical School)

Statins could reduce the risk of breast cancer

Statins could reducethe risk of pancreatic cancer

Statin use and risk of liver cancer: an update meta-analysis

 Conclusions This meta-analysis suggests that statin is associated with a significant risk reduction of liver cancer when taken daily for cardiovascular event prevention. However, this preventive effect might be overestimated due to the exposure period, the indication and contraindication of statins and other confounders. Statins might be considered as an adjuvant in the treatment of liver cancer.

Statins and PTEN

I am no cancer expert, but I can read the literature and the evidence is pretty compelling to me.  It is not enough, however, for doctors to prescribe statins to avoid cancer.  They are so busy prescribing statins to over 50s for other reasons, it does not really matter.

We came across PPAR previously.  PPAR gamma is a pathway to treat type 2 diabetes and the old type 2 diabetes drug Pioglitazone has shown promise in an autism study.

PPAR alpha, beta and gamma in Autism, Heart Disease and Diabetes

 Effect of pioglitazone treatment on behavioral symptoms in autistic children

At that time I was more interested in PPAR-alpha, due to its role in mast cell stabilization.

It is via PPAR-gamma, that statins up regulate PTEN.

You do not want to overdo it, because at very high doses too much PPAR gamma protein will be produced and you risk causing type 2 diabetes.

Low doses of statins are trouble free for most people, but high doses are associated with increased risk of diabetes and all kinds of aches and pains.

The statin effect in autism does not increase with higher doses, only a small dose is required.

Regulation of the PTEN promoter by statins and SREBP.

Abstract

Germline mutations in the tumor-suppressor gene PTEN predispose to heritable breast cancer. The transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma) has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. We previously demonstrated that lovastatin may signal through PPARgamma and directly upregulate PTEN expression at the transcriptional level. In our current study, we show that simvastatin, pravastatin and fluvastatin can induce PTEN expression in a dose-dependent manner. This resulted from an increase in PTEN mRNA indicating transcriptional upregulation. In addition, we observed, for the first time, that upregulation of sterol response element-binding protein (SREBP), known to induce PPARgamma expression, can increase PTEN expression. Using reporter assays, we observed that both the statins and SREBP could specifically induce PPARgamma-mediated transcription. However, the statins do not appear to signal through SREBP. Furthermore, our results indicate that SREBP utilizes PPARgamma's transcriptional activity to induce PTEN transcription, whereas the statins signal through PPARgamma's protein activity to upregulate PTEN expression. Overall, our observations suggest that statins signal through another transcription factor, in a PPARgamma-dependent manner, which in turn induces PTEN transcription. We, therefore, studied the full-length PTEN promoter through serial deletion reporter assays and electromobility shift assays and identified a region between -854 and -791 that binds an as-yet-unidentified transcription factor, through which the statins induce PTEN expression. Since PTEN is constitutively active, our data indicate it may be worthwhile to examine statin and SREBP stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies in cancer, diabetes mellitus and cardiovascular disease

PTEN dysfunction in Cancer and Autism

I will cover this point in more detail in the post on PTEN, but note that the PTEN gene dysfunctions found in 10% of people with autism are generally different to the ones found in cancer.  We also have the difference between whether the PTEN gene is mutated or there is PTEN loss.

There should be two identical copies of the PTEN gene. When one copy is mutated, the protein it produces was found to inhibit the protein produced by the good copy. In other cases, one copy of the PTEN gene is OK, but the other got deleted.   This turned out to be better than having one mutant version.

Different mutations in PTEN are linked to different outcomes.  The known autism mutations are called H118P, H93R and H123Q.  If you have a C124S mutation you would be at risk of something called thyroid follicular carcinoma and not autism.

It is all very complicated and I have to say some conclusions in the research are contradictory.

But it is reported that about 10% of people with autism have an identifiable PTEN mutation.  I am more interested in whether PTEN is an interesting protein in the other 90%.

We saw in the fragile X research that even though this affects only 1% of cases with autism, some experimental therapies for fragile X worked on people with autism, but without fragile X.  At the time I thought that very odd.

My assumption is that PTEN is interesting for more than the 10%.

Conclusion

So there are now 2 plausible reasons why statin therapy may be effective in people with classic autism and elevated cholesterol:-

·        Reduction in inflammatory cytokines 

·        Up-regulation of PTEN

Maybe it is both.

It may be that in people with autism and low cholesterol, and so not suited to statins, they may also have low levels of PTEN.

We saw in a recent post that when you eat fresh broccoli in addition to Sulforaphane, you also produce Indole-3-carbinol (I3C).   I3C also up-regulates  PTEN.

Using Peter logic, if statins have an immediate effect then quite likely so would I3C.

Whatever Next?

Well, for those few of you who have discovered the “magical” beneficial effects of mast cell stabilizers, like Verapamil and Cromolyn Sodium, on both autistic behaviours and severe allergies, here is a preview of what is coming next:-

PPAR-gamma modulates allergic inflammation through up-regulation of PTEN

Recent studies have indicated that PPAR-gamma plays an important role in anti-inflammatory responses and that PPAR-gamma signaling is associated with regulation of PTEN expression. It is known that up-regulation of PTEN expression reduces asthmatic pathogenesis.

These findings suggest that PPAR-gamma uses PTEN to modulate asthmatic responses The signaling mechanism by which stimulation of PPAR-gamma with the agonists regulates PTEN expression as well as Akt phosphorylation remains to be lucidated. However, our results agree with the observation that the anti-inflammatory action of PPAR-gamma agonists is mediated via up-regulation of PTEN.

In other words, increasing PTEN minimizes allergies.  Perhaps, via feedback loops, increasing allergies reduces PTEN?

Seizures also reduce PTEN.

Reduced PTEN leads to increased autistic behaviours.

Not surprisingly we will come back, yet again, to mast cells.

For us, it really does seem that PTEN is a key piece in the puzzle;  but a puzzle with a solution.