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Showing posts with label TBI. Show all posts
Showing posts with label TBI. Show all posts

Wednesday, 14 December 2016

Refining Antioxidant (ROS & RNS) Therapy in Autism -  Selenium and Molybdenum




Today’s post is about further refining antioxidant therapy.

As we saw in a recent post, oxidative and nitrosative stress is a very common feature of autism and is treatable with OTC products.

The cheapest antioxidant, N-acetylcysteine (NAC), looks to be the best one, but there are numerous others with exotic names and equally exotic prices.

Today we just look at selenium and molybdenum.  Selenium was on my to-do list for a long time because it affects some key enzymes call GPX (glutathione peroxodases).
Molybdenum was enthusiastically recommended in a recent comment and this blog has previously touched on Molybdenum Cofactor Sulfurase (MOCOS).

Rather surprisingly, there is a commercial product that contains NAC, Selenium and Molybdenum. 


Selenium and GPX (glutathione peroxodases)

There are eight different glutathione peroxodases, but GPx1, GPx2, GPx3, and GPx4 are all made from selenium.

GPX speeds up the antioxidant reactions that involve glutathione (GSH).

In autism we know that both GSH and GPX are lacking.

We know how to make more GSH, just take some NAC.  But what about the catalyst GPX? 
There may be an equally easy way to increase that. 


Selenium and Thyroid  Enzymes

Selenium is also part of the three deiodinase enzymes D1, D2 and D3.

The active thyroid hormone is called T3, but most of what is circulating in your body is the inactive pro-hormone form called T4.

Deiodinase 1 (D1)  both activates T4 to produce T3 and inactivates T4. Besides its increased function in producing extrathyroid T3, its function is less well understood than D2 or D3.

Deiodinase 2 (D2), located in the ER membrane, converts T4 into T3 and is a major source of the cytoplasmic T3 pool.  It looks like some people with autism may lack D2 in their brain.

Deiodinase 3 (D3) prevents T4 activation and inactivates T3. It looks like some people with autism have too much D3 in their brain.

D2 and D3 are important in homeostatic regulation in maintaining T3 levels at the plasma and cellular levels.


·        In hyperthyroidism D2 is down regulated and D3 is upregulated to clear extra T3

·        in hypothyroidism D2 is upregulated and D3 is downregulated to increase cytoplasmic T3 levels


Serum T3 levels remain fairly constant in healthy individuals, but D2 and D3 can regulate tissue specific intracellular levels of T3 to maintain homeostasis since T3 and T4 levels may vary by organ.  

It appears that some people with autism may have central hyperthyroidism, meaning in their brain.

Regular readers may recall this post:-


The major source of the biologically active hormone T3 in the brain is the local intra-brain conversion of T4 to T3, while a small fraction comes from circulating T3. 

As evidence derived from in vitro studies suggests, in response to oxidative stress D3 increases while D2 decreases (Lamirand et al., 2008; Freitas et al., 2010).  As we know in the autistic brain we have a lot of oxidative stress.



Furthermore, in ASD, the lower intra-brain T3 levels occur in the

Absence of a systemic T3 deficiency (Davis et al., 2008), most likely due to the increased activity of D3.



So in some autistic brains we have too much D3 which is inactivating T3 and preventing T4 being converted to T3.

Reduced D2 is reducing the conversion of T4 to T3. 

We would therefore want to increase D2 in some autism.

This can be achieved by:-

·        Reducing oxidative stress, which we are already sold on. 

·        We can also potentially upregulate the gene that produces D2 using some food-based genetic therapy. Kaempferol (KPF) appears to work and may explain why broccoli sprout powder makes some people go hyper and some others cannot sleep  



The cAMP-responsive gene for type 2 iodothyronine deiodinase (D2), an intracellular enzyme that activates thyroid hormone (T3) for the nucleus, is approximately threefold upregulated by KPF



·        Perhaps low levels of selenium differentially affect the synthesis of D1, D2 and D3?

  

Where does selenium come from? 

We know from Chauham/James that selenium levels are reduced in autism, but we also know that selenium levels vary widely by geography.  

You get selenium from your diet and the level of selenium in the soil varies widely.  It is widely held that most healthy people should have plenty selenium in their diet. 

In the following paper there is an analysis of Selenium status in Europe and the Middle East.
Since we have plenty of Polish readers I have included the chart with the Polish data (on the left).  It shows that Polish people may be a little deficient in selenium.
You can see the level of selenium in Poland is below that needed to optimise plasma GPx activity.
So if you already have reduced GPx activity, because of autism, and you really need to make the most of your limited glutathione (GSH) because you have oxidative/nitrosative stress, then a little extra selenium could be just what the doctor should have ordered.

  

Se is an essential non-metal trace element [3] that is required for selenocysteine synthesis and is essential for the production of selenoproteins [4]. Selenoproteins are primarily either structural or enzymatic [2], acting as catalysts for the activation of thyroid hormone and as antioxidants, such as glutathione peroxidases (GPxs) [5]. GPx activity is commonly used as a marker for Se sufficiency in the body [6], where serum or plasma Se concentrations are believed to achieve maximum GPx expression at 90–100 μg/L (90.01 μg/L as proposed by Duffield and colleagues [7] and 98.7 μg/L according to Alfthan et al. [8]). However, plasma selenoprotein P (SEPP1) concentration is a more suitable marker than plasma GPx activity [9]. Prospective studies provide some evidence that adequate Se status may reduce the risk of some cancers, while elevated risk of type 2 diabetes and some cancers occurs when the Se concentration exceeds 120 μg/L [10]. Higher Se status has been linked to enhanced immune competence with better outcomes for cancer, viral infections, including HIV progression to AIDS, male infertility, pregnancy, cardiovascular disease, mood disorders [2] and, possibly, bone health [11–14].





  




Selenium and NAC for Rats with TBI

Perhaps not surprisingly, selenium and NAC have been found beneficial for Rats unfortunate enough to have sufferred a traumatic brain injury (TBI).




It has been suggested that oxidative stress plays an important role in the pathophysiology of traumatic brain injury (TBI). N-acetylcysteine (NAC) and selenium (Se) display neuroprotective activities mediated at least in part by their antioxidant and anti-inflammatory properties although there is no report on oxidative stress, antioxidant vitamin, interleukin-1 beta (IL)-1β and IL-4 levels in brain and blood of TBI-induced rats. We investigated effects of NAC and Se administration on physical injury-induced brain toxicity in rats. Thirty-six male Sprague–Dawley rats were equally divided into four groups. First and second groups were used as control and TBI groups, respectively. NAC and Se were administrated to rats constituting third and forth groups at 1, 24, 48 and 72 h after TBI induction, respectively. At the end of 72 h, plasma, erythrocytes and brain cortex samples were taken. TBI resulted in significant increase in brain cortex, erythrocytes and plasma lipid peroxidation, total oxidant status (TOS) in brain cortex, and plasma IL-1β values although brain cortex vitamin A, β-carotene, vitamin C, vitamin E, reduced glutathione (GSH) and total antioxidant status (TAS) values, and plasma vitamin E concentrations, plasma IL-4 level and brain cortex and erythrocyte glutathione peroxidase (GSH-Px) activities decreased by TBI. The lipid peroxidation and IL-1β values were decreased by NAC and Se treatments. Plasma IL-4, brain cortex GSH, TAS, vitamin C and vitamin E values were increased by NAC and Se treatments although the brain cortex vitamin A and erythrocyte GSH-Px values were increased through NAC only. In conclusion, NAC and Se caused protective effects on the TBI-induced oxidative brain injury and interleukin production by inhibiting free radical production, regulation of cytokine-dependent processes and supporting antioxidant redox system.

  


  

And now to Molybdenum 

Molybdenum (Mo) is a trace dietary element necessary for human survival.

Low soil concentration of molybdenum in a geographical band from northern China to Iran results in a general dietary molybdenum deficiency, and is associated with increased rates of esophageal cancer.  Compared to the United States, which has a greater supply of molybdenum in the soil, people living in those areas have about 16 times greater risk for esophageal cancer.
So you would not want to have molybdenum deficiency.

Four Molybdenum-dependent enzymes are known, all of them include molybdenum cofactor (Moco) in their active site: sulfite oxidase, xanthine oxidoreductase, aldehyde oxidase, and mitochondrial amidoxime reductase.

Moco cannot be taken up as a nutrient, and thus it requires to made in your body from molybdenum.

If your body cannot make enough Moco you may develop what is called molybdenum cofactor deficiency, which would ultimately kill you. It is ultra rare.

Symptoms include early seizures, low blood levels of uric acid, and high levels of sulphite, xanthine, and uric acid in urine.


When caused by a mutation in the MOCS1 gene it is called the type A variant.

Molybdenum cofactor deficiency may indeed be extremely rare, but MOCS1 is a known autism gene.  Perhaps there exists partial molybdenum cofactor deficiency, which is not rare at all?





Source:-  Identification of candidate intergenic risk loci in autism spectrum disorder



MOCOS (Molybdenum cofactor sulfurase)


Molybdenum cofactor sulfurase is an enzyme that in humans is encoded by the MOCOS gene.

MOCOS sulfurates the molybdenum cofactor of xanthine dehydrogenase (XDH) and aldehyde oxidase (AOX1), which is required for their enzymatic activities.

MOCOS is downregulated in autism and is suggested to induce increased oxidative-stress sensitivity, which would not be good.

So it looks like we need a clever way to upregulate MOCOS.

You need adequate molybdenum cofactor (Moco), for which you do need adequate molybdenum.

You need the genes MOCS1 and MOCOS to be correctly expressed.

SIRT1 activation, which is a future therapy for Alzheimer’s, is suggested to increase MOCOS, as may NRF2.

Sirtuin-activating compounds (STAC) are chemical compounds having an effect on sirtuins, a group of enzymes that use NAD+ to remove acetyl groups from proteins. They are molecules able to prevent aging related diseases like Alzheimer's, diabetes, and obesity.  There is quite a long list that includes ranges from polyphenols such as resveratrol, the flavonols fisetin, and quercetin also butein, piceatannol, isoliquiritigenin,


Fisetin is found in strawberries, cucumbers and supplements.  In normal animals, fisetin can improve memory; it also can have an effect on animals prone to Alzheimer's.




Here is the excellent French paper on MOCOS:-



With an onset under the age of 3 years, autism spectrum disorders (ASDs) are now understood as diseases arising from pre- and/or early postnatal brain developmental anomalies and/or early brain insults. To unveil the molecular mechanisms taking place during the misshaping of the developing brain, we chose to study cells that are representative of the very early stages of ontogenesis, namely stem cells. Here we report on MOlybdenum COfactor Sulfurase (MOCOS), an enzyme involved in purine metabolism, as a newly identified player in ASD. We found in adult nasal olfactory stem cells of 11 adults with ASD that MOCOS is downregulated in most of them when compared with 11 age- and gender-matched control adults without any neuropsychiatric disorders. Genetic approaches using in vivo and in vitro engineered models converge to indicate that altered expression of MOCOS results in neurotransmission and synaptic defects. Furthermore, we found that MOCOS misexpression induces increased oxidative-stress sensitivity. Our results demonstrate that altered MOCOS expression is likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders. We anticipate our discovery to be a fresh starting point for the study on the roles of MOCOS in brain development and its functional implications in ASD clinical symptoms. Moreover, our study suggests the possible development of new diagnostic tests based on MOCOS expression, and paves the way for drug screening targeting MOCOS and/or the purine metabolism to ultimately develop novel treatments in ASD.  

Lately, a diminished seric expression of glutathione, glutathione peroxidase, methionine and cysteine has been highlighted in a meta-analysis from 29 studies on ASD subjects.45 Along this line, purines and purine-associated enzymes are recognized markers of oxidative stress. ROS are generated during the production of uric acid, catalyzed by xanthine oxidase and XDH.46 Conversely, uric acid is nowadays recognized as a protective factor acting as a ROS scavenger.47, 48 Interestingly, allopurinol, a xanthine oxidase inhibitor, was found efficient in reducing symptoms, especially epileptic seizures, in ASD patients displaying high levels of uric acid.49 However, in our cohort, only 3 out of 10 patients exhibited an abnormal uric acid secretion. It can therefore be postulated that still unknown other MOCOS-associated mechanisms may have a role in the unbalanced stress response observed in ASD OSCs.
Identifying and manipulating downstream effectors of MOCOS will be the next critical step to better understand its mechanisms of action. In parallel, we plan to ascertain some of its upstream regulators. For example, bioinformatic analyses revealed that the promoter region of MOCOS includes conserved binding sites for transcription factors such as GATA3 and NRF2. In addition, other putative interactors, such as the NAD-dependent deacetylase sirtuin-1 (SIRT1), may have a regulatory role on MOCOS expression. Interestingly, these three genes have been associated with ASD, fragile X syndrome, epilepsy and/or oxidative stress.54, 55, 56, 57 In conclusion, our study opens an unexplored new avenue for the study of MOCOS in ASD, and could set bases for the development of new diagnostic tools as well as the search of new therapeutics.

Conclusion

It looks like a little extra selenium may be in order to increase those GPx enzymes that are need to speed up aspects of the antioxidant activity of GSH.

When it comes to molybdenum, things get much more complex. You certainly do not want to be deficient in molybdenum and you do not want Molybdenum cofactor deficiency; you also do not want molybdenum cofactor Sulfurase (MOCOS) mis-expression.

It is fair to say that quite likely there is a problem related to molybdenum that affects oxidative stress in autism; but it is not yet clear what to do about it.  I rather doubt the solution is as simple as just a little extra molybdenum, but it is easy to try.

On the plus side, we see that if you have autism, epilepsy and high uric acid you are likely to benefit from allopurinol, which also seems to help in COPD.

There is nothing new about allopurinol possibly be effective in some autism, as from this 25 year old book, Diagnosis and Treatment of Autism.



Again we see that activating NRF2 looks a good idea, that applies to both autism and COPD.
One thing to note is that NRF2 activators are good for cancer prevention, but if you have a cancer you want NRF2 inhibitors.

NRF2 activators include sulforaphane (SFN), R-alphalipoic acid (ALA), resveratrol and curcumin.  SFN is by far the most potent.  Resveratrol and curcumin have a problem with bioavailability.











Wednesday, 15 June 2016

Treating KCC2 Down-Regulation in Autism, Rett/Down Syndromes, Epilepsy and Neuronal Trauma ?



In this composite image, a human nerve cell derived from a patient with Rett syndrome shows significantly decreased levels of KCC2 compared to a control cell.  This will be equally true of about 50% people with classic autism, people with Down syndrome, many with TBI and many with epilepsy


In a recent post I highlighted an idea from the epilepsy research to treat a common phenomenon also found in much classic autism.  Neurons are in an immature state with too much intracellular chloride, the transporter that brings it in, called NKCC1, is over-expressed and the one that takes it out, KCC2, is under-expressed.  The net result is high levels of intracellular chloride and this leaves the brain in an over-excited state (GABA working in reverse) reducing cognitive function and with a reduced threshold to seizures.

The epilepsy research noted that increased BDNF is one factor that down regulates KCC2, which would have taken chloride out of the cells.  So it was suggested to block BDNF, or something closely related called trkB.

Unfortunately there is no easy way to this.  But I did some more digging and found various other ways to upregulate KCC2.

There is indeed a clever safe way that may achieve this and it is a therapy that I have already suggested for other reasons, intranasal insulin.

BDNF is a neurotrophin and other neurothrophins also have the ability to regulate KCC2. IGF-1 is another such neurotrophin and we even have very recent experimental data showing its effect on KCC2.

Regular readers will know that several trials with IGF-1, or analogs thereof, are underway.

I actually am rather biased against IGF-1 as a therapy, since in my son’s case the level of IGF-1 in blood is already high.  So I do not want to inject him with IGF-1 or even give him an oral analog.

However by using intranasal insulin the effect would be just within the CNS and insulin binds at the same receptors as IGF-1. So if IGF-1 upregulates KCC2 so will insulin.

We know from extensive existing trial data and direct feedback from one researcher that intranasal insulin is well tolerated and has no effect outside the CNS.

So rather to my surprise there seems to be a safe, cheap way to treat KCC2 down-regulation and this would also be applicable in epilepsy, traumatic brain injury (TBI) and any other condition involving immature neurons or neuronal trauma. 


The Science

There is a very thorough recent review paper that looks at all the ways that KCC2 expression is regulated.




The epilepsy researchers consider trkB, top left in the figure below.  But just next to it is IGFR which can be activated by both insulin and IGF-1.

In Rett syndrome they are already using IGF-1 to modulate KCC2.  The research is done at Penn State.

As you can see in the figure the mechanism for IGF-1 and insulin is not the same as BNDF/trkb, but Penn State have already shown that IGF-1 works in vitro.

We saw in early posts regarding intranasal insulin that this was a safe way to deliver insulin to the brain without effects in the rest of the body.

So we know it is safe and in theory it should achieve the same thing that the Penn State researchers are trying to achieve.








Signaling pathways controlling KCC2 function. The regulation of KCC2 activity is mediated by many proteins including kinases and phosphatases. It affects either the steady state protein expression at the plasma membrane or the KCC2 protein recycling. All the different pathways are explained and discussed in the main text. The schematic drawings of KCC2 as well as other membrane molecules do not reflect their oligomeric structure. GRFα2, GDNF family receptor α2; BDNF, Brain-derived neurotrophic factor; TrKB, Tropomyosin receptor kinase B; Insulin, Insulin-like growth factor 1 (IGF-1); IGFR, Insulin-like growth factor 1 receptor; mGluR1, Group I metabotropic glutamate receptor; 5-HT-2A, 5-hydroxytryptamine (5-HT) type 2A receptor; mAChR, Muscarinic acetylcholine receptor; NMDAR, N-methyl-D-aspartate receptor; mZnR, Metabotropic zinc-sensing receptor (mZnR); GPR39, G-protein-coupled receptor (GPR39); ERK-1,2, Extracellular signal-regulated kinases 1, 2; PKC, Protein kinase C; Src-TK, cytosolic Scr tyrosine kinase; WNKs1–4, with-no-lysine [K] kinase 1–4; SPAK, Ste20p-related proline/alanine-rich kinase; OSR1, oxidative stress-responsive kinase -1; Tph, Tyrosine phosphatase; PP1, protein phosphatase 1; Egr4, Early growth response transcription factor 4; USF 1/2, Upstream stimulating factor 1, 2.




The Penn State research on using IGF-1 to increase KCC2 in Rett Syndrome



The researchers also showed that treating diseased nerve cells with insulin-like growth factor 1 (IGF1) elevated the level of KCC2 and corrected the function of the GABA neurotransmitter. IGF1 is a molecule that has been shown to alleviate symptoms in a mouse model of Rett Syndrome and is the subject of an ongoing phase-2 clinical trial for the treatment of the disease in humans.
"The finding that IGF1 can rescue the impaired KCC2 level in Rett neurons is important not only because it provides an explanation for the action of IGF1," said Xin Tang, a graduate student in Chen's Lab and the first-listed author of the paper, "but also because it opens the possibility of finding more small molecules that can act on KCC2 to treat Rett syndrome and other autism spectrum disorders."





More Melatonin?

As Agnieszka pointed out in the previous post it appears that extremely high doses of melatonin can increase KCC2 in traumatic brain injury (TBI). In this example BDNF was increased by the therapy, so I think TBI may be a specific case.  In most autism BDNF starts out elevated and in epilepsy, seizures are known to increase BDNF and that process is seen as down regulating KCC2 expression.  So in much autism and epilepsy you want less BDNF.

Melatonin attenuates neuronal apoptosis through up-regulation of K+ -Cl- cotransporter KCC2 expression following traumatic brain injury in rats



Compared with the vehicle group, melatonin treatment altered the down-regulation of KCC2 expression in both mRNA and protein levels after TBI. Also, melatonin treatment increased the protein levels of brain-derived neurotrophic factor (BDNF) and phosphorylated extracellular signal-regulated kinase (p-ERK). Simultaneously, melatonin administration ameliorated cortical neuronal apoptosis, reduced brain edema, and attenuated neurological deficits after TBI. In conclusion, our findings suggested that melatonin restores KCC2 expression, inhibits neuronal apoptosis and attenuates secondary brain injury after TBI, partially through activation of BDNF/ERK pathway.



More Science

There is plenty more science on this subject.

It is suggested that in addition to IGF-1/insulin it may be necessary to involve Protein tyrosine kinase (PTK).




Protein tyrosine kinase (PTK) phosphorylation is considered a key biochemical event in numerous cellular processes, including proliferation, growth, and differentiation, and has also been implicated in synaptogenesis. Protein tyrosine kinases are subdivided into the cytosolic nonreceptor family and the transmembrane growth factor receptor family, which includes receptors for insulin and insulin-like growth factor (IGF-1). The maturation of postsynaptic inhibition may require both a cytoplasmic PTK, which increases GABAA receptor-mediated currents, and insulin, which was shown to induce a rapid translocation of GABAA receptors from intracellular compartments to the plasma membrane. KCC2 is also known to have a C-terminal PTK consensus site. Therefore, the maturation of postsynaptic inhibition may, in addition to other mechanisms, also involve the effects of PTK and insulin acting on KCC2.








Conclusion

I would infer from all this science that intranasal insulin is likely to increase KCC2 expression in the brain, certainly worthy of investigation.

Protein tyrosine kinase (PTK) phosphorylation is considered a key biochemical event in numerous cellular processes.  This might be a limiting factor on the effectiveness of insulin in raising KCC2.  This would then add yet more complexity.

Protein kinases are enzymes that add a phosphate(PO4) group to a protein, and can modulate its function.  A protein kinase inhibitor is a type of enzyme inhibitor that blocks the action of one or more protein kinases.

Abnormal protein tyrosine kinases (PTKs) cause many human leukaemias, so there is research into PTK inhibitors (PTK-Is).

As we know from Abha Chauhan’s mammoth book, oxidative stress controls the activities of PTK.




Thursday, 30 October 2014

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.


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.



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.






 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.



 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.



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:-


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.