Is DJ-1 expression negatively associated with severity of Autism? If so, Sodium Benzoate (Cinnamon) may well be beneficial

   

I do not expect this to be one of my popular posts, but it might deserve to be.

There will be lots of science, but it ends up with a safe potential intervention that can be tried at home.  The good news is that it is inexpensive, tasty and there is already a pretty solid experimental basis for the intervention.

Look in your extended family for relatives with diabetes, COPD (Chronic Obstructive Pulmonary Disease) and Parkinson’s Disease.  This might be useful indicator.

The conclusion is to put some cinnamon in your tea or coffee.

Parkinson’s Disease

Two people recently mentioned Parkinson’s disease to me.

Oxidative stress contributes to the cascade leading to dopamine cell degeneration in Parkinson's disease. This oxidative stress is linked to other components of the degenerative process, such as mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and inflammation.

The familiar motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain.

One example of motor symptoms in Parkinson’s can be the inability to walk unaided across a room.  When a series of parallel lines are placed on the floor, the person is then able to cross the room, unaided.  This story was told to me when I explained how Monty, aged 11 with ASD, would sometimes get “stuck” and be unable to leave a room or walk downstairs.  Treatment with Atorvastatin, in Monty, makes these symptoms go away.

It seems that Statins have also been shown to lower the incidence of Parkinson’s.

Statins Protective Against Parkinson's: More Evidence

Further evidence that statin use is associated with a reduction in risk for Parkinson's disease has come from a population study from Taiwan.

The study, published online in Neurology on July 24, was conducted by a team led by Yen-Chieh Lee, MD, Cathay General Hospital, Taipei, Taiwan.

In a large population of statin users, they found a lower risk for Parkinson's in those who continued taking lipophilic statins compared with those who discontinued statins upon having reached their cholesterol goal.

Authors of an accompanying editorial conclude, "For those who have to be on statins, it is a comforting thought that there is a potential added advantage of having a lower risk of PD [Parkinson's disease], and possibly other neurologic disorders as well."

Discontinuation of statin therapy associates with Parkinson disease

Abstract

Objective: To evaluate the effect of discontinuing statin therapy on incidence of Parkinson disease (PD) in statin users.

Methods: Participants who were free of PD and initiated statin therapy were recruited between 2001 and 2008. We examined the association between discontinuing use of statins with different lipophilicity and the incidence of PD using the Cox regression model with time-varying statin use.

Results: Among the 43,810 statin initiators, the incidence rate for PD was 1.68 and 3.52 per 1,000,000 person-days for lipophilic and hydrophilic statins, respectively. Continuation of lipophilic statins was associated with a decreased risk of PD (hazard ratio [HR] 0.42 [95% confidence interval 0.27–0.64]) as compared with statin discontinuation, which was not modified by comorbidities or medications. There was no association between hydrophilic statins and occurrence of PD. Among lipophilic statins, a significant association was observed for simvastatin (HR 0.23 [0.07–0.73]) and atorvastatin (HR 0.33 [0.17–0.65]), especially in female users (HR 0.11 [0.02–0.80] for simvastatin; HR 0.24 [0.09–0.64] for atorvastatin). As for atorvastatin users, the beneficial effect was seen in the elderly subgroup (HR 0.42 [0.21–0.87]). However, long-term use of statins, either lipophilic or hydrophilic, was not significantly associated with PD in a dose/duration-response relation.

Conclusions: Continuation of lipophilic statin therapy was associated with a decreased incidence of PD as compared to discontinuation in statin users, especially in subgroups of women and elderly. Long-term follow-up study is needed to clarify the potential beneficial role of lipophilic statins in PD.

Comorbidities, Coincidence and Connections

I am no medical expert, but I am good at noticing connections.

I have already decided that there are some interesting conditions that in some way are connected to autism.  These include:-

·        Diabetes
·        Cancer
·        COPD (Chronic obstructive pulmonary disease)

The connection between Parkinson’s disease and autism are:-

·        Oxidative stress
·        Mitochondrial dysfunction
·        Cognitive and behavioral problems (in late stage Parkinson’s)
·        Motor problems (in early stage and onwards in Parkinson’s and mainly in early stage in Autism)

The motor problems in autism are rarely talked about, but in ABA training programs for young children, teaching fine and gross motor skills plays a major role.  In such children, skills that are automatic in typical children can be totally missing.  You then have to teach very basic skills like controlling a crayon, kicking a ball, catching a ball or stacking wooden blocks.

Later on, motor skills seem to become “normal”.  I am amazed to see how Monty, aged 11 with ASD, can now play the piano with all fingers of both hands racing across the ivory.  A few years ago motor skills were clearly impaired. 

This comes back to autism being a dynamic encephalopathy.  An interesting research finding, I noticed recently, was that while oxidative stress appears life-long in autism, mitochondrial dysfunction appears not to be.  In the samples taken from older people with ASD, mitochondria appeared normal, whereas in young people it was typically abnormal.

It is generally accepted that in most people, autistic symptoms seem to moderate with age.  Either they are getting better at managing themselves, or the dysfunctions themselves are moderating with age.

Parkinson’s is a degenerative disease; in autism only childhood disintegrative disorder seems to be degenerative.

COPD & Parkinson’s

There is a proven connection between COPD (Chronic obstructive pulmonary disease) and Parkinson’s, it is a gene/protein called DJ-1 in COPD, also known as Parkinson disease (autosomal recessive, early onset) 7 or PARK7.

In both conditions DJ-1/PARK7 dysfunction causes a cascade of further events that result in the body losing much of its anti-oxidative defenses.

The protein DJ-1 should act to stabilize NRf2, which is released when there is oxidative stress.  Nrf2 should then activate a large number of anti-oxidant genes that then results in a reaction to the oxidative attack.

The problem is that when DJ-1 is insufficient, Nrf2 never gets as far as activating those anti-oxidant genes and so nothing halts the oxidative attack.

The less DJ-1 expression in a person, the worse their COPD (severe asthma) would be.

As is usually the case in human biology, DJ-1 has numerous other functions.

Note that not only does DJ-1 affect Nrf2, it also is a key negative regulator of PTEN that may be a useful prognostic marker for cancer.

DJ-1, a novel regulator of the tumor suppressor PTEN

In my earlier post on PTEN and statins we saw that:

Statins up-regulate a known key dysfunctional autism gene, and protein, called PTEN.  I mentioned PTEN in a previous post, since one chemical (Indole-3-carbinol (I3C)) released by eating broccoli also up-regulates PTEN.

From my perspective, upregulating PTEN in autism seems to be helpful.

Parkin, DJ-1, and PINK1 dysfunction in Parkinson’s and Autism

It appears that you need three genetic dysfunctions to develop Parkinson’s disease: parkin, DJ-1, and PINK1. Remarkably very similar dysfunctions seem to exist in autism as well.

As we see in COPD, the DJ-1 dysfunction aggravates the oxidative stress problems.

Note that PINK1, known by its full name, is PTEN-induced putative kinase 1.

The following paper shows how statins affect mitochondria, the role of the Parkinson’s genes and how statins help to clear away the dysfunctional mitochondria that can lead to heart disease.  One can assume that the protective effect of statins against Parkinson’s, must relate to a similar “spring cleaning” of dysfunctional mitochondria, but this time in the brain.

Simvastatin Induces mitochondrial loss and PTEN-mediated autophagy

Cells treated with simvastatin also displayed slight mitochondrial depolarization as compared to controls. Induction of autophagy was accompanied by decreases in the pro-growth and proliferation pathways mediated by Akt and mTOR, as well as increases in PTEN. PTEN is linked to mitochondrial quality control via the PTEN-induced putative kinase 1 (PINK1), which recruits the E3 ubiquitin ligase Parkin to mitochondrial membranes in response to depolarization. Parkin, in turn, primes the mitochondria for degradation. Reductions in mitochondria were accompanied by decreasing reactive oxygen species (ROS), which are known to cause oxidative injury and stress. By both depolarizing mitochondria and increasing expression of key autophagic proteins, simvastatin fosters a cellular environment that encourages mitochondrial autophagy (mitophagy), which has been linked to cardioprotection. We therefore propose that these mechanisms underlie the cardioprotective effects of statins that are independent of serum cholesterol levels.

For those wondering what is Mitochondrial Autophagy, read this:-

Mitochondrial Autophagy

An Essential Quality Control Mechanismfor Myocardial Homeostasis

Abstract

Efficient and functional mitochondrial networks are essential for myocardial contraction and cardiomyocyte survival. Mitochondrial autophagy (mitophagy) refers to selective sequestration of mitochondria by autophagosomes, which subsequently deliver them to lysosomes for destruction. This process is essential for myocardial homeostasis and adaptation to stress. Elimination of damaged mitochondria protects against cell death, as well as stimulates mitochondrial biogenesis. Mitophagy is a tightly controlled and highly selective process. It is modulated by mitochondrial fission and fusion proteins, BCL-2 family proteins, and the PINK1/Parkin pathway. Recent studies have provided evidence that miRNAs can regulate mitophagy by controlling the expression of essential proteins involved in the process. Disruption of autophagy leads to rapid accumulation of dysfunctional mitochondria, and diseases associated with impaired autophagy produce severe cardiomyopathies. Thus, autophagy and mitophagy pathways hold promise as new therapeutic targets for clinical cardiac care.

Parkin is a protein which in humans is encoded by the PARK2 gene.

How loss of function of the parkin protein leads to dopaminergic cell death in this disease is unclear. The prevailing hypothesis is that parkin helps degrade one or more proteins toxic to dopaminergic neurons.

PARK2 has now been linked to autism:-

Genetics: Parkinson's disease gene linked to autism

Researchers first fingered PARK2, or parkinson protein 2, in 1998 in five people with Parkinson's disease. The protein has since been shown to help degrade neurons that accumulate in the brains of individuals with the disorder.

PARK2 is an ubiquitin ligase E3, which targets proteins for degradation in the cell. Another protein in the same family, UBE3A, is associated with both autism and Angelman syndrome.

PARK2 is also believed to function in the mitochondria. Several studies have linked mitochondrial dysfunction to autism, suggesting a basis for PARK2's association with the disorder.

Novel target for Angelman Syndrome and Autism spectrum disorders

This debilitating neurological disorder is caused by mutation of the E3 ubiquitin ligase (Ube3A), a gene whose mutation has also recently been associated with autism spectrum disorders (ASD). However, the function of Ube3A in mediating cognitive impairment in individuals with AS and ASDs, as well as its substrates, have been unknown.

Invention: The Greenberg laboratory first demonstrated that neural activity induces Ube3A transcription, and that a decrease in Ube3A expression decreases the plasma membrane expression of, and synaptic transmission through AMPA glutamate receptors (AMPARs). To better understand the role of Ube3A in AS and ASD, the Greenberg lab identified key neural substrates of Ube3A, Arc and Ephexin5, and the mechanisms for their regulation of synaptic transmission. Their findings suggest mechanisms by which Ube3A contributes to cognitive dysfunction in AS and ASD.

Arc: The Greenberg lab demonstrated that disruption of Ube3A activity leads to an increase of Arc and decrease in AMPAR expression at synapses. Drugs that promote AMPAR expression at synapses, such as metabotropic glutamate receptor subtype 5 (mGluR5) antagonists or compounds that inhibit the expression or function or Arc, may reverse symptoms associated with AS and ASD.
Fragile X is a human disorder in which a similar decrease in AMPAR expression at synapses has been demonstrated. This decrease has further been shown to be a result of excessive mGluR5 signaling, resulting in increased Arc translation and excessive AMPAR internalization. Selective mGluR5 antagonists are now entering clinical trials for the treatment of Fragile X, indicating that this type of therapeutic strategy has potential  



Now to understand what goes wrong in Parkinson's

Dopamine Signaling in Parkinson's

Parkinson’s disease is the second most prevalent neurodegenerative disorder. Clinically, this disease is characterized by bradykinesia, resting tremors, and rigidity due to loss of dopaminergic neurons within the substania nigra section of the ventral midbrain. In the normal state, release of the neurotransmitter dopamine in the presynaptic neuron results in signaling in the postsynaptic neuron through D1- and D2-type dopamine receptors. D1 receptors signal through G proteins to activate adenylate cyclase, causing cAMP formation and activation of PKA. D2-type receptors block this signaling by inhibiting adenylate cyclase. Parkinson’s disease can occur through both genetic mutation (familial) and exposure to environmental and neurotoxins (sporadic). Recessively inherited loss-of-function mutations in parkin, DJ-1, and PINK1 cause mitochondrial dysfunction and accumulation of reactive oxidative species (ROS), whereas dominantly inherited missense mutations in α-synuclein and LRRK2 may affect protein degradation pathways, leading to protein aggregation and accumulation of Lewy bodies. Mitochondrial dysfunction and protein aggregation in dopaminergic neurons may be responsible for their premature degeneration. Another common feature of the mutations in α-synuclein, parkin, DJ-1, PINK1, and LRRK2 is the impairment in dopamine release and dopaminergic neurotransmission, which may be an early pathogenic precursor prior to death of dopaminergic neurons. Exposure to environmental and neurotoxins can also cause mitochondrial functional impairment and release of ROS, leading to a number of cellular responses including apoptosis and disruption of protein degradation pathways. There is also an inflammatory component to this disease, resulting from activation of microglia that causes the release of inflammatory cytokines and cell stress. This microglia activation causes apoptosis via the JNK pathway and by blocking the Akt signaling pathway via REDD1. 

  

DJ-1 and Autism

We know that oxidative stress is life-long in many people with autism.  We know that anti-oxidants like NAC (N-acteyl cysteine) and ALA (alpha lipoic acid) improve autism.  It is suggested that ALA in particular may stabilize mitochondrial disease.

ALA also has an interesting effect on glial (dys)function and I am wondering if NAC has the same effect.

Alpha-lipoic acid effects on brainglial functions accompanying double-stranded RNA antiviral and inflammatory signaling.

Viral products in the brain cause glial cell dysfunction, and are a putative etiologic factor in neuropsychiatric disorders, notably schizophrenia, bipolar disorder, Parkinson's, and autism spectrum. Alpha-lipoic acid (LA) has been proposed as a possible therapeutic neuroprotectant.

One of the reasons there is some much oxidative stress in autism may be that those anti-oxidant genes were never activated.  That would happen if DJ-1 expression was low.

The less DJ-1, the more oxidative stress.  This in turn would do many things:-

·        damage the mitochondria

·        damage the DNA

·        upset the homeostasis of the endocrine (hormone) system 

·        disrupt the developing brain (Purkinje cell loss etc)

The end result is a big mess, but amazingly not a degenerative one.

A quick recap on oxidative stress

How to up regulate DJ-1

Thanks to all the research into Parkinson’s, an interesting therapy is available to upregulate DJ-1.  A food additive, Sodium Benzoate, known as E211 or even NaC₇H₅O₂ has been shown to be effective (in mice).

Rather than taking E211 you can eat cinnamon and let your body metabolize it into Sodium Benzoate.  As long as you take the Ceylon type of Cinnamon and not one of the cheaper ones, even very high consumption seems to be risk free.

In the cheaper cinnamon, called Cassia, or Chinese, high levels of a substance called coumarin can be found.  This can be harmful to the kidneys and liver and there are legal limits on this type of cinnamon.

Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Upregulates Neuroprotective Parkinson Disease Protein DJ-1 in Astrocytes and Neurons

Abstract

DJ-1 (PARK7) is a neuroprotective protein that protects cells from oxidative stress. Accordingly, loss-of-function DJ-1 mutations have been linked with a familial form of early onset Parkinson disease. Mechanisms by which DJ-1 level could be enriched in the CNS are poorly understood. Recently we have discovered anti-inflammatory activity of sodium benzoate (NaB), a metabolite of cinnamon and a widely-used food additive. Here we delineate that NaB is also capable of increasing the level of DJ-1 in primary mouse and human astrocytes and human neurons highlighting another novel neuroprotective effect of this compound. Reversal of DJ-1-inducing effect of NaB by mevalonate, farnesyl phosphate, but not cholesterol and ubiquinone, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the induction of DJ-1 by NaB. Accordingly, either an inhibitor of p21^ras farnesyl protein transferase (FPTI) or a dominant-negative mutant of p21^ras alone was also able to increase the expression of DJ-1 in astrocytes suggesting an involvement of p21^ras in DJ-1 expression. However, an inhibitor of geranyl transferase (GGTI) and a dominant-negative mutant of p21^rac had no effect on the expression of DJ-1, indicating the specificity of the effect. Similarly lipopolysaccharide (LPS), an activator of small G proteins, also inhibited the expression of DJ-1, and NaB and FPTI, but not GGTI, abrogated LPS-mediated inhibition. Together, these results suggest that NaB upregulates DJ-1 via modulation of mevalonate metabolites and that p21^ras, but not p21^rac, is involved in the regulation of DJ-1

Cinnamon is well known for its antioxidant potential.  In other research other compounds within it are seen as the active ones.

Here is a very interesting trial showing the effect of cinnamon on lowering cholesterol and blood glucose levels.

Hypolipidemic and Antioxidative Stress Potential Of Cinnamon ZeylanicumIn Type- II Diabetes Mellitus With IHD

This Indian study looked at the effect of 3g a day of cinnamon taken with tea.  Below are the results from the control group, without type II diabetes.

The results are remarkable.  Good cholesterol (HDL) goes up, bad cholesterol (LDL) goes down, tryglicerides go down.  Glucose levels go down.  All the antioxidant indicators go up.

In table 2 in the full report you can see that the effect on people with diabetes was even better.

The Cinnamon-derived Dietary Factor Cinnamic Aldehyde Activates theNrf2-dependent Antioxidant Response in Human Epithelial Colon Cells

Abstract

Colorectal cancer (CRC) is a major cause of tumor-related morbidity and mortality worldwide. Recent research suggests that pharmacological intervention using dietary factors that activate the redox sensitive Nrf2/Keap1-ARE signaling pathway may represent a promising strategy for chemoprevention of human cancer including CRC. In our search for dietary Nrf2 activators with potential chemopreventive activity targeting CRC, we have focused our studies on trans-cinnamic aldehyde (cinnamaldeyde, CA), the key flavor compound in cinnamon essential oil. Here we demonstrate that CA and an ethanolic extract (CE) prepared from Cinnamomum cassia bark, standardized for CA content by GC-MS analysis, display equipotent activity as inducers of Nrf2 transcriptional activity. In human colon cancer cells (HCT116, HT29) and non-immortalized primary fetal colon cells (FHC), CA- and CE-treatment upregulated cellular protein levels of Nrf2 and established Nrf2 targets involved in the antioxidant response including heme oxygenase 1 (HO-1) and γ-glutamylcysteine synthetase (γ-GCS, catalytic subunit). CA- and CE-pretreatment strongly upregulated cellular glutathione levels and protected HCT116 cells against hydrogen peroxide-induced genotoxicity and arsenic-induced oxidative insult. Taken together our data demonstrate that the cinnamon-derived food factor CA is a potent activator of the Nrf2-orchestrated antioxidant response in cultured human epithelial colon cells. CA may therefore represent an underappreciated chemopreventive dietary factor targeting colorectal carcinogenesis.

Conclusion

I think it is fair to say that cinnamon has some very interesting effects in human health, but they are not yet fully understood.

It looks like people with Parkinson’s, COPD, diabetes or high cholesterol could well benefit, for one reason or another.

What is interesting to note is that in some countries the age old herbal remedy for COPD is cinnamon.

I think most people likely would benefit to some extent from cinnamon.  The effective dose is very small, 2 to 4 grams, depending on the study.  

As to the effect in autism, there is only one way to find out.

What does Cancer Risk and Autism tell us?

Today’s post is a short one.

As you look deeper into how the body functions you come across many, only recently understood, pathways.  In reality these are still “works in progress”, but some will eventually lead to a better understanding of diseases like cancer, diabetes, Parkinson’s, Alzheimer’s and, eventually, many types of autism.

Within this blog we have seen how many common diseases share some underpinnings with autism.  As a result these diseases appear more commonly in people with autism, and so they get called comorbidities.

Some comorbidities get talked about quite a lot, things like epilepsy and MR/intellectual impairment.

For me the really interesting ones and the ones that might actual lead you to some therapeutic implication.  In this respect, allergies (food and airborne) have proved to be the most useful.

Not far behind are heart disease, diabetes and cancer.

In Paul Whiteley’s blog he recently highlighted a study showing how heart disease was increased in autism.  This has been noted before and I believe leads back to calcium channels, known to be dysfunctional in autism.  One particular channel is called Cav1.2 and it is widely expressed in the brain and the heart.  In earlier posts I have covered this channelopathy from the point of view of autism.  Not surprisingly, if you have Cav1.2 dysfunction in the brain, it might very well occur elsewhere.

There are little genetic errors called Single Nucleotide Polymorphisms, or SNPs.  In the CACNA1C gene there are 12,932 known SNPs.  Some of the most common ones are associated with autism, bipolar and schizophrenia.

You can look up this gene, or any other one, and see for yourself.

Genecards database

If you read the gene description above, the idea that heart disease is comorbid with autism is no surprise. 

The lower red arrow points at hypokalemic periodic paralysis.  This has appeared many times on this blog, along with Hypokalemic Sensory Overload.  I discovered long ago that there is a potassium ion channel dysfunction in autism; it appears to be behind the odd sensory overload experienced by many with autism and also in some people with ADHD.  What is interesting is that this dysfunction co-occurs with CACNA1C dysfunctions.

Cancer and Autism

The science behind cancer is complex and so as not to research it in vain, it is useful to know that there is solid evidence linking autism and cancer.

The following study of 8,438 people with autism, compared their incidence of cancer with the incidence in the general population

To understand the jargon first read this excerpt from a fact sheet on cancer statistics:

Fact Sheet: Explanation of Standardized Incidence Ratios

How an SIR Is Calculated

The expected number is calculated by multiplying each age-specific cancer incidence rate of the reference population by each age-specific population of the community in question and then adding up the results. If the observed number of cancer cases equals the expected number, the SIR is 1. If more cases are observed than expected, the SIR is greater than 1. If fewer cases are observed than expected, the SIR is less than 1.

Examples:

60 observed cases / 30 expected cases: the SIR is 60/30 = 2.0

Since 2.0 is 100% greater than 1.0, the SIR indicates an excess of 100%.

45 observed cases / 30 expected cases: the SIR is 45/30 = 1.5

Since 1.5 is 50% greater than 1.0, the SIR indicates an excess of 50%.

30 observed cases / 30 expected cases: the SIR is 30/30 = 1.0

A SIR of 1 would indicate no increase or decrease.

Here is the autism study:-

Risk of Cancer in Children, Adolescents, and Young Adults with Autistic Disorder

Objectives

To investigate whether individuals with autism have an increased risk for cancer relative to the general population.

Study design

We enrolled patients with autistic disorder from the Taiwan National Health Insurance database in years 1997-2011. A total of 8438 patients diagnosed with autism were retrieved from the Registry for Catastrophic Illness Patients database. The diagnosis of cancers was also based on the certificate of catastrophic illness, which requires histological confirmation. The risk of cancer among the autism cohort was determined with a standardized incidence ratio (SIR).

Results

During the observation period, cancer occurred in 20 individuals with autism, which was significantly higher than a total number of expected cancers with a SIR estimate of 1.94 (95% CI 1.18-2.99). The number of cancer in males was greater than the expected number with a SIR of 1.95 (1.11-3.16), but no excess risk was found for females with a SIR of 1.91 (0.52-4.88). Cancer developed more than expected in individuals age 15-19 years with the SIR of 3.58 (1.44-7.38), but did not differ in other age range groups. The number of cancers of genitourinary system was significantly in excess of the expected number (SIR 4.15; 95% CI 1.13-10.65), and increased risk was found in ovarian cancer with SIR of 9.21 (1.12-33.29).

Conclusions

Our study demonstrated that patients with autistic disorder have an increased risk of cancer.

So, overall, the risk of all cancers is about twice as high if you have autism.  

Certain cancers are particularly high risk and understanding why this is the case might lead to a better understanding of the “pathways” leading to some types of autism. Due to the rarity of some cancers, like ovarian, one might need to validate the result; note the (1.12-33.29) range for ovarian cancer.

Rather than worry about this risk, we should use these observations to understand and treat autism.

Just as we can counter the elevated risk of heart disease we can do the same for cancer.

Clearly the cancer pathways that will soon be appearing in this blog are relevant to autism.  But in the meantime anyone can reduce their cancer risk by ensuring a high level of antioxidants in their body.  People at higher risk are those with low levels of antioxidants, which include almost all older people and people of all ages with autism.

A vast wealth of information already exists showing the chemo-protective effect of antioxidants.  Cancer clearly generally results from multiple hits, and you may be unlucky to have a single gene that “ups” your risk.  By upping your antioxidant intake you can slash one risk, in this multiple step process.

It does not seem to matter which potent antioxidant you take, but you do need enough of it.  They are all slightly different and most likely a mix of several will yield the best result.

My current favourites are:-

·        NAC (N-acetyl cysteine)

·        ALA (Alpha lipoic acid) - Nrf2 activator

·        Sulforaphane – Nrf2 activator

·        Cocoa Flavanols

·        Lycopene (cooked tomato)

These should reduce both the risk of cancer risk and heart disease.

Other antioxidants mentioned in this blog include:-

·        L-Carnosine

·        Silibinin – Nrf2 activator

·        Selenium

One should be aware that avoiding cancer and treating an existing cancer are different tasks.  Once a cancer has developed, some antioxidants can interfere with the body’s own response mechanism.

My focus is preventative “medicine”.

We saw in an earlier post how children at risk of developing asthma could be identified by their atopic dermatitis.  By treating these children with a cheap mast cell stabilizer called Ketotifen, a trial showed how it was possible to avoid the onset of asthma.

I suspect that the same thing might be possible with epilepsy.  We saw in an earlier post that the first epileptic attack make a (epigenetic?) change, and thereafter there is a greatly increased risk of future seizures.

Other interesting preventative interventions, include statins to avoid Parkinson’s disease and Verapamil to avoid the onset of Type II diabetes.

I did explain all this to the European Medicines Agency some months ago, the idea of treating the comorbidities of autism BEFORE they occur.  Perhaps an idea before its time?

The over-activated immune system, Kv1.3, ASD-IE, Acacetin and sloppy science

One of the people I have met during my investigation into autism, recently pointed out to me that much scientific research cannot be trusted.  He forwarded a study to me showing just how many researchers admit is omitting data that did not suit what they were trying to prove.  I replied that I made a point of checking the credentials of the lead author.  He then replied that it is not the lead researcher who collects the data, he has a little army of PhD students doing this and nobody is checking them.

The study showed it was the younger researchers, eager to prove themselves that were the most likely to “fiddle” the results.  The problem is that by the time you become an “older researcher” you are not the one collecting the data.

Doubts about Sprouts 

One of the people who I keep forgetting to add to my Dean’s list is John Gargus; he is a professor at University of California at Irvine and Director of the Center for Autism Research and Treatment at UCI.  He is also a specialist in the complex field of ion channels and channelopathies.

He was asked to comment about the Johns Hopkins broccoli/Sulforaphane autism trial.

Trial sprouts doubts about broccoli extract for autism

Cruciferous caution: 

Some independent researchers have similar reservations, noting that the control group showed an unusually small placebo response.“You always see a 20 to 25 percent improvement in placebo,” says John Jay Gargus, director of the Center for Autism Research and Translation at the University of California, Irvine. For example, the placebo effect plagued trials of the gut hormone secretin and antidepressants for autism.
“It’s stunning that they’ve managed to have found a placebo that doesn’t give the placebo effect that we see in every other neuropsychiatric drug trial,” Gargus says.

Now as regular readers will know, at least in Monty, aged 11 with ASD, broccoli sprout powder and we assume the Sulforaphane produced by it, does have a near immediate effect.

But as Gargus says, you will always have some people with the placebo appearing to improve.  In an old post I looked at the placebo effect in autism.  It seems that the more involved the trial and hence the more 1:1 attention the child gets, the more the placebo appears to make things better.  In fact it was not the placebo, it was the 1:1 attention that improved the autism.

So, just as we have to be cautious of the placebo effect, we have to be cautious of sloppy science/scientists.  When financial interests are involved you need to be even more cautious.

The other thing I have learnt to be cautious of, is scientists who have spent many years in one very narrow field, often trying to prove their initial hypothesis to be correct.  Their eyes are then closed to everything else.

Autism Flare-ups, Summertime raging and GI issues

We have investigated in depth the fact that in some people with autism their immune system appears to be over-activated, as the result of an allergic response.  What then happens is that their autism “flares-up” and therapies that previously worked, seem to stop doing so.

The conclusion was that the allergy had caused mast cell activation and this triggered the release of pro-inflammatory chemicals (IL-6, histamine etc).  The solution was:-

·        Avoid the allergen (a type of food, or even airborne pollen)
·        Use mast cell stabilizers to minimize degranulation; even common H1 anti-histamines are partially effective
·        Inhibit the potassium ion channel Kv1.3, which seems to mediate the resulting “over-activation” of the immune response.

The good news is that it really does work and not just in Monty.  The bad news is that the optimal therapy uses a prescription drug (Verapamil).

While trawling through the research on novel anti-oxidants, I stumbled upon something that may help those people who cannot access Verapamil.

There is a flavonoid called Acacetin, which is found in asplenioid ferns.  This flavonoid has long been has used for its anti-inflammatory and immunomodulatory effects.  Now it has been shown to block Kv1.3 channels and inhibits human T cell activation.  This is one of the effects of Verapamil (there are others).  Acacetin has also been shown to have anti-cancer properties in prostate cancer cells.

Acacetin Blocks Kv1.3 Channels and Inhibits Human T Cell Activation

Acacetin (5,7-dihydroxy-4'-methoxyflavone)exhibits in vitro and in vivo anticancer activity through the suppression of NF-κB/Akt signaling in prostate cancer cells

Remember the odd therapy used to block Kv1.3, those TSO parasites, I mentioned in previous posts.  My favorite is this one:-

Immunomodulatory Therapy in Autism - Potassium ChannelKv1.3, Parasitic Worms, and their ShK–related peptides

Acacetin is available as a supplement.  So if you think blocking Kv1.3 might help and cannot access Verapamil or TSO, there are other options.

Indeed, for completeness, there at least two other Kv1.3 blockers that are available.  One is progesterone, the hormone and the other is Curcumin.

  

A nongenomic mechanism for progesterone-mediated immunosuppression: inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes.  Curcumin serves as a human kv1.3 blocker to inhibit effector memory T lymphocyte activities.

  

You may recall that Progesterone was found to be highly neuro-protective and for this reason was trialed for use in the ER, immediately after a traumatic brain injury.  It was shown to save lives.  In autism, we previously found that some people, at the high functioning end, find they feel better when they apply progesterone cream, i.e. transdermal route.

Curcumin has been used for centuries as a drug.

I have not tried them, but I will continue to use Verapamil.  Acacetin, Progesterone and Curcumin share some, but not all of each other’s effects.

Progesterone, in common with Verapamil, affects both potassium and calcium channels.

There are many different potassium and calcium channels and you would hope to find a selective channel blocker and hence affect only the ones you need to.

ASD-IS  (Inflammatory Subtype)

I came across a promising study on Paul Whiteley’s blog.  It is a study of a sub-type of autism characterized by fluctuating behavioral symptoms following immune insults.  In the trial group the children all had GI problems, some had enterocolitis or esophagitis.  The entire group had been noticed by teachers/therapists to lose cognitive skills following immune insults.

Cytokine profilesby peripheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an inflammatory subtype?

Regular readers of this blog will see lots of familiar points.  This appears to be exactly the same thing as my “over-activated immune response”.

Now this study comprised children who had Non-IgE mediated allergies.  This does matter because classic allergies are called IgE-mediated and they result in little cells called mast cells getting activated and then releasing IL-6 and histamine in the blood supply.

From Wikipedia we have a summary:-

Conditions caused by food allergies are classified into 3 groups according to the mechanism of the allergic response:

1.     IgE-mediated (classic) – the most common type, occurs shortly after eating and may involve anaphalaxis.

2.     Non-IgE mediated – characterized by an immune response not involving immunoglobulin E; may occur some hours after eating, complicating diagnosis.

3.     IgE and/or non-IgE-mediated – a hybrid of the above two types.

Treating allergy is a “fuzzy” area and, depending on which country you live in, some aspects are seen as science and others pseudo-science. 

Perhaps we should see it as an important, but emerging field of science.

I am not an allergist/immunologist, so I have to look things up.

Since in the trial the children had Non-IgE mediated allergies, we can then look to see whether mast cell activation is relevant.

NON-IgE MEDIATED FOOD ALLERGY 

Mast cell and eosinophil activation is an important component of the non-IgE-mediated response

The authors of the autism study believe that the research subjects with allergy did not have mast cell activation, because they had NON-IgE mediated allergies.

Since I am not an allergist, all I can say is the author of the above paper from the Royal Free & University College School of Medicine in London thinks that mast cell activation is an important component of the non-IgE-mediated response.

Anyway, make your own mind up and continue to see what the study found.

The study looked at children with autism and allergy, whose autism flares up and affects (impairs) their cognitive function.  This group is ASD-IS (Inflammatory Subtype)

ASD-IS children: ASD-IS children are defined as those with a history of fluctuating behavioral symptoms following immune insults (mainly microbial infection). Symptoms must have been documented by individuals other than parents, such as teachers/therapists, a minimum of three times. In addition, a history of persistent GI symptoms, often diagnosed as non-IgE mediated food allergy (NFA - see next section for diagnostic criteria), is required. Among the ASD-IS subjects, 14/24 subjects were diagnosed with food protein induced enterocolitis syndrome (FPIES), a severe form of NFA, prior to enrollment in this study, and two ASD-IS subjects were diagnosed with eosinophilic esophagitis (EoE) on the basis of biopsy results. These ASD-IS subjects reported to have had loss of once-acquired cognitive skills based on the reports of teachers, therapists and/or previous records of developmental assessment.

We defined ‘flares’ as worsening behavioral symptoms following immune insults, despite the resolution of acute conditions such as viral syndrome (that is, the resolution of other infectious symptoms if associated with a microbial infection, lack of fever, and no other acute physical symptoms associated with immune insults). Most of the immune insults in this study were clinically judged to be microbial infection (mainly viral syndrome). In ASD-IS children, we obtained samples at least once in the ‘flare’ and ‘non-flare’ states. Changes in behavioral symptoms by parental reports were confirmed by reports from

teachers and other caregivers.

The authors have an entirely different hypothesis to mine.

But I find their data remarkably similar to what I see being caused by a pollen allergy in my son - summertime autism flare-up and regression.  This is why there were so many posts about the inflammatory cytokine IL-6 and how to minimize it.

Have the authors stumbled upon exactly the same phenomenon as I did?  I very much think so.

I have shared my therapy with the authors, but they think that Non-IgE mediated allergies have nothing to do with mast cell activation.   That sounds odd to me.