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Monday, 22 May 2017

Green Tea Catechin EGCG in Down Syndrome, but Autism? and Cerebrolysin



In a recent comment a reader from Poland highlighted the popularity there of a drug called cerebrolysin to treat autism and Down syndrome.  It turns out that this treatment in also widespread in the former Soviet Union.

Green tea as a source of Epigallocatechin gallate (EGCG)

Cerebrolysin is a mixture of peptides purified from pig brains, including  brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and ciliary neurotrophic factor (CNTF).

While cerebrolysin is used for stroke and vascular dementia, it is used by some as a nootropic. 

There are two Russian studies supporting the use of Cerebrolysin:



 
I was informed that cerebrolysin is prescribed off-label in Poland to treat autism, with some good results.
Three other substances were then mentioned.
MemoProve, an oral OTC product made by the same Austrian company that produces cerebrolysin, and then two research compounds P6 and P21. The P21 research is also part funded by the same Austrians. People in the US are using intranasal P21 as a nootropic.
It does seem that some people with autism do indeed benefit from cerebrolysin. 
As we have seen in previous posts the various growth factors (BDNF, NGF, IGF-1 etc) are disturbed in autism and they play a key role in various signaling cascades. There certainly is logic in using growth factors as autism therapies, but it would be important to use the right ones. In Rett syndrome there is almost no nerve growth factor (NGF), whereas in much autism there are elevated levels. Insulin-like growth factor IGF-1 already is a target autism therapy.
The disadvantage of cerebrolysin is that it is made from pigs’ brains and you need to inject it every day.
Unless you live in Poland, Russia or Romania, I doubt you will be able to try cerebrolysin, even if you want to.
Another therapy I am told is used in Poland is EGCG, which stands for Epigallocatechin gallate, or just green tea. 

Epigallocatechin gallate (EGCG)

EGCG is another natural substance like resveratrol, curcumin and indeed quercetin that has potent properties in lab, but never quite makes it in the human world.
The normal problem is low bioavailability and the lack of funding to do conclusive clinical trials.
In the case of EGCG there are now some serious studies being done in Spain. 


There is a mounting evidence of the modulation properties of the major catechin in green tea, epigallocatechin-3-gallate (EGCG), on dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene overexpression in the brains of DS mouse models. The aims are to investigate the clinical benefits and safety of EGCG administration in young adults with DS, to establish short-term EGCG effects (three months) on neurocognitive performance, and to determine the persistency or reversibility of EGCG related effects after three months of discontinued use. 


The flavonoid epigallocatechin gallate (EGCG) is a modulator of neuronal plasticity useful in other neurodevelopmental diseases. A recent study showed that EGCG is a promising tool for cognitive and health related quality of life improvement in Down's syndrome.

The objective is to determine the efficacy of EGCG as a therapeutic candidate for the improvement of cognitive performance in FAS patients  


Fragile X syndrome (FXS) present alterations in synaptic plasticity that produce intellectual disability. can produce improvement. Estrogens (targeting Estrogen Receptors beta (ER-β) can act as neuroprotective agents, promoting synaptic plasticity and neurite outgrowth, and health benefits derived from flavonoids, as the flavonol epigallocatechin gallate (EGCG), phytoestrogens of natural origin are partially explained by their interaction with membrane ER. Selective ER-β flavonoids are thus good candidates for their therapeutic evaluation in intellectual disabilities. EGCG also targets central intracellular transduction signals altered in FXS and improves memory recognition in a FXS animal model(adenosine triphosphate (ATP)-inhibitor of phosphatidylinositol 3-kinase (PI3K)and mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK1/2). This study targets the synaptic plasticity alterations that underlie the learning and memory impairment but also the computational disability in FXS. The hypothesis is that EGCG can act by favoring the physiological processes involved in cognition. 

The Spanish Science.

You might wonder why a hospital in Barcelona is doing all this research into a green tea extract.

EGCG has numerous biological effects and in the three trials they are not claiming the same mode of action.  In the fragile X trial it is the effect on Estrogen receptor beta, while in Down syndrome it is the effect on DYRK1A gene overexpression. 

Trial results

The only trial to have yet published results is the one on Down Syndrome.  Here the results were pretty good, given that this is a cheap supplement and the dose was modest.

The easy reading version:-

What were the basic results?


For most of the tests (21 of 24) there were no differences between the groups.

However, in three tests people who'd taken EGCG did better. This improvement lasted for six months after the study ended.

These were:

·         remembering and recognizing patterns

·         inhibitory control – the ability to override instinct to follow instructions; for example; in this test, to say "cat" when shown a picture of a dog, and vice versa

·         ability to carry out everyday living tasks (adaptive behaviour)   

I am very surprised that the benefit lasted six months after the study ended.  It would be great if they could validate that in their phase 3 trial. 

The full study:- 


We enrolled adults (aged 16–34 years) with Down's syndrome from outpatient settings in Catalonia, Spain, with any of the Down's syndrome genetic variations (trisomy 21, partial trisomy, mosaic, or translocation) in a double-blind, placebo-controlled, phase 2, single centre trial (TESDAD). Participants were randomly assigned at the IMIM-Hospital del Mar Medical Research Institute to receive EGCG (9 mg/kg per day) or placebo and cognitive training for 12 months. We followed up participants for 6 months after treatment discontinuation. We randomly assigned participants using random-number tables and balanced allocation by sex and intellectual quotient. Participants, families, and researchers assessing the participants were masked to treatment allocation. The primary endpoint was cognitive improvement assessed by neuropsychologists with a battery of cognitive tests for episodic memory, executive function, and functional measurements. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01699711.

Findings

The study was done between June 5, 2012, and June 6, 2014. 84 of 87 participants with Down's syndrome were included in the intention-to-treat analysis at 12 months (43 in the EGCG and cognitive training group and 41 in the placebo and cognitive training group). Differences between the groups were not significant on 13 of 15 tests in the TESDAD battery and eight of nine adaptive skills in the Adaptive Behavior Assessment System II (ABAS-II). At 12 months, participants treated with EGCG and cognitive training had significantly higher scores in visual recognition memory (Pattern Recognition Memory test immediate recall, adjusted mean difference: 6·23 percentage points [95% CI 0·31 to 12·14], p=0·039; d 0·4 [0·05 to 0·84]), inhibitory control (Cats and Dogs total score, adjusted mean difference: 0·48 [0·02 to 0·93], p=0·041; d 0·28 [0·19 to 0·74]; Cats and Dogs total response time, adjusted mean difference: −4·58 s [–8·54 to −0·62], p=0·024; d −0·27 [–0·72 to −0·20]), and adaptive behaviour (ABAS-II functional academics score, adjusted mean difference: 5·49 [2·13 to 8·86], p=0·002; d 0·39 [–0·06 to 0·84]). No differences were noted in adverse effects between the two treatment groups.

Interpretation

EGCG and cognitive training for 12 months was significantly more effective than placebo and cognitive training at improving visual recognition memory, inhibitory control, and adaptive behaviour. Phase 3 trials with a larger population of individuals with Down's syndrome will be needed to assess and confirm the long-term efficacy of EGCG and cognitive training.  



The science behind EGCG


An expanding body of preclinical evidence suggests EGCG, the major catechin found in green tea (Camellia sinensis), has the potential to impact a variety of human diseases. Apparently, EGCG functions as a powerful antioxidant, preventing oxidative damage in healthy cells, but also as an antiangiogenic and antitumor agent and as a modulator of tumor cell response to chemotherapy. Much of the cancer chemopreventive properties of green tea are mediated by EGCG that induces apoptosis and promotes cell growth arrest by altering the expression of cell cycle regulatory proteins, activating killer caspases, and suppressing oncogenic transcription factors and pluripotency maintain factors. In vitro studies have demonstrated that EGCG blocks carcinogenesis by affecting a wide array of signal transduction pathways including JAK/STAT, MAPK, PI3K/AKT, Wnt and Notch. EGCG stimulates telomere fragmentation through inhibiting telomerase activity. Various clinical studies have revealed that treatment by EGCG inhibits tumor incidence and multiplicity in different organ sites such as liver, stomach, skin, lung, mammary gland and colon. Recent work demonstrated that EGCG reduced DNMTs, proteases, and DHFR activities, which would affect transcription of TSGs and protein synthesis. EGCG has great potential in cancer prevention because of it’s safety, low cost and bioavailability. In this review, we discuss its cancer preventive properties and it’s mechanism of action at numerous points regulating cancer cell growth, survival, angiogenesis and metastasis. Therefore, non-toxic natural agent could be useful either alone or in combination with conventional therapeutics for the prevention of tumor progression and/or treatment of human malignancies.















Mast Cells and EGCG
One interesting effect of EGCG, at least in the lab, is that it can stabilize mast cells. This would mean that it might he helpful in treating allergy and some types of GI problems, if you have enough of it.

Epigallocatechin-3-gallate Reduces Mast Cells Activity TNF-α and NFKB in Colitis by Interrupting an Inflammatory Cascade (MUC2P.827)


Epigallocatechin-3-gallate inhibits mast cell degranulation, leukotriene C4 secretion, and calcium influx via mitochondrial calcium dysfunction.


Conclusion
The green tea extract EGCG is inexpensive and widely available. It is often taken for its antioxidant properties. In most trials so-called phytoestrogens like EGCG have almost no estrogen-like effect in humans, so I doubt this mode of action.
The trials all used a dosage of 9mg/kg of EGCG which is easy to achieve with OTC supplements.
Given the positive results from the small trial in Down Syndrome (DS), it would fall into the “no-brainer” category to make a home trial, if you have a child with DS.
This is quite different to injecting your child with Cerebrolysin from pig’s brains, where there are some drawbacks.
Will EGCG help in Fragile-X or Fetal Alcohol Syndrome? I have no idea; but being having well established antioxidant properties, I expect it is almost guaranteed to help a least marginally.
Will EGCG help in autism? Given its safety profile, price and availability, it really should have a place on your to-do list. It is an antioxidant with numerous other possible effects, some of which hopefully may be evident in humans.  Compared to some exotic antioxidants that people buy, it is cheap.
With no great expectations, I will see if EGCG has any effect. It might help an as antioxidant, it might help stabilize mast cells and, if has enough potency as an estrogen, it would help via RORa. As you can see in the chart above it actually has dozens of potential effects.
Some natural substances like quercetin have undoubted positive effects, but after continued usage can give side effects.  The EGCG trial was 12 months long and they did not find adverse effects compared to the placebo.
The amount of EGCG in green tea varies wildly, making standardized supplements a safer bet.  Apparently, Lipton Green Tea bags contain about 70mg of EGCG per serving. So my son would need to drink 6 cups of green tea a day to match the trial dose.




12 comments:

  1. Peter saves the day ! Timely post. Was just asking Agnieszka about this yesterday! My son used to drink green tea regularly - maybe not 6 cups a day, but several. For some reason, I stopped giving when I was just learning about mast cells involvement. I'm thinking I read it needed to be avoided? Or maybe it was cnfusion over th1/th2 balance. Anyway, yesterday read about it being histidine decarboxylase inhibitor - and with my son's negative reaction to supplementing hist., I thought I'd give it an earnest try again. He loves to drink tea with meals, so I'm sure we can easily get to 6 cups a day with meals and with a snack or two. Will share our results here.

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    1. Tanya, EGCG has been on my mind for some time. At the moment my concern is the potential for interaction as it seems like it can inhibit some drug metabolizing enzymes:

      "The ingestion of beverages containing large amounts of green tea catechins together with drugs that are metabolized by CYP1A2, CYP2C9, and CYP3A4 should be avoided".

      https://www.ncbi.nlm.nih.gov/pubmed/27518169

      Peter, if you plan to trial EGCG, how would you approach the interactions issue with regard to verapamil and atorvastatin?

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    2. Agnieszka, there already is a possible reaction between verapamil and atorvastatin. If you are taking atorvastatin and verapamil, the concentration of verapamil in your blood may increase. This means you would need a lower dose of verapamil.

      Some similar drugs, like simvastatin with amlodipine, have bigger interactions so Simvastatin 20 mg has the effect of Simvastatin 40mg. This is only a problem if it is unexpected.

      Some of the well known specific interactions with green tea are here:-

      http://www.umm.edu/health/medical/altmed/herb-interaction/possible-interactions-with-green-tea

      I think if you have low doses of drugs metabolized by by CYP1A2, CYP2C9, and CYP3A4 and do not use one already know to interact with green tea, you start in a good position.

      I do think there are interactions with low dose clonazepam and other therapies, but you then just adjust the dosage.

      The big risk would seem to be with people taking Monoamine Oxidase Inhibitors (MAOIs) or undergoing Chemotherapy.

      In the Japanese study they are talking about old people rather than children, who are much more likely to be on the therapies that do interact in a substantial way.

      There is a another paper here, which concludes that the interactions with the drugs they reviewed were minimal.

      https://www.researchgate.net/publication/266948634_Overview_of_Green_Tea_Interaction_with_Cardiovascular_Drugs

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  2. Here is an interesting paper on preventing low-grade inflammation related to obesity via the use of capsaicin (what makes chili powder hot)

    Press Release:

    https://www.sciencedaily.com/releases/2017/05/170523124155.htm

    Paper:

    http://mbio.asm.org/content/8/3/e00470-17

    Now gut dysbiosis and chronic inflammation both seem to be comorbid conditions with many who are diagnosed with autism, and obesity itself in the mother is one of the highest (if not the highest) correlated environmental factors with autism. Assuming a normal pregnancy, obese mothers will pass on their gut microbiota onto their children and if this gut microbiota is predisposed towards inflammation, there is a good chance the children of the obese mother will be predisposed towards inflammation with the same micobiota community.

    So perhaps capsaicin could be legitimate way of reducing intestinal related inflammation in those with autism. I had already posted some other recent research and comments on capsaicin:

    https://epiphanyasd.blogspot.com/2017/01/enhancing-effect-of-bumetanide-in-autism.html?showComment=1484272826963#c28704921474122691

    https://epiphanyasd.blogspot.com/2017/04/the-excitatoryinhibitory-imbalance.html?showComment=1493191963265#c7859277540268614326

    https://epiphanyasd.blogspot.com/2017/01/histidine-for-allergy-but-as-effective.html?showComment=1483948036479#c7567409562934250098

    There is also Peter's mention of capsaicin for upregulating apidonectin production (which is low in autism):

    https://epiphanyasd.blogspot.com/2017/03/leptin-signaling-and-jak-inhibitors-in.html

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    1. Tyler, also interesting is another paper on the same page as your press release. One reader just commented that prior to starting bumetanide the only benefit from broccoli powder was better GI health, the paper explains why:-

      Sulforaphane, a phytochemical in broccoli sprouts, ameliorates obesity
      https://www.sciencedaily.com/releases/2017/03/170307100402.htm

      "Sulforaphane, a phytochemical in broccoli sprouts, is known to exert effects of cancer prevention by detoxicating chemical compounds taken into the body and by enhancing anti-oxidation ability. In the present study, experiments with mice demonstrate that sulforaphane ameliorates obesity, the conclusion based on the two functions of sulforaphane newly uncovered; amelioration of obesity through enhancing energy consumption by browning of adipocytes, and reduction of metabolic endotoxemia through improving gut bacterial flora"

      So it looks like broccoli and capsaicin could benefit many people.

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    2. I think I remember reading a while back on a paper on nrf2 signaling with respect to GI inflammation but could not remember where to find it (I didn't bookmark it). Nevertheless, manipulating nrf2 signaling is one of the latest areas of longevity research as it seems to be pretty important as time goes on and stress signaling degrades in the human body. Us over 40 somethings would definitely benefit from it, and of course in diseases involving chronic cellular stress (such as some autisms), getting this important cellular stress response signaling going again potentially could help with some of the more severe symptoms in a manner similar to what NAC does for many people.

      Of course, all the enhanced stress response signaling in the world won't do much good if the stress repair machinery is broken for some reason, unless you can of course figure out a way to repair the stress response machinery or else figure a way around it.

      Nevertheless, there is good reason to believe that sulphoraphane and capsaicin both are low-hanging fruit that can be trialed safely in significant amounts to see if they improve symptoms considerably.

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  3. Good morning everyone,

    I would really appreciate input from the community on what you believe are the most helpful / informative tests that can be run on our ASD kids. I know there is OAT testing, but are there others? I want to have some testing done soon and would appreciate any input on what tests would be most helpful.

    Also, saw an article today that I think may be relevant to us:

    https://www.washingtonpost.com/national/health-science/when-scientists-saw-the-mouse-heads-glowing-they-knew-the-discovery-was-big/2017/05/19/f33cc574-246a-11e7-a1b3-faff0034e2de_story.html?utm_term=.d427a4ea3cb3

    Thanks in advance and have a great day everyone!

    AJ

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    1. AJ, that is a very hard question because the answer depends on who you are, what problems you are facing and so on. There are so many things to test.
      I would start by thinking on what illnesses and conditions near relatives are having. Diabetes, depression, allergies, short stature or hypothyroidism could probably point in different directions on what to test.
      There is genetic testing, tests for mitochondrial diseases, overnight EEG and (what you maybe are asking for) a lot of tests on biomarkers.
      Though I am not able to answer, I do think it would be a good idea to create a list on existing tests that could be relevant in autism.
      /Ling

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    2. Hi AJ, we did OAT, metabolic tests (to compare with Dr Kelley mitochondrial evaluation, see Peter post about regressive autism), EEG and MRI.

      OAT was through a naturopath, the results were mostly normal except B vitamins, but supplementing didn't work for us. So I'm not sure how useful it really is/could be.

      The others we did through his pediatritian after a "bit" of convincing.

      I did buy a 23andme kit (2 years waiting since our referal for geneticist and counting...) but we weren't able to succesfully collect a sample to send, so we collected from big sister to see if we could learn something useful. So far I'm finding it fun, but not very helpful.

      Cheers,

      Jane.

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    3. Hi AJ, maybe you would find protein electrophoresis useful, in case there is an underlying disease. Abnormal proteins may give you an indication of inflammation, infection, autoimmunity or other.

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    4. Good morning Jane, Ling, and Petra,

      Thank you all for your input! I have wanted to pursue genetic testing, and still do, but they often want blood drawn for the test, and we're not ready for that at this point. We are going to try to see a doctor that works with ASD patients, and I believe he may do OAT testing, and wanted to see if there was anything he may recommend, or we may recommend that he does.

      Really appreciate everyone's input!

      AJ

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  4. Considering one reader of this blog suggested an unorthodox intervention in improving their son's "social symptoms" with autism using alcohol, some new research concerning alcohol addiction seems very interesting:

    https://www.elsevier.com/about/press-releases/research-and-journals/resetting-balance-in-reward-centers-may-help-treat-alcohol-addiction

    What the researchers effectively found was that alcohol somehow upregulates glutamate signaling in the D1 direct pathway of the dorsal striatum (caudate/putamen) while also upregulate GABA signaling in the D2 indirect pathway of the dorsal striatum. In effect this means alcohol both promotes the D1 pathway and inhibits the D2 pathway at the same time, which helps promote addiction to alcohol. While dopamine itself activates both pathways, higher levels of dopamine in the brain tends to activate the D1 pathway stronger. This all may be confusing, but you can think of these individual cells as having many different types of levers on them that can be pushed forward or backward a little bit which eventually if pushed enough forward will lead to the neuron firing which is why these cells can be influenced by glutamate, GABA, dopamine, and several other neurotransmitters all at the same time. Different types of neurons respond differently to different types of neurotransmitters.

    So in the case of normalizing striatum neurotransmission, you could have a situation where if the D1 pathway is activated too strongly relative to the D2 pathway, it may not be because of the overall level of dopamine signaling, but it could be a combination of glutamate and GABA signaling in these respective pathways. This means proper normalization of signaling may involve addressing one or many different types of neurotransmitter input into the brain to get a desired therapeutic result.

    Unfortunately with this research it suggests that for many autisms it looks like alcohol may do the exact opposite of what we want here, and what we may want is a reverse-alcohol type molecule that both suppresses the D1 pathway while enhancing the D2 pathway via glutamatergic and GABA signaling, while also being selective for that area of the brain (if that is possible).

    It would also be interesting to peruse some of the adult autism support forums like wrongplanet.org and see if there are any anecdotal reports of alcohol consumption improving or worsening core autism symptoms, even though this research mentioned above suggests that alcohol in significant amounts would definitely worsen core autism symptoms in those with striatal dysfunction.

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