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:

The effect of cerebrolysin on cognitive functions in childhood autism and in Asperger syndrome

An effect of long-term cerebrolysin therapyin combination with neuroleptics on behavioral and cognitive disturbances in endogenous childhood autism

 

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. 

Egcg, a dyrk1a Inhibitor as Therapeutic Tool for Reversing Cognitive Deficits in Down Syndrome Individuals.

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. 

Epigallocatechin Gallate (EGCG) to Improve Cognitive Performance in Foetal Alcohol Syndrome (FAS) Children (Neuro-SAF)

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  

Using Epigallocatechin Gallate (EGCG) and Cognitive Training to Modulate Cognitive Performance in Patients With Fragile X Syndrome" (TESFX)

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:-

Green tea extract 'boosts mental ability' in people with Down's 

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:- 

Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial 

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.  

Epigallocatechin gallate: A useful therapy for cognitive disability in Down syndrome?

The science behind EGCG

Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications 

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.