Research: Anyone for Green Tea. A Crucial Brew?

Herges K, Millward JM, Hentschel N, Infante-Duarte C, Aktas O, et al. (2011) Neuroprotective Effect of Combination Therapy of Glatiramer Acetate and Epigallocatechin-3-Gallate in Neuroinflammation. PLoS ONE 6(10): e25456. doi:10.1371/ journal.pone.0025456


Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system. However, studies of MS and the animal model, experimental autoimmune encephalomyelitis (EAE), indicate that neuronal pathology is the principle cause of clinical disability. Thus, there is need to develop new therapeutic strategies that not only address immunomodulation but also neuroprotection. Here we show that the combination therapy of Glatiramer acetate (GA), an immunomodulatory MS therapeutic, and the neuroprotectant epigallocatechin-3-gallate (EGCG), the main phenol in green tea, have synergistic protective effects in vitro and in the EAE model. EGCG and GA together led to increased protection from glutamate- and TRAIL-induced neuronal cell death in vitro. EGCG combined with GA induced regeneration of hippocampal axons in an outgrowth assay. The combined application of EGCG and GA did not result in unexpected adverse events in vivo. Neuroprotective and neuroregenerative effects could be translated in the in vivo model, where combination treatment with EGCG and GA significantly delayed disease onset, strongly reduced clinical severity, even after onset of symptoms and reduced inflammatory infiltrates. These results illustrate the promise of combining neuroprotective and anti-inflammatory treatments and strengthen the prospects of EGCG as an adjunct therapy for neuroinflammatory and neurodegenerative diseases.


This is exciting! So you have asked about this paper in one of the comments. So maybe it is time to look at what it shows. Well as it is in PLOSone you can all get the paper to read.
 
The paper proclaims synergistic effect. Compared to an "additive effect" that is 2 + 3 = 5, a "synergistic effect" is 2 + 3 = 7, i.e. together you get more than the sum of the individual parts. So let us quickly look at the figures.

First up (Figure 1) what happens when they see what happens to the killing of brain nerve (HT22) and Astrocyte (LN18) tumor cell lines induced by a molecule called TNF-related apoptosis-inducing ligand (TRAIL). Well GA appeared to do nothing in nerves and EGCG may have limited cell death in nerve and astrocyte cell lines. The two together was the best as stopping cell death...but was there any real biological difference between the effect of EGCG alone and EGCG and GA together. We don't know because they never reported that test, but does not look like it.
Figure 1.

Next (Figure 2) they looked to see if it makes a difference if it makes nerves grow in brain cultures and low and behold there were more nerves, with a higher density of nerve outgrowths and there was an increase in two growth factors namely glial derived neurotrophic (GDNF) and (BDNF) brain derived neurotrophic factor. Is this synergy where there is an effect of the two added together? or is this just the effect of GA alone? Is there any difference between GA and EGCG + GA. Not so sure there again.

Figure 2

So now lets us look at what happens in EAE (Figure 3-5). Treat with suboptimal GA and essentially nothing happens. Treat with epigallocatechin-3-gallate and there is an inhibition of the severity of disease (Figure 3) and now treat with both together and you get less disease again.

Is this synergy? Is the benefit really that different from EGCG and EGCG + GA?. Is the benefit more than additive?

The problem here is to compared to a mean score of 2.5 with control is top score of 2.0 with GA and 1 with EGCG and a score of 0.5 with EGCG + GA.
 
Is this synergistic?, it is impossible to say! Why? Because the scoring system is not linear. The amount of inflammation required to make a score change from 0-1 is not the same as that required to make a score change from 2-3. 
Figure 3
Now let us look at what is happening with our so called neuroprotective drug (Figure 3). It is actually immunosuppressive because it is stopping animals from developing disease such that at day 12, there are 75% of animals getting the combination that are disease free compared to the others. As the mean score of EAE in animals getting EGCG is one and they all got disease means that they only got a limp tail compared to animals getting neither who had limb paralysis (Figure 3). This again shows that the drug is immunosuppressive and we know that this should be associated with less infiltrate of white blood cells into the CNS, because this is what the clinical course should be telling us.
 
So let us see what happened (Figure 5)

Figure 5.

Well just as expected in the control and GA there is more black (infiltration (black stain) of the spinal cord in the pale rim= white matter) than in the EGCG and the EGCG + GA groups which look more or less the same. So this is what the neurological score in figure 3 Told us should occur. This stain tells us about infiltration and tells us nothing about nerve content. Yet the title of the paper says "Neuroprotection" but where is it?
 
Now let us give the combination after onset (Figure 4) and see what happens
Figure 4
There are difference between the two groups for 5 days out of 34 (10-44). But is this correct?. If animals were randomised (arbitrary selected to drug or placebo) to have a score of 2 or more before treatment why does the treatment group never reach a score of two and why do the two groups not look identical to start with until drug is administered? It looks like there is a difference but again is it due to the combination. Used in this way GA, in my opinion may not be doing much so is it all EGCG. We will never know because the experiment is not reported.

As you may know EGCG is an anti-oxidant found in tea. According to Wiki a 200-ml cup of tea has a the mean total content of 267mg flavinoids in green tea, and 233mg for black tea (1g tea leaves per 100ml hot water). The mean averages are much lower for instant tea mixes, decaffeinated, flavored, or ready-to-drink tea products.

So about 1mg/ml drunk by a 70kg person, so about 3mg/kg assuming all of the flavinoids are EGCG. In this paper they were giving 300 microgram per mouse so this is about 15mg/kg twice a day, so 10 cups a day but more likely to be 30-40 as not all the flavinoids in the tea will be EGCG. Maybe running to the toilet to get rid of all the fluid from drinking so much tea may affect your MS.
 
This study shows that EGCG at the doses tested is immunosuppressive but hey we knew all this already because the same group published this type of data back in 2004. So why bother with GA? In the study they use it so it does abit, so two immunosuppressives can be better than one, but when used in the optimum configuration GA can do just as good as EGCG or EGCG + GA. It is a no-brainer to show that immunosuppressive drugs are neuroprotective in EAE......this study tells us little about true neuroprotection.

I think it is also a no-brainer that we should aim to combine neuroprotection with immunosuppression...however this is not what this paper actually shows it shows immunosuppression. However, we need an evidence base before we start adding on drug to others, as doing this is not always beneficial.
 
 Can Green Tea be beneficial? As every we do not know about this nutricieutical

Advice as always. Get your medicines from Neuros not the Tea shop.


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