Neuroprotective properties of green tea 101: implications to Alzheimer's disease

The use of alternative medicine for the treatment of several human chronic diseases has gained popularity over the past few decades. An ever increasing amount of scientific evidence has described the medical benefits of many Asian herbs. As reviewed in previous articles, ingesting curcumin, the main component of curry, or ingesting high amounts of phenethyl isothiocyanate , a compound found in cruciferous vegetables, confer anti-cancer, anti-inflammatory, anti-retroviral and neuroprotective properties. Moreover, green tea (Camellia sinensis), a herb whose consumption was initiated five thousand years ago in China, has important biological and pharmacological properties. In support of this notion, there is a plethora of scientific evidence showing beneficial pharmacological effects of this wonderful elixir. In a similar manner to curcumin, ingesting green tea confers anti-inflammatory, anti-oxidant, thermogenic (pro-metabolic) and neuroprotective properties. When combined with exercise, many consumers of green tea extracts are jumping on the band-wagon to reap the thermogenic effects of this herb as a weight-loss strategy.

The beneficial effects of green tea has been ascribed to the presence of three groups of compounds: phenolic acids, flavonoids, and non-flavonoid polyphenols. In addition to green tea, natural phenolic compounds are also found in berries, fruits and spices. Polyphenolic compounds are biochemically characterized by the presence of aromatic rings that possess anti-oxidant activity by scavenging free radicals, highly reactive molecules containing uncoupled electrons which cause oxidation of other important biological macromolecules with harmful consequences to cells. Moreover, catechins, a family of flavan-3-ols, have been shown to also scavenge free radicals, iron and other damaging transition metals in vitro. Since the deposition of ferric iron (Fe+3) in neurons has been shown to progressively accumulate in neurons of Alzheimer’s disease (AD) and Parkinson’s disease (PD) patients with time, an accumulation of transition metals may contribute to neuronal degeneration by generating free radicals through Fenton's reactions. Phenolic compounds found in green tea possess both powerful anti-oxidant and free iron scavenging activities. Of all the catechins found in green tea (epicatechin (EC), epigallocatechin (EGC), depicatechin-3-gallate, and epigallocatechin- 3-gallate (EGCG)), EGCG is the main active ingredient of green tea and its beneficial properties have been previously described (Mandel et al., 2006). EGCG has important neuroprotective properties. For instance, a few studies have shown that EGCG reverses pathology associated with age-related neurodegenerative disorders such as Alzheimer’s disease.

Alzheimer’s disease (AD) is a relentless, chronic and incurable neurodegenerative disease characterized by the progressive loss of neurons of the hippocampus and the cortex, leading to impairment of memory and a progressive cognitive decline. The pathological hallmarks of AD is characterized by the presence of insoluble (water repelling/resistant) protein aggregates localized in neurites (axons or dendrites) and in cell bodies of neurons termed neurofibrillary tangles, protein aggregates mainly composed of hyper-phosphorylated tau, and of senile plaques, protein aggregates mainly composed of beta-amyloid. In tissue culture experiments, the accumulation of beta-amyloid induces cell death of primary hippocampal neurons and neuronal cell lines (neuroblastoma SH-SY5Y cells). Amyloid precursor protein (APP), the precursor protein of beta-amyloid, can be cleaved by processing enzymes termed alpha, beta or gamma secretase to generate either soluble (mediated by alpha secretase) or the insoluble, harmful form of APP (mediated by beta and gamma secretase). Thus the insoluble form of beta-amyloid is believed to contribute to neurodegeneration in AD patients. Amazingly, EGCG has direct plaque-busting activity by binding to beta-amyloid and preventing its formation of insoluble toxic fibrils in vitro. Furthermore, very small amounts (micromolar) of EGCG is sufficient to protect neuronal cell lines from beta-amyloid mediated cell death. More importantly, a recent landmark paper highlighted the neuroprotective effects of green tea in vivo. The authors of this study showed that AD mice that ingest EGCG (50mg/Kg) decreases the burden of both beta-amyloid and tangles (tau) in the cortex, entorhinal cortex and in the hippocampus, the region in the brain involved in storing memory (Rezai-Zadeh et al., 2008). Amazingly, the amount of soluble beta-amyloid increased while the amount of insoluble form of beta-amyloid was decreased in brains of AD mice, suggesting that EGCG has direct anti-protein aggregating activity possibly by directly binding to protein aggregates. Moreover, ingesting high amounts of EGCG reversed the AD associated cognitive decline and memory loss in 14 month old AD mice which were pretreated with EGCG for two months (Rezai-Zadeh et al., 2008) The results of these behavioral tests strongly suggest that EGCG intake may be a promising AD therapy that may halt or at least partly reverse AD associated cognitive decline in individuals with a modest to severe disease progression.

What are the mechanisms by which EGCG confers neuroprotection in models of AD?

1) As stated above, there is some scientific evidence that shows that EGCG directly binds to protein aggregates and prevents monomeric beta-amyloid from aggregating and forming plaques. Not only does it prevents beta-amyloid from aggregating into toxic fibrils in vitro, but it also binds to alpha-synuclein, protein aggregates seen in brains of Parkinson's disease patients.

2) Ingesting EGCG may increase the expression levels and APP processing activity of alpha-secretase enzymes, enzymes that favor the formation of the soluble (good) form of beta-amyloid while reducing the formation of the bad, insoluble form of beta-amyloid. Although the evidence is correlative at best, the study performed by Rezhai-Zadeh et al.. showed that ingestion of EGCG in AD mice decreases the levels of beta-amyloid protein aggregates by possibly increasing the expression levels of adamalysin-10, an alpha-secretase candidate enzyme that cleaves full-length APP into its soluble, non-harmful form (Rezai-Zadeh K et al., 2008). Furthermore, the expression levels of TACE, another alpha secretase that cleaves APP into a soluble form, is also increased with EGCG treatment (Mandel et al., 2006).

3) EGCG, in addition to the other catechins and flavonoid compounds, possess anti-oxidant activity by scavenging free radicals. Since the increased generation of free radicals favors neurodegeneration in AD and in other neurodegenerative diseases such as PD and Huntington's disease, ingesting high amounts of green tea or EGCG may help to delay neurodegeneration in these diseases by scavenging free radicals.

4) EGCG treatment increases prosurvival signaling in neurons while opposing apoptotic signal transduction pathways. For instance, EGCG treatment in neurons has been shown to increase prosurvival mitogen- activated protein (MAP) kinase signaling while opposing the p38/MAPK and JNK pathways, cell signal transduction pathways associated with cell stress and apoptosis.

Overall, the research described in this article shows the beneficial and neuroprotective effects of green tea in mouse models of AD which paves the way for creating novel therapeutic alternatives for reversing AD pathology in patients. It is likely that clinical trials may be underway to test the beneficial effects of EGCG and other catechins in the treatment of AD. It is possible that EGCG may pass phase I clinical trials given that green tea consumption is safe and is widely popular. Like other polyphenolic compounds and catechins, EGCG is unstable in room temperature, in neutral pH and has to be mixed with metal chelators (to avoid contamination with other metals) and ascorbic acid to prevent its oxidation. Moreover, EGCG consumption achieves a low bioavailability upon ingestion. Thus a more stable form of this compound may have to be synthesized for therapeutic use. However, a strong advantage of using EGCG over other antioxidants is that this particular compound easily penetrates the blood brain barrier and can be purified in large amounts from green tea leaves. It is likely that ingesting curcumin, EGCG , caffeine and other anti-oxidants may form a very powerful combination therapy and may be part of a growing arsenal used to combat AD.

(This is a two part series of articles describing the neuroprotective effects of natural compounds on AD).

Bibliography

1. Mandel S, Amit T, Reznichenko L, Weinreb O, Youdim MB.. Links Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the treatment of neurodegenerative disorders. (2006) Mol Nutr Food Res.;50(2):229-34

2. Rezai-Zadeh K, Arendash GW, Hou H, Fernandez F, Jensen M, Runfeldt M, Shytle RD, Tan J
Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice. (2008) Brain Res. 1214:177-87.

For more information click on the following links:

Effects of green tea on Alzheimer's disease mice.

Free scientific article showing the beneficial effects of green tea in modulating APP processing.

Review describing beneficial effects of green tea consumption with implications to AD and PD.

Article and abstract describing the metal scavenging properties of green tea flavonoid EGCG

Other articles from other Examiners describing neuroprotective effects of natural compounds::

More on beneficial effects of:

curcumin

Of flies and worms: is the science behind the benefits of resveratrol in peril? - Pittsburgh Medical Technology | Examiner.com

A research study published a week ago in Nature will shake the credibility of the research that supports the notion that sirtuin-2 is an anti-aging gene and also challenge the view that resveratrol extends the lifespan. Today's study published in Nature was spearheaded by Dr. David Gems from the Institute of Heatly Ageing and Department of Genetics, Evolution and Environment, University College London. Contrary to popular belief, his group proved that sirtuin-2 gene does not expand the lifespan in both worms and flies. This is a very bold claim that goes against a huge wave of scientific research that consistently showed that modulating the levels of sirtuin-2 can reverse the aging process in different animal models.

In 2003, a study also published in Nature showed that increasing the number of copies (1- 3) of sirtuin-2 robustly and significantly increased the lifespan of worms. The story caught the attention of the news media and it revolutionized the field of aging research. Hence, many other research groups started looking at different natural compounds that regulated the activity of sirtuin-2 and suddenly reseveratrol, a component of red wind, was discovered to increase sirtuin activity and extend lifespan. Resveratrol was regarded as the new "fountain of youth" ever since and many natural supplement companies and investors capitalized to spend millions to develop and sell a product that is currently available at the market.

However, Dr. Gem's group claimed the initial observation that sirtuin-2 extends the lifespan in C. elegans (worm model) was flawed since the worm containing the extra copies of sirtuin-2 was compared to a parental wild-type worm that does not have the same genetic background. In other words, the worms containing the sirtuin 2 gene were not backcrossed five generations in order to obtain wild-type worms of the same genetic background. Hence, the right comparisons were never made. The authors of the study also showed that flies that overexpressed sirtuin-2, used in a previously published study, also lived longer compared to the parental wild-type fly strain but did not live longer compared to a fly strain of the same genetic background. These results were independently and blindly repeated by a different research group.

So what caused the worms to live longer in the first study? Interestingly, Dr. Gem's group found that another gene, called "neuronal dye filling defect", but not Sirt-2 was actually the gene responsible for extending lifespan in worms in the 2003 Nature study (go figure). Adding more insult to injury, Dr. Gem's group showed biochemically that resveratrol does not activate sirtuin-2. Interestingly, Dr. Gem's group did not refute the observation that simply increasing the number of sirtuin 2 genes to three copies in worms did efficiently extended the lifespan of worms just expressing one copy of the gene. This observation seems to hold water at least in my view.

Is the science behind sirtuin-2 in peril?

Yes and no. Aging is a very complicated biological process that cannot be explained by a single gene in either worms or flies, let alone in humans. Although today's Nature study damages the view that sirtuin-2 alone can extend lifespan, many other studies in mice and worms have shown that sirtuin-2 can extend the lifespan when interacting with other genes (Daf) and other studies have shown that sirtuin can efficiently regulate insulin growth factor metabolism. Sirtuin-2 may not be a drug target. Moreover, many other studies have shown that resveratrol can be a neuroprotective aging in models of Alzheimer's disease and has been extremely well characterized as an antioxidant. In other words, people will still buy resveratrol based on this other research showing the medical benefits of resveratrol.

Take home message

It is interesting to know that the paper that refutes the work of others which was originally published in Nature gets to be published in the same journal which it is in itself a stunning revelation. So what happened here? It is on the scientist's responsibility to design good hypothesis driven experiments which can lead to publishing false results. However, the reviewers in this case bear the most responsibility for not demanding the appropriate experimental controls from the authors. Ironically, this new study may have revealed another anti-aging gene to pursue: the "dye filling defect"

The controversy will sure go on for many more years...

Although this Examiner article thoroughly reviewed many C. elegans and Drosophila anti-aging studies and makes a scientific argument for both sides of the debate, you can read a sample article published in the media today that somewhat exaggerates the impact of this Nature study.

References:

1.Burnett et al., 2011 Absence of the effects of increasing the expression of Sirt-2 on lifespan of C. elegans and Drosophila. Nature.

2. Tissenbaum, H. A. & Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230 (2001).

3. Viswanathan, M., Kim, S. K., Berdichevsky, A. & Guarente, L. A role for SIR-2.1 regulation ofERstress response genes in determining C. elegans life span.Dev. Cell 9, 605–615 (2005

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Pain management applications for the iPhone and Android - Pittsburgh Medical Technology | Examiner.com

Although there is a great emphasis in disease prevention and treatment, very little emphasis has been given to pain management and control in the hospital or outside the hospital. Currently, there are over 5820 medical related applications available for free or a small fee for the iPhone and Android phones. Approximately about 111 smartphone applications help to record and manage pain.


What are applications?

Applications are downloadable, highly visual and easy to use programs coded in different languages based on the smartphone's running operating system (OS, UNIX or Windows based). Most applications these days connect to the web and collect information live (GPS, read barcodes, etc..) and are usually available free of charge or for a very small fee (<$15.00 USD).
It is worrisome that there is currently no FDA approval or expert oversight required for the generation and selling of medical related smartphone applications. In addition, only a small fraction of those applications are created by a medical doctor, nurse or healthcare professional which underscores the need to involve the healthcare industry in creating more and robust valuable medical related applications to improve the quality of life.
A study published recently in the Journal of Telemedicine and Telecare carried out a thorough and robust study analyzing the validity, usefulness, and practicality of all pain management applications across all smartphone platforms. Not surprisingly, the authors of the study found that the majority of pain management applications were available for the iPhone (79%), the Android (16%) or Blackberry (5%) while no applications have been created for the Nokia/Symbian or Windows Mobile.
The applications focused on a range of pain categories (acute, chronic, sharp, localized, diffused, low, moderate, high, neuropathic, phantom pain, etc...) and specific health conditions with some overlap and the authors found that approximately 79% of applications were classified as primarily designed to be pain-relevant.
Types of applications
Application sizes ranged from a few kilobytes to a hundreds of megabytes and cost ranged from free to about $10.00 USD. About 24% of all applications have some type of journal component in order to record the localization, type and intensity of pain on a daily basis and how the pain affected daily chores and the quality of life. A few of the applications also emphasized the emotional aspect of pain which usually contributes significantly to pain intensity. In addition to using a pain scale (1 through 10 for most intense), these applications provide emoticons that can be used to describe the emotional component of pain. Over half of the applications included medical and technical related information about pain (symptoms, underlying causes, treatment) and includes a variety of pain reducing or quelling techniques such as massage therapy, and topical treatments. Information about acupuncture and headache prevention were included in a few applications. Only 17% of all applications contain hypnosis and relaxation related techniques as additional tools to help alleviate and quell different types of pain.
These are the most popular pain related applications:
1. Habit changer- It costs $2.00 and maybe a quick and simple e-book for pain management. Habit Changer is a 42 Day Challenge system that helps you kick old habits and experience a new way of living by accessing and heeding a full range of medical related advice. There are no videos and is mostly a text-based application.
2.Pocket Therapy- Costs $4.00. Own a pain management medical encyclopedia with all sorts of factoids! The Pocket Therapy app provides a list of painful injuries. Information on cause, location and symptoms associated with each injury is provided, along with exercises to improve range of motion and strength.
3. Chronic Pain Tracker- The best application with great reviews so far! It is free for the raw/bare version of the application and other modules can be added for a fee. Statistics is the key for making fundamental medical related decisions and the application allows the user to usually highlight the area of the body that is affected by pain on an hourly to daily basis. The application will graph intensity and duration of pain and generate all sorts of quantifiable data that can be analyzed by healthcare professional. It also contains a medication diary that keeps track of the doses and types of medication taken by the patient on a daily basis.
4. My Pain Diary- For a very small price, you can track and record the pain intensity, location, type, trigger, remedy taken and free-text notes. it is a very simple application. Pain intensity is rated on a scale from 0–10 and the data can be relayed to a healthcare professional for further analysis.
5. iPosture- This application tracks the posture and stance of each patient using the iPosture tracking sensor (this device is not free for $70.00 USD). The more the patient crouches or arches the body is related to increased propensity for developing abdominal or back pain. The sensor will alert you through your application of maintaining a correct posture and monitors your balance on a daily basis.