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
No comments:
Post a Comment