Epigallocatechin Gallate (EGCG) and Cognitive Function
WHAT IS EGCG?
Epigallocatechin gallate (EGCG) is a phytochemical found in green tea. Green tea, a popular beverage produced from the leaves of the Cammelia sinesis plant, is made up of several chemical compounds called polyphenols. Polyphenols are naturally occur-ring compounds found in most plant-derived foods with tea, red wine, fruits, and vegetables among the richest dietary sources (Kondratyuk and Pezzuto, 2004). Polyphenols can be divided into three classes: tannins, lignins, and flavonoids. The polyphenols in tea are classified as flavonoids. Flavonoids are distinguished by their chemical structure under the categories: anthocyanidins, carotenes, catechins, flavones, flavonols, flavanones, glucosinolates, isoflavones, lavones, and organosulfides.
The major flavonoids in tea are catechins (Kaur et al., 2008). In green tea the catechins account for 30%–40% of the contents in a normal tea bag (Pan et al., 2003). Catechins are present in higher quantities in green tea than in black or oolong tea (Neilson et al., 2006). This is because during processing green tea is exposed to the least amount of oxidation. The catechins in green tea include epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCG). EGCG is the most abundant catechin found in green tea and accounts for 65% of the total catechin content (González de Mejía, 2003; Zaveri, 2006). A normal cup of green tea contains approximately 200 mg of EGCG (McKay and Blumberg, 2007; Pietta et al., 1998). There is evidence to suggest the catechins in green tea can be used for preventing and treating cancer, cardiovascular diseases, inflammatory diseases, and neurodegenerative diseases (Zaveri, 2006).
Most of the beneficial effects of green tea are attributed to EGCG (Lee et al., 2004). Extracts of green tea, made almost exclusively of EGCG (e.g., Teavigo®), are currently marketed and sold for weight management and improving oral and cardiovascular health. The consumption of EGCG has also been associated with various neurological benefits such as reducing symptoms of Parkinson’s disease and Alzheimer’s disease (Weinreb et al., 2004) and in improving cognitive function in general (Xie et al., 2008). The beneficial effects of EGCG are often attributed to its potent antioxidant properties (Zaveri, 2006), although recent studies have discovered potential neuroprotective properties of the catechin (Mandel et al., 2005).
Currently there are no clinical trials investigating the relationship between EGCG and cognitive function in humans. The premise that EGCG may improve cognitive function is generated from the results of animal studies, and research on antioxidants, flavonoids, and green tea. The following sections of this postoutline previous research investigating the relationship between antioxidants, flavonoids, green tea, EGCG, and cognitive function. The biological mechanisms by which EGCG may improve cognitive function and suggestions for future research in the area are also discussed.
ANTIOXIDANTS, FLAVONOIDS, AND COGNITIVE FUNCTION
Several studies have examined the general relationship between antioxidants or flavonoids and cognitive function. Flavonoids are rapidly absorbed by the human body and have been reported to have positive effects on numerous aspects of health, including a reduced risk of coronary heart disease (Hertog and Feskens, 1993), cancer (Luisa Castellani et al., 2007), and neurodegenerative diseases (Rao and Balachandran, 2002). The beneficial effects of flavonoids are often attributed to the antioxidants they provide (Mandel et al., 2005; Zaveri, 2006). Tea consumption has been reported to increase the prevalence of antioxidants in the body (van het Hof et al. 1998; Salah et al., 1995). This is supported by findings demonstrating that tea catechins, particularly EGCG, are more powerful antioxidants than vitamins C and E (Kimura et al., 2002; Kuriyama et al., 2006).
ANTIOXIDANTS AND COGNITIVE FUNCTION
Epidemiological and longitudinal studies investigating the relationship between antioxidants and cognitive function have been conducted. One study found the use of supplemental antioxidants (vitamins C and E) prevented cognitive decline (Gray et al., 2003). Cognitive function was assessed using the short portable mental status questionnaire (SPMSQ), a brief 10-item cognitive screen. Those who consumed antioxidants regularly were reported to have a 29%–34% lower risk of developing cognitive deficits. Similar results were obtained in a larger study, where the regular consumption of supplemental antioxidants (vitamins A, C, and E) was associated with significant improvements in cognitive function (Grodstein et al., 2003). A telephone version of the mini-mental state examination (MMSE) was used as the main measure to assess cognitive function. The MMSE includes questions pertaining to attention and short-term memory (Kuriyama et al., 2006). However, it is important to note the SPMSQ and MMSE have been criticized for being crude and nonspecific measures of cognitive function (Poole and Higgo, 2006). They were designed as screening instruments for dementia (Cress, 2006), rather than for comprehensive evaluations of cognitive function. Measures of criterion validity have also revealed that the MMSE is not sensitive to mild cognitive impairments or differences in individuals with normal cognitive function (Ng et al., 2009; Wind et al., 1997).
Several studies have found that the dietary intake of antioxidants is associated with a lower risk of Alzheimer’s disease (Corrada et al., 2005; Engelhart et al., 2002; Morris et al., 2002). Due to the cognitive nature of Alzheimer’s disease, the results of these studies could have important implications for cognitive function. However, some studies have found no association between Alzheimer’s disease and antioxidant intake (Laurin et al., 2004; Luchsinger et al., 2003).
Although several studies indicate a relationship between antioxidant consumption and cognitive function, other studies do not. One longitudinal study, using data from a battery of 15 neuropsychological tests measuring cognitive performance, examined whether the use of antioxidant supplements was associated with cognitive function (Mendelsohn et al., 1998). Those who consumed antioxidants performed better than those who did not; however, the results were not significant after participant demographics were controlled. A similar study found no significant association between antioxidant vitamin consumption and cognitive function (Peacock et al., 2000). Cognitive function was assessed using the delayed word recall test, the Wechsler Adult Intelligence Scale-Revised digit symbol subtest, and the controlled oral word association test of the multilingual aphasia examination.
Inconsistent results in the literature may be due to differences in the population samples, such as differences in the distribution of age or socioeconomic status, being studied. Furthermore, unlike several of the studies indicating a positive relationship, Laurin et al. (2004), Lushinger et al. (2003), Mendelsohn et al. (1998), and Peacock et al. (2000) used less comprehensive dietary assessment methods. Therefore, they may have investigated samples consuming smaller doses of antioxidants for shorter periods of time, accounting for nonsignificant results. In addition, a variety of methods of measuring cognitive function have been used throughout the studies, making it difficult to compare findings.
FLAVONOIDS AND COGNITIVE FUNCTION
Epidemiological and longitudinal studies have also been conducted investigating the relationship between flavonoids and cognitive function. A recent study examined flavonoid intake in relation to cognitive function over 10 years (Letenneur et al., 2007). The MMSE, Benton’s visual retention test and Isaacs set test were used to assess cognitive function. After adjustments for participant demographics, flavonoid intake was significantly associated with better cognitive function over time. Positive effects on cognitive function in healthy volunteers as well as those with cognitive deficits (Mohsen et al., 2002) have been found using treat-ment with Gingko biloba extract, known to contain flavonoids (Cotman et al., 2002; Mandel et al., 2004b). Burns and Nettelbeck (2003) conducted a 12 week, placebo-controlled study assessing the effects of G. biloba on cognitive abilities. Long-term memory assessed by associational learning tasks and tested in immediate and delayed-recall forms showed significant improvement in those consuming the G. biloba. A similar 30 day, randomized, double-blind, placebo-controlled clinical trial found significant improvements in speed of information processing working memory and executive processing in participants consuming G. biloba (Stough et al., 2001). According to the authors these improvements are likely to be due to the antioxidant and flavonoid characteristics of the extract (Burns and Nettelbeck, 2003; Stough et al., 2001).
METHODOLOGICAL LIMITATIONS OF EPIDEMIOLOGICAL STUDIES INVESTIGATING ANTIOXIDANT AND FLAVONOID CONSUMPTION
Most of the studies investigating the relationship between antioxidant/flavonoid consumption and cognitive function are epidemiological. Unfortunately, epidemiological studies have several methodological limitations. Finding the time and equipment needed for assessing the cognitive function of large groups of people is difficult. Therefore, most studies use short cognitive questionnaires (e.g., MMSE), or small subsets of tests within much larger test batteries, rather than comprehensive cognitive assessments. Furthermore, in most cases no rationale was provided to validate the combination of tests used. Studies using more accurate and specific methods of assessment would provide a clearer understanding of the relationship between cognitive function and antioxidant consumption.
Epidemiological studies also have no control over participants’ antioxidant/ flavonoid consumption. There are various factors that could influence the effects of supplement consumption. These include “the length of time taking the supple-ment, the constancy, amount, purity and type of preparation, and the composition of the mixture” (Martin and Mayer, 2003, p. 71). This makes it difficult to examine the effects of individual antioxidants on cognitive function (Gray et al., 2003), given the wide variety of antioxidant preparations publicly consumed in supplements and in everyday diet.
Another limitation of epidemiological study designs is that they do not allow researchers to fully exclude the possibility of confounding by unmeasured factors (Kuriyama et al., 2006). For example, supplement intake may indicate a healthier diet or different social and lifestyle factors in those consuming supplements, which independently affect cognitive function. Furthermore, epidemiological designs do not enable researchers to make causal associations between antioxidant/flavonoid consumption and cognitive function. Even if it is possible to successfully adjust the findings for covariates, it is impossible to ensure there is not any hidden unmeasured covariates that could affect the results (Little and Rubin, 2000).
Several animal studies have investigated the relationship between antioxidants/ flavonoids and cognitive function. Milgram et al. (2004) investigated the long-term effects of antioxidant supplementation on cognitive function, specifically learning, in a longitudinal study of aged dogs. Dogs administered the antioxidant supplement for 1 year presented with significantly improved learning ability on a size discrimination learning task and on a size discrimination reversal learning task. In a similar study, the consumption of an antioxidant-enriched supplement for 6 months resulted in a significant improvement in the ability of aged dogs to perform difficult learn-ing tasks (Cotman et al., 2002). The dogs’ cognitive ability improved most on tasks involving oddity discrimination. The authors attributed these results to the cognitive enhancing effects of the flavonoids in the supplements. This is supported by studies on flavonoids. Joseph et al. (1999) found that aged rats fed flavonoid-rich supplemented food (including blueberry, spinach, and strawberry) for 8 weeks significantly improved in spatial learning and memory as assessed by the working memory ver-sion of the Morris water maze.
GREEN TEA AND COGNITIVE FUNCTION
Only four studies have investigated the relationship between tea and cognitive function in humans. The first study analyzed data collected from the Tsurugaya Project, an extensive health assessment of elderly Japanese people (Kuriyama et al., 2006). They found a higher consumption of green tea was associated with a lower prevalence of cognitive impairment. There was no association between the consumption of black tea, oolong tea, or coffee and cognitive function. The lower prevalence of cognitive impairment was attributed to the unique effects of EGCG. The second study analyzed the association between tea consumption and cognitive function using a cross-sectional and longitudinal methodological design (Ng et al., 2008). Participants were a cohort of Chinese older adults from the Singapore longitudinal aging study (SLAS). Statistical analysis supported an association between green tea consumption and lowered cognitive impairment. However, this association cannot be separated from the influence of black or oolong tea, given only 10 participants in the study consumed green tea exclusively (Ng et al., 2008). Another limitation is both Kuriyama et al. and Ng et al. used the MMSE as their primary measure of cognitive function. As mentioned earlier, the MMSE was designed as a screening instrument for dementia (Cress, 2006), consequently it does not comprehensively evaluate cognitive function.
There are two more studies that have investigated the relationship between tea and cognitive function in humans. Both of the studies assessed cognitive function using comprehensive batteries of tests. Nurk and associates (2009) found a positive association between flavonoid-enriched foods (including wine, tea, and chocolate) and improved cognitive test performance. Participants who consumed tea performed
significantly better on tests assessing attention, perceptual speed, visuospatial skills, and global cognition than those who did not. Several mechanisms by which flavonoid consumption might protect against cognitive impairment were proposed with major emphasis on the antioxidant actions of flavonoids (Nurk et al., 2009). However, the type of tea consumed was not recorded; therefore, it is impossible to determine the unique influence of green tea in comparison to black or oolong tea. The fourth study, a continuation of the study conducted by Ng et al. (2008), analyzed the relation-ship between tea consumption and cognitive function in a subsample of participants from the SLAS cohort (Feng et al., 2010). Tea consumption was associated with improved memory, executive function, and information processing speed. Coffee consumption and cognitive function were not related, indicating the cognitive effects observed were due to a component specific to tea consumption. Both black/oolong tea consumption and green tea consumption were associated with better cognitive performance. However, of the 716 participants only four participants consumed green tea exclusively, making it difficult to examine the unique effects of green tea.
The studies conducted by Kuriyama et al. (2006), Ng et al. (2008), Nurk et al. (2009), and Feng et al. (2010) are methodologically limited due to the limitations of epidemiological designs. As mentioned earlier, epidemiological studies do not allow researchers to fully exclude the possibility of confounding by unmeasured factors. Tea intake may indicate a healthier diet or more favorable social and lifestyle factors in those consuming tea, which independently improve cognitive function. There is also large intersubject and intrasubject variability in the consumption of tea polyphenols (Chow et al., 2001). As only epidemiological studies have been conducted on this topic, it is impossible to determine a causal relationship between tea consump-tion and cognitive function.
EGCG AND COGNITIVE FUNCTION
Several animal studies have examined the relationship between EGCG and cognitive function. A recent study found EC consumption improves spatial memory in mice (Praag et al., 2007). The mice were trained in a water maze for 2 weeks with four trials per day for 8 days. Learning was faster and retention longer in EC-treated mice. Praag et al. attributed the memory-enhancing benefits of EC to its ability to increase cortical blood flow. The relationship between catechin consumption and cognitive function has also been investigated in rats. Haque et al. (2006) investigated the effect of long-term oral administration of green tea catechins (60% EGCG) on the spatial learning ability of young rats. Rats administered green tea catechins presented with improved memory-related learning ability as measured by completion of the eight-arm radial maze. The authors attributed this improvement to the antioxidative activity of green tea catechins (Haque et al., 2006). Similarly, another study investigated the effects of green tea extract administration (30% EGCG) on cognitive function, as measured by passive avoidance and an elevated maze task, in young and old rats (Kaur et al., 2008). The extract significantly improved learning and memory in older rats.
EGCG has also been implicated in preventing cognitive decline in cognitively impaired animals. Unno and associates (2006) found the usual decline of memory
in senescence-accelerated (SAMP10) mice was significantly slowed when the mice consumed green tea catechins (31.7% EGCG) on a daily basis for 1 year. Memory was assessed using the passive avoidance task. SAMP10 mice are a model of brain senescence with cerebral atrophy and cognitive dysfunction. The administration of green tea polyphenols (60% EGCG) has also been found to reduce cognitive impairments induced by psychological stress in rats (Chen et al., 2009). The animal model of psychological stress was developed by restraint where the rats’ movement was limited periodically for 3 weeks. The rats’ cognitive function, as measured by performance in an open-field test, step-through test, and water maze, was improved by the consumption of the green tea polyphenols.
EGCG has also been found to enhance long-term potentiation (LTP). In a study conducted by Xie et al. (2008), LTP in Ts65Dn mice was significantly enhanced when hippocampal slices were pre-incubated with EGCG for 1 h prior to the experiment. This is important because LTP is a “well-characterized form of synaptic plasticity that fulfils many of the criteria for a neural correlate of memory” (Cooke and Bliss, 2006, p. 1659), and is widely considered the major cellular mechanism that influences learning and memory (Abraham and Williams, 2003). Furthermore, Xie et al. investigated Ts65Dn mice, a Down syndrome mouse model with deficits in LTP and spatial learning and memory, further implicating the potential of EGCG in influencing organisms with cognitive impairments.
ACUTE COGNITIVE EFFECTS OF EGCG
Of the studies reviewed, the majority have involved the administration of antioxidants, flavonoids, green tea, or EGCG for at least 2 weeks. However, there is evidence that EGCG may also have an acute effect (Pietta et al., 1998; Xie et al., 2008). Several studies have investigated the absorption of EGCG. The time to maximum absorption of catechins has been reported to be approximately 2 h (Duffy et al., 2001; Pietta et al., 1998), with the plasma elimination half-life of approximately 2–3 h (Collie and Morley, 2007; McKay and Blumberg, 2007). In line with these findings, the highest concentrations of catechins in humans have been reported to occur around 1 h after ingestion (Kimura et al., 2002).
Several studies have investigated the effect of EGCG consumption on acute anti-oxidant activity. In one study a sample of 12 participants were supplemented with single doses of green tea catechins equivalent to 400 mg EGCG, both in free and in phospholipid complex forms (Pietta et al., 1998). Blood samples were collected before and 60, 120, 180, 240, 300, and 360 min after ingestion. A single dose of both forms of EGCG produced an increase in total radical antioxidant parameter, with a peak at 2 h after ingestion (Pietta et al., 1998). Similarly, Kimura and associates (2002) investigated the consumption of a single (164 mg) and double (328 mg) dose of EGCG on ferric-reducing antioxidant power. In contrast to Pietta and associates, there were no significant differences in either dose from baseline 30, 60, or 180 min after ingestion. However, Kimura et al. had a sample of five participants, which may have been insufficient to detect an effect. Furthermore, the studies measured anti-oxidant activity using different assays that differ in their chemistry and their mechanisms in detecting differences in activity (Pellegrini et al., 2003).
Given its acute physiological effects, two recent studies have examined the acute neurocognitive effects of EGCG administration (Scholey et al., 2012; Wightman et al., 2012). Scholey and colleagues found increased self-rated calmness and reduced stress 2 h following a 300 mg dose of EGCG (Teavigo). The behavioral effects were coupled with treatment-related changes in overall EEG activity—and increases in alpha, beta, and theta waveform activity localized to frontal regions. Wightman et al.’s (2012) results also indicate changes in frontal activity, with decreased blood flow to this region as measured using near infrared spectroscopy following 135 mg of the same extract. The Wightman study found no change in mood or cognitive per-formance (repeated cycles of cognitively demanding tasks) following 135 or 270 mg of the extract.
The acute effects of flavonoids, more specifically the consumption of G. biloba and Bacopa monniera, on cognitive function have been investigated. Kennedy et al. (2000) investigated the cognitive effects of an acute administration of G. biloba. Their results showed acute G. biloba administration enhances cognitive performance in healthy young adults. This cognitive enhancement was most noticeable in tasks assessing attention. The effect was time-dependent, with significant improve-ments found at 150, 240, and 360 min following ingestion. Contrastingly, a similar study conducted by Nathan et al. (2001) found no relationship between a single dose of B. monniera, known to have similar antioxidant activities to EGCG, and cognitive function. The authors suggested a chronic administration of B. monniera may be required to significantly improve cognitive function.
BIOLOGICAL MECHANISMS OF EGCG RELATED TO COGNITIVE FUNCTION ANTIOXIDANT PROPERTIES
Although the mechanisms underlying the cognitive effects of EGCG are not fully understood, its benefits are commonly attributed to its antioxidant properties (Zaveri, 2006). EGCG is a more powerful antioxidant than vitamins C and E (Kimura et al., 2002; Kuriyama et al., 2006). Several studies have investigated the antioxidant power of EGCG. Kimura and associates (2002) investigated the consumption of a single dose of EGCG on ferric-reducing antioxidant power. They found no significant differences from baseline 30, 60, or 180 min after the ingestion of 328 mg of EGCG. Conversely, other studies have found a single dose of green tea causes an increase in ferric-reducing ability of plasma assay (Leenan et al., 2000) and total radical antioxidant parameter (Pietta et al., 1998), measuring antioxidant power. However, in the later studies participants ingested a larger than normal amount of tea catechins (400–900 mg vs. a normal value of 300 mg), suggesting larger amounts of EGCG may need to be consumed to exert its antioxidant power. The regular consumption of green tea catechins, as evidenced in a 30 day study conducted by Pietta and Simonetti (1998), has also been found to provide antioxidant protection.
The antioxidative effect of EGCG may also influence cognitive function by ameliorating the effects of oxidative stress. Oxidative stress refers to the damages in cellular structure and functions that occur due to the increased production of free radicals, reactive species, and oxidant-related reactions (Yu and Chung, 2006). Research has shown the brain is particularly vulnerable to oxidative stress over time because of its high oxygen consumption, 20% of the total body oxygen, and its deficiency in free radical protection (Joseph et al., 1999; Kaur et al., 2008). Antioxidants, in particular EGCG, may improve cellular functioning and minimize oxidative stress in aged organisms (Blokhina et al., 2003; Yu and Chung, 2006). The antioxidant properties of EGCG have also been found to promote the inhibition of xanthine oxidase, which can lower the production of oxygen-free radicals in the brain (Lee et al., 2004; Pietta and Simonetti, 1998). Furthermore, Unno and associates (2006) found oxidative damage in DNA was suppressed in aged mice fed EGCG. The consumption of EGCG has been suggested as a treatment for Alzheimer’s disease due to its ability to reduce the effects of oxidative stress (Engelhart et al., 2002).
The metal-chelating properties of green tea catechins are also important con-tributors to their antioxidative activity (Zaveri, 2006). Although EGCG is a rela-tively selective chelator of iron (Mandel et al., 2007), it also chelates other metals (Reznichenko et al., 2006). Metal chelators are compounds that bind to metals consequently rendering them motionless and unable to participate in neurodegenerative progression (Chaston and Richardson, 2003). It has been suggested in neurodegenerative metals accumulate in the brain where neuronal death occurs (Mandel and Youdim, 2004). However, the causal direction is unclear. The metal-chelating characteristic of EGCG has been associated with its ability in treating Parkinson’s dis-ease and Alzheimer’s disease (Mandel et al., 2006).
Researchers have proposed several other explanations for the improvements in cognitive function seen after antioxidant consumption. The consumption of antioxi-dants may result in reduced inflammatory responses (Joseph et al., 1999) and ace-tylcholinesterase activity (Kaur et al., 2008), which is part of the central cholinergic system involved in regulating cognitive functions (Kim et al., 004). While some have also proposed an increase in cortical blood flow (Pragg et al., 2007) and in the production of neurons (Spencer, 2009) may explain the effects. This is supported by recent research that has shown flavanol-enriched foods can increase cerebral blood flow velocity (Sorond et al., 2008). Furthermore, the oral administration of EC has been found to enhance angiogenesis, the development of new blood vessels from pre-existing blood vessels (Pragg et al., 2007). Cerebral blood flow has been found to be correlated with cognitive function (Ruitenberg et al., 2005).
Data from several studies indicate the antioxidant properties of green tea catechins are unlikely to be the sole explanation for their effects (Mandel et al., 2005). Both in vivo and in vitro studies have demonstrated green tea catechins exert a neuroprotective role, and several researchers attribute this to their diverse pharmacological activities (Mandel et al., 2004b, 2005; Mandel and Youdim 2004). Bastianetto et al. (2006) showed that EGCG is the sole catechin to contribute to the neuroprotective effects of green tea. This characteristic of EGCG could be involved in the prevention of cognitive decline. Over the last 5 years research has demonstrated green tea catechins, through their neuroprotective properties, have the ability to effect cell survival or death genes and signal transduction (Kalfon et al., 2006; Lee et al., 2004; Levites et al., 2003; Mandel and Youdim, 2004; Mandel et al., 2004a, 2006; Weinreb et al., 2004; Youdim et al., 2002). These effects have been reported in a variety of models of toxicity (Bastianetto et al., 2006) including that induced by ischemia (Lee et al., 2004), N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Levites et al., 2001), glutamate (Lee et al., 2004), and 0-amyloid peptides (Levites et al., 2003).
It is important to note it is still unclear whether these neuroprotective effects are due to antioxidant activities or due to the unique activities of EGCG on a range of molecular targets. Furthermore, most of the mechanisms that have been proposed are based on in vitro studies with amounts of EGCG much higher than those achievable in vivo (Zaveri, 2006). Plasma tea catechin concentrations determined in humans after the oral consumption green tea catechins have been found to be 5–50 times less than the concentrations shown to exert biological activities (Chow et al., 2005). Whether the neuroprotective mechanisms of EGCG can be replicated in vivo is still unknown (Zaveri, 2006).
BIOAVAILABILITY OF EGCG
Understanding the biological effects of tea consumption in humans is made dif-ficult by inadequate information on the bioavailability and biotransformation of tea catechins. There is evidence EGCG can cross the blood–brain barrier and has access to the brain after oral ingestion (Bastianetto et al., 2006; Mohsen et al., 2002). Suganuma et al. (1998) found after 3 h 33% of the total amount of catechin absorbed was found in the mouse brain from a single administration of EGCG. Human studies on the pharmacokinetics of tea catechins have been limited in scope. However, the studies that have been done indicate the bioavailability of EGCG in humans to be limited. Levels in plasma up to a maximum of 7.3 µmol/L (±3.6) have been reported, but more often are in the submicromolar range (Howells et al., 2007; Yang et al., 2008). Higher plasma concentrations have been found in fasting patients compared to those consuming EGCG with food (Naumovski, 2010). Peperine, derived from black pepper, has also been found to enhance the bioavailability of EGCG in mice (Lambert et al., 2004). However, oral consumption of EGCG in humans results in high plasma clearance levels and volume distribution, suggesting the bioavailability of EGCG in the blood may be low (Howells et al., 2007). In addition, a large variability between people in the pharmacokinetics of green tea catechins has been reported (Chow et al., 2005). Although green tea extracts have been marketed as nutritional supplements, it appears large doses may need to be used because of the limited pharmacokinetics mechanisms of the catechin (Zaveri, 2006).
Research investigating the relationship between EGCG and cognitive function is in its infancy. The effect of EGCG consumption on cognitive function in humans has not been adequately investigated. Positive associations between antioxidants, flavonoids, green tea, and cognitive function have been found in several epidemiological studies. However, the inherent limitations of epidemiological designs make it difficult to infer causal relationships from these results. The premise that EGCG improves cognitive function is generated predominantly from the results of several animal studies. Therefore, additional acute and chronic clinical trials investigating the relationship between EGCG and cognitive function in humans are needed.
Further understanding of the bioavailability and pharmacokinetic profiles of EGCG in the human brain is crucial to understanding the influence of EGCG on cognitive function. Previous studies indicate the bioavailability of EGCG to be low. Therefore, it is important to determine regimens which can enhance EGCG bioavail-ability. The biological mechanisms of EGCG related to brain function also need further research. Several animal studies have validated the use of EGCG in a variety of models of toxicity (Bastianetto et al., 2006). However, no human studies have been conducted.
Nootropics, particularly nutraceuticals, are becoming a popular alternative to conventional medicine (Hill, 2008). However, most nutraceuticals still need support of extensive scientific studies to determine the extent of their effects (Kalra, 2003). As a result, it is becoming increasingly important to establish the efficacy of sub-stances, such as EGCG, which may provide psychological and physiological benefits to everyday cognitive functioning.