BackgroundThe consumption of green tea catechins (GTCs) suppresses age-related cognitive dysfunction in mice. GTCs are composed of several catechins, of which epigallocatechin gallate (EGCG) is the most abundant, followed by epigallocatechin (EGC). Orally ingested EGCG is hydrolyzed by intestinal biota to EGC and gallic acid (GA). To understand the mechanism of action of GTCs on the brain, their permeability of the blood brain barrier (BBB) as well as their effects on cognitive function in mice and on nerve cell proliferation in vitro were examined.MethodsThe BBB permeability of EGCG, EGC and GA was examined using a BBB model kit. SAMP10, a mouse model of brain senescence, was used to test cognitive function in vivo. Human neuroblastoma SH-SY5Y cells were used to test nerve cell proliferation and differentiation.ResultsThe in vitro BBB permeability (%, in 30 min) of EGCG, EGC and GA was 2.8±0.1, 3.4±0.3 and 6.5±0.6, respectively. The permeability of EGCG into the BBB indicates that EGCG reached the brain parenchyma even at a very low concentration. The learning ability of SAMP10 mice that ingested EGCG (20 mg/kg) was significantly higher than of mice that ingested EGC or GA. However, combined ingestion of EGC and GA showed a significant improvement comparable to EGCG. SH-SY5Y cell growth was significantly enhanced by 0.05 µM EGCG, but this effect was reduced at higher concentrations. The effect of EGC and GA was lower than that of EGCG at 0.05 µM. Co-administration of EGC and GA increased neurite length more than EGC or GA alone.ConclusionCognitive dysfunction in mice is suppressed after ingesting GTCs when a low concentration of EGCG is incorporated into the brain parenchyma via the BBB. Nerve cell proliferation/differentiation was enhanced by a low concentration of EGCG. Furthermore, the additive effect of EGC and GA suggests that EGCG sustains a preventive effect after the hydrolysis to EGC and GA.

The permeability of EGC-M5 and its conjugated forms into the BBB suggests that they reached the brain parenchyma. In addition, the ability of EGC-M5 to affect nerve cell proliferation and neuritogenesis suggests that EGC-M5 may promote neurogenesis in the brain.

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To evaluate the psychosocial effect on lifespan and cognitive function, this study investigated the effect of confrontational housing on mice because conflict among male mice is a psychosocial stress. In addition, it investigated the anti-stress effect of theanine (γ-glutamylethylamide), an amino acid in tea. Mice were housed under confrontation. That is, two male mice were separately housed in the same cage with a partition for establishing the territorial imperative in each mouse. Then, the partition was removed and mice were co-housed confrontationally (confront-housing) using a model mouse of accelerated-senescence (SAMP10) that exhibited cerebral atrophy and cognitive dysfunction with ageing. It was found that mice began to die earlier under confront-housing than group-housed control mice. Additionally, it was found that cerebral atrophy, learning impairment and behavioural depression were higher in mice under the stressed condition of confront-housing than age-matched mice under group-housing. Furthermore, the level of oxidative damage in cerebral DNA was higher in mice housed confrontationally than group-housed control mice. On the other hand, the consumption of purified theanine (20 μg/ml, 5-6 mg/kg) suppressed the shortened lifespan, cerebral atrophy, learning impairment, behavioural depression and oxidative damage in cerebral DNA. These results suggest that psychosocial stress accelerates age-related alterations such as oxidative damage, lifespan, cognitive dysfunction and behavioural depression. The intake of theanine might be a potential candidate for suppression of disadvantage under psychosocial stress.

The antistress effect of theanine (γ-glutamylethylamide), an amino acid in tea, was investigated using mice that were psychosocially stressed from a conflict among male mice in conditions of confrontational housing. Two male mice were housed in the same cage separated by a partition to establish a territorial imperative. When the partition was removed, the mice were co-housed confrontationally. As a marker for the stress response, changes in the adrenal gland were studied in comparison to group-housed control mice (six mice in a cage). Significant adrenal hypertrophy was observed in mice during confrontational housing, which was developed within 24 h and persisted for at least 1 week. The size of cells in the zona fasciculata of the adrenal gland, from which glucocorticoid is mainly secreted, increased (∼1.11-fold) in mice during confrontational housing, which was accompanied by a flattened diurnal rhythm of corticosterone and ACTH in blood. The ingestion of theanine (>5 μg ml(-1)) prior to confrontational housing significantly suppressed adrenal hypertrophy. An antidepressant, paroxetin, suppressed adrenal hypertrophy in a similar manner in mice during confrontational housing. In mice that ingested theanine, behavioural depression was also suppressed, and a diurnal rhythm of corticosterone and ACTH was observed, even in mice that were undergoing confrontational housing. Furthermore, the daily dose of theanine (40 μg ml(-1)) blocked the counteracting effects of caffeine (30 μg ml(-1)) and catechin (200 μg ml(-1)). The present study demonstrated that theanine prevents and relieves psychosocial stress through the modulation of hypothalamic-pituitary-adrenal axis activity.

Theanine, a major amino acid in green tea, exhibits a stress-reducing effect in mice and humans. Matcha, which is essentially theanine-rich powdered green tea, is abundant in caffeine. Caffeine has a strong antagonistic effect against theanine. The stress-reducing effect of matcha was examined with an animal experiment and a clinical trial. The stress-reducing effect of matcha marketed in Japan and abroad was assessed based on its composition. The stress-reducing effect of matcha in mice was evaluated as suppressed adrenal hypertrophy using territorially-based loaded stress. High contents of theanine and arginine in matcha exhibited a high stress-reducing effect. However, an effective stress-reducing outcome was only possible when the molar ratio of caffeine and epigallocatechin gallate (EGCG) to theanine and arginine was less than two. Participants (n = 39) consumed test-matcha, which was expected to have a stress-reducing effect, or placebo-matcha, where no effect was expected. Anxiety, a reaction to stress, was significantly lower in the test-matcha group than in the placebo group. To predict mental function of each matcha, both the quantity of theanine and the ratios of caffeine, EGCG, and arginine against theanine need to be verified.

Caffeine, one of the main components in green tea, can interfere with sleep and block the effect of theanine. Since theanine, the main amino acid in tea leaves, has significant anti-stress effects in animals and humans, we examined the effects of green tea with lowered caffeine content, i.e., low-caffeine green tea (LCGT), on stress and quality of sleep of middle–aged individuals (n = 20, mean age 51.3 ± 6.7 years) in a double-blind crossover design. Standard green tea (SGT) was used as the control. These teas (≥300 mL/day), which were eluted with room temperature water, were consumed over a period of seven days after a single washout term. The level of salivary α-amylase activity (sAA), a stress marker, was significantly lower in participants that consumed LCGT (64.7 U/mL) than in those that consumed SGT (73.9 U/mL). Sleep quality was higher in participants that consumed a larger quantity of LCGT. In addition, a self-diagnostic check for accumulated fatigue was significantly lower in those participants that consumed LCGT than SGT. These results indicate that LCGT intake can reduce stress in middle-aged individuals and improve their quality of sleep. The reduction in caffeine is suggested to be a valid reason for enhancing the anti-stress effect of green tea.