Ingestive Behavior and Neurosciences
Long-Term Administration of Green Tea Catechins Improves Spatial
Cognition Learning Ability in Rats1
Abdul M. Haque,* Michio Hashimoto,*2Masanori Katakura,* Yoko Tanabe,*
Yukihiko Hara,yand Osamu Shido*
*Department of Environmental Physiology, Shimane University Faculty of Medicine, Izumo 693-8501,
Japan andyMitsui Norin Company, Limited, Shinjuku-ku, Tokyo 160-8381, Japan
scavenging. We investigated the effect of long-term oral administration of green tea catechins (PolyphenonRE, PE:
EGCG 63%; EC 11%; EGC 6%; ECG 6%) mixed with water on the spatial cognition learning ability of young rats. The
learning ability of rats administered PE (0%, 0.1%, 0.5%) for 26 wk was assessed in the partially baited 8-arm radial
maze. Relative to controls, those administered PE had improved reference and working memory–related learning
ability. They also had lower plasma concentrations of lipid peroxides and greater plasma ferric-reducing antioxidation
power than controls. Furthermore, rats administered PE had lower hippocampus reactive oxygen species concen-
trations than controls. We suggest that this improvement in spatial cognitive learning ability is due to the antioxidative
activity of green tea catechins.J. Nutr. 136: 1043–1047, 2006.
Green tea catechins confer potent biological properties including antioxidation and free-radical
KEY WORDS: ? green tea catechins ? memory learning ? antioxidants ? rats
The free-radical hypothesis suggests that increased produc-
tion of lipid peroxide (LPO)3and reactive oxygen species
(ROS), which are produced with free radicals in membrane
lipids, causes deterioration of a wide variety of cellular enzymes,
subsequently exacerbating the neurodegenerative process (1).
Oxidative stress, a condition of cellular prooxidant-antioxidant
disturbance in favor of the prooxidant state, also induces the
production of ROS, leading to serious functional impairments
such as cognitive decline (2). On the other hand, a decrease in
hippocampal LPO improves spatial cognition learning memory
in aged rats (3), and an increase in antioxidative activity in the
hippocampus prevents (4) or ameliorates (5) the impairment of
learning ability in rats produced by the infusion of amyloid-b
peptide 1–40 into the cerebral ventricle.
Tea is rich in polyphenols contained in the leaves and stems
of the tea plant. The main polyphenolic components in green
(-)-epigallocatechin (EGC), and (-)-epicatechin gallate (ECG)
(6). EGCG, the major and most active component of green tea
catechins, acts as an antioxidant in the biological system (7)
and is rapidly absorbed and distributed mainly into the mucous
membranes of the small intestine and the liver; more interest-
ingly, it can cross the blood brain barrier (8). Moreover, oxi-
dative stress–induced neuronal apoptosis is prevented by EGCG
treatment of neuronal cells (7). Therefore, in the present study,
we investigated, through radial maze tasks, how long-term (26
wk) administration of water containing green tea catechins af-
fected spatial cognition learning ability in rats and the oxidative
status of their plasma and brain.
MATERIALS AND METHODS
Animals. All animal experiment protocols were carried out in
accordance with the guidelines for animal experimentation of Shimane
University compiled from the guidelines for animal experimentation of
the Japanese Association for Laboratory Animal Science. Male Wistar
rats (n 5 24; 5 wk old; Jcl: Wistar; Clea Japan) were randomly divided
into 3 groups and orally administered green tea catechins (Polyphenon
E, PE: Mitsui Norin) mixed with water, or water alone for 26 wk as
follows: a 0.1% group (administered 1 g/L PE; n 5 7), a 0.5% group
(5 g/L PE; n 5 9) and a control group (given water alone; n 5 8). The
rats were maintained in an air-conditioned animal room with a 12-h
dark:light cycle under controlled temperature (23 6 28C) and
humidity (50 6 10% relative humidity); the rats had free access to a
normal laboratory diet, MF (Oriental Yeast) and tap water with or
without PE. The MF diet, a nutritionally adequate and standard solid
diet, comprising (in descending order of amount) flour, corn, soybean
meal, whitefish meal, yeast, alfalfa meal and soybean oil, included the
following (g/kg): 70 water, 240 crude protein, 51 crude fat, 62 crude
ash, 32 crude fiber, and 545 nitrogen free extract (.90% starch).
Water containing PE as EGCG (63%), EC (11%), EGC (6%), and
ECG (6%) was freshly prepared every other day.
1Presented in abstract form at the 2004 International Conference on
O-CHA(tea) Culture and Science (ICOS), November 2004, Shizuoka, Japan
[Haque MA, Hashimoto M, Tanabe Y, Hara Y, Shido O. Chronic administration of
polyphenon E improves spatial cognitive learning ability in rats (abstract)].
2To whom correspondence should be addressed. E-mail: michio1@med.
3Abbreviations used: 0.5% PE rats, rats administered 5 g/L PE; 0.1% PE rats,
rats administered 1 g/L PE; BW, body weight; EC, (-)-epicatechin; ECG, (-)-
epicatechin; EGC, (-)-epigallocatechin; EGCG, (-)-epigallocatechin gallate; FRAP,
ferric reducing antioxidation power; LPO, lipid peroxide; PE, PolyphenonRE; RME:
reference memory error; ROS, reactive oxygen species; TBARS, thiobarbituric
acid reactive substance; WME, working memory error.
0022-3166/06 $8.00 ? 2006 American Society for Nutrition.
Manuscript received 25 October 2005. Initial review completed 21 November 2005. Revision accepted 20 January 2006.
by guest on May 30, 2013
Radial maze–learning ability. Both 2 and 5 mo after starting the
PE administration, the rats’ learning ability was tested by an assess-
ment of their behavior in an 8-arm radial maze (Toyo Sangyo) as
described (9). Briefly, the rats were trained to acquire a reward (food
pellet) at the end of each of the 4 arms of an 8-arm radial maze. The
ory error (RME), i.e., entry into unbaited arms; and working memory
error (WME), i.e., repeated entry into arms that had already been
visited in the same trial. Each rat was given 2 trials, 6 d/wk, for a total
of 5 wk.
Tissue preparation. After completing the maze task, the rats were
anesthetized with sodium pentobarbital (50 mg/kg BW, i.p.), and their
blood was collected; the cerebral cortex and hippocampus were then
separated as described (4,5). A portion of the frontal cortex (100 mg)
was immediately homogenized on ice in 1.0 mL of ice-cold 0.32 mol/L
sucrose buffer (pH 7.4) containing 2 mmol/L EDTA, 0.5 mg/L leupeptin,
0.5 mg/L pepstatin, 0.5 mg/L aprotinin, and 0.2 mmol/L phenyl-
methylsulfonyl fluoride using a Polytron homogenizer (PCU 2–110;
Kinematica). The residual tissues were stored at 2808C after flash-
freezing in liquid N2until use. The homogenates were immediately
subjected to the assays described below or stored at 2808C after liquid
N2flash and bath until use.
Measurements of antioxidative status. The LPO concentration
was assessed by the TBARS assay of Ohkawa et al. (10), as described
(4,5), with the concentration measured in nanomoles malondialde-
hyde/mg protein. Malondialdehyde levels were calculated relative to a
standard preparation of 1,1,3,3-tetraethoxypropane.
Plasma total antioxidant activity was measured by the ferric
reducing antioxidation power (FRAP) assay of Benzic and Strain (11)
with slight modification. The working FRAP reagent was prepared
by mixing 300 mmol/L acetate buffer (pH 3.6), 10 mmol/L 2,4,6-
tripyridyl-s-triazine (TP) in 40 mmol/L HCl and 20 mmol/L FeCl3?
6H2O solution. After mixing 3 mL of the working FRAP reagent with
400 mL plasma or standard solution in a test tube, a second reading was
taken at 600 nm. A blank reading with only the FRAP reagent was
subtracted from the absorbance of the FRAP reagent with a sample to
measure the actual FRAP value of each tube.
The levels of ROS were determined as described (4,5). Briefly, 50
mL of freshly prepared tissue homogenate was mixed with 4.85 mL of
0.1 mol/L potassium phosphate buffer (pH 7.4) and incubated with
29,79-dichlorofluorescein diacetate (Molecular Probes) in methanol at
a final concentration of 5 mmol/L for 15 min at 378C. The dye-loaded
samples were centrifuged at 12,500 3 g for 10 min at 48C. The pellet
buffer (pH 7.4) and incubated for 60 min at 378C. Fluorescence was
measured with a Hitachi 850 spectrofluorometer at wavelengths of 488
nm for excitation and 525 nm for emission. The cuvette holder was
maintained at 378C. ROS were quantified from a dichlorofluorescein
standard curve in methanol. The protein concentration was estimated
by the method of Lowry et al. (12).
Statistical analysis. Results are expressed as means 6 SEM.
Behavioral data were analyzed by a 2-factor (group and block)
randomized block factorial ANOVA; all other variables were analyzed
for intergroup differences by 1-way ANOVA. ANOVA was followed
parisons. Correlation was determined by simple regression analysis. The
statistical programs used were GB-STAT 6.5.4(DynamicMicrosystems)
and StatView 4.01 (MindVision Software, Abacus Concepts). A level
of P , 0.05 was considered significant.
PE intake and body weight.
differ among the control [27.7 6 1.7 mL/(rat?d)], 0.1% PE
[26.0 6 1.4 mL/(rat?d)], and 0.5% PE [26.2 6 1.0 mL/(rat?d)]
groups. PE intakes were 26.0 6 1.4 mg/(rat?d) in the 0.1% PE
group and 131 6 7.0 in the 0.5% PE group. Final body weights
did not differ among the groups and were 496 6 8 g in the
control group, 503 6 10 g in the 0.1% PE group, and 508 6 11
g in the 0.5% PE group.
Daily water intake did not
Radial-maze learning ability.
tration, the scores of RME and WME in block 10 of the radial
maze tasks undergone by the 0.5% PE rats were not lower than
those of the control and the 0.1% PE rats. Therefore, we
reestimated the learning ability (over a period of 6 wk) 20 wk
after starting the administration of PE.
The effect of PE administration for 26 wk on reference (Fig.
1A) and working (Fig. 1B) memory-related learning ability is
expressed as the mean number of RME and WME for each
group, with the data averaged over blocks of 6 trials (Fig. 1).
Randomized 2-factor (block and group) ANOVA, for analyzing
the effect of PE (0.1 and 0.5%), revealed significant main
effects of both blocks of trials (P , 0.0001) and groups (P ,
0.0001) on the number of RME (Fig. 1A), but without a
significant block 3 group interaction. Similarly, a significant
main effect of both blocks of trials (P , 0.0001) and groups
(P 5 0.0002) was observed on the number of WME (Fig. 1B),
but with a significant block 3 group interaction (P , 0.0001).
Subtest analysis (Table 1) of the number of RME showed the
effect of 0.1% PE group on control group (blocks of trials and
groups, without a significant block 3 group interaction); the
effect of 0.5% PE group on control group (blocks of trials and
groups, without a significant block 3 group interaction); and
the effect of the PE dose on PE-administered rats (blocks
of trials and groups, without a significant block 3 group
interaction), demonstrating that rats administered 0.1 and
0.5% PE had a lower RME score than the control rats (Fig.1A).
Similarly, subtest analysis (Table 1) of the number of WME
showed the effect of 0.1% PE group on control group (blocks of
trials and groups, with a significant block 3 group interaction);
the effect of 0.5% PE group on control group (blocks of trials
and groups, with a significant block 3 group interaction); and
the effect of the PE dose on PE-administered rats (blocks of
trials, but not groups), without a significant block 3 group
interaction, demonstrating that rats administered 0.1% and
0.5% PE had a lower WME score than the control rats (Fig.
1B). These analyses suggested that long-term administration of
PE improved reference and working memory–related learning
ability of rats.
Oxidative status of rat plasma and brains.
concentrations were dose dependently decreased in the groups
administered PE compared with the control group (P 5 0.0002,
Table 2). The plasma FRAP concentration was higher in the
0.5% PE group than in the control group (P 5 0.007) (Table 2).
TBARS levels in the hippocampus were reduced in the 0.1
and 0.5% groups, compared with the control group (P 5 0.002)
After 2 mo of PE adminis-
ability in the radial maze task of rats administered 0 (control, n ¼ 8), 0.1%
PE (n ¼ 7), or 0.5% PE (n ¼ 9) for 26 wk. Values are means 6 SEM in
each block of 6 trials. Groups without a common letter differ, P , 0.05.
Reference (A) and working (B) memory–related learning
HAQUE ET AL.
by guest on May 30, 2013
(Table 3). Similarly, the levels of ROS in the hippocampus were
reduced in the 0.1 and 0.5% groups, compared with the control
group (P 5 0.021). Cortex TBARS and ROS levels did not
differ among the rat groups. These results indicate that PE has
antioxidative effects on oxidative status in rat plasma and the
Regression analysis revealed a significant positive correlation
(r 5 0.520, P 5 0.032) between the hippocampal TBARS
levels and the number of RME in block 10 of the radial maze
task in control and 0.5% PE-administered rats (Table 4). There
was a significant negative correlation between the plasma
FRAP levels and the number of RME in block 10 of the radial
maze task in control rats and those administered 0.5% PE (r 5
20.570, P 5 0.017) (Table 4). Similarly, the number of WME
in block 10 of the radial maze task in control rats and those
administered 0.5% PE correlated positively with plasma
TBARS levels (r 5 0.622, P 5 0.008). The hippocampal
TBARS levels and the number of WME tended to be positively
correlated (r 5 0.480, P 5 0.051; Table 4).
The present study demonstrated that long-term administra-
tion of green tea catechins (PE) improves the performance in
radial maze tasks and that the level of LPO in the hippocampus
correlates significantly with the RME score. Thus, green tea
catechins may be involved in protecting against neuronal degen-
erative stress and in the accumulation of LPO and ROS.
Green tea catechins comprise EGCG, EGC, ECG, and EC
and protect the brain, liver, and kidney from lipid peroxidation
injury (13). The relative antioxidant activity among tea
catechins is EGCG ¼ ECG . EGC . EC (14) Catechins
have a protective effect against age-related neurological dis-
eases associated with ROS (15). In this study, long-term (26
wk) administration of PE decreased the plasma and hippocam-
pal oxidative status. In the process of aging, LPO and ROS
accumulate and are constantly involved in some of the path-
ophysiologic effects associated with oxidative stress in cells and
tissues. An increase in the production of LPO exacerbates the
neurodegenerative process by deteriorating cellular enzymes
(1). Antioxidative enzymes are activated by green tea catechin
intake (16), and the antioxidative potency of human plasma
increases with continual ingestion of green tea (17). These
antioxidative defense systems might also prevent oxidative
damage in the brain. Long-term intake of green tea catechins
may be important because cells are constantly exposed to
Aging leads to a decline in spatial memory–related learning
ability. Oxidative damage to the brain is associated with age-
related cognitive dysfunction (18), and some antioxidants are
effective in improving such dysfunction; examples include the
effects of a garlic extract on aged SAMP10 mice, a model of
brain senescence with cerebral atrophy and cognitive dysfunc-
tion (19), and of vitamin E on rats with oxidative stress (20).
Catechins are more effective radical scavengers than vitamins E
and C (21,22). Long-term administration of green tea catechins
to SAMP10 mice also suppressed cognitive dysfunction, as
demonstrated by the duration of learning needed to acquire an
avoidance response and by the assessment of working memory
in the Y-maze (23). Chronic administration of catechins for 3.5
mo improved learning memory in maze behavior of both adult
and old mice, although the mechanism of the improvement has
not been clarified (24). In this study, to estimate the effects of
the administration of green tea catechins on the learning ability
of rats, PE was administered for 26 wk starting at 5 wk of age.
Therefore, the point in time at which the effect of green tea
catechins on the improvement of learning ability becomes
apparent may differ among animal species.
The hippocampus and the cerebral cortex are the key
structures of memory formation. Because the hippocampus is
especially indispensable in the integration of spatial informa-
tion, a decline in learning ability may be induced by the
deterioration of hippocampal function. In this study, both a
decrease in TBARS levels in the hippocampus and an increase
in FRAP levels in the plasma were related to the acquisition of
higher reference memory-related learning ability; in addition, a
decrease in plasma TBARS levels was related to the acquisition
of higher working memory-related learning ability (Table 4). A
decrease in hippocampal LPO levels suggests an improvement
in spatial cognitive learning memory in aged rats (3). Further-
more, an increase in the antioxidative effects of docosahex-
aenoic acid on the hippocampus prevents impairment of
Results of the 2-factor ANOVA and PLSD test conducted on RME and WME data obtained in rats
administered 0 (control, n 5 8), 0.1% PE (n 5 7), or 0.5% PE (n 5 9) for 26 wk1
Reference memory errorWorking memory error
GroupBlock GroupBlock 3 Group interactionBlockGroupBlock 3 Group interaction
0 vs. 0.1% PE, 0.0001
(F9, 423= 17.55)
(F9, 477= 34.69)
(F9, 477= 35.05)
(F1, 47= 15.18)
(F1, 53= 42.91)
(F1, 53= 5.29)
(F9, 423= 0.99)
(F9, 477= 0.15)
(F9, 477= 1.86)
(F9, 423= 23.31)
(F9, 477= 24.58)
(F9, 477= 25.83)
(F1, 47= 9.38)
(F1, 53= 13.56)
(F1, 53= 0.02)
(F9, 423= 2.83)
(F9, 477= 3.61)
(F9, 477= 0.76)
0 vs. 0.5% PE
0.1% PE vs.
1Data are presented in Figure 1. NS, not significant, P . 0.05.
Plasma oxidative status of rats administered 0, 0.1% PE,
or 0.5% PE for 26 wk1
4.02 6 0.18a
3.51 6 0.12b
3.00 6 0.12c
223.7 6 10.8b
257.2 6 17.7ab
270.9 6 11.4a
1Values are means 6 SEM. Means in a column without a common
letter differ, P , 0.05.
CATECHINS IMPROVE SPATIAL COGNITION ABILITY
by guest on May 30, 2013
reference-memory learning ability in a rat model of Alzheimer’s
disease, in which an accompanying increase in the level of
hippocampal LPO was demonstrated (4). Intraperitoneal injec-
tion of EGCG markedly protects against hippocampal neuronal
damage after transient global ischemia in gerbils (25). Taken
together, these findings suggest that PE-induced improvement
in spatial cognitive learning ability is due to the antioxidative
effect of PE. In this study, PE administration decreased levels of
both TBARS and ROS in the hippocampus but not in the
cerebral cortex (Table 3), suggesting that chronic administra-
tion of green tea catechins reduces prooxidant levels and
oxidative stress in the hippocampus but not in the cerebral
cortex. It is difficult to explain why these variables were not
affected in the cerebral cortex. The level of protein carbonyl,
one of the markers of oxidative stress, increased in the hip-
pocampus but not in the cerebral cortex of 16-mo-old rats
compared with 4-mo-old controls (26). In addition, chronic
administration of docosahexaenoic acid decreased the levels of
TBARS in the hippocampus but not in the cerebral cortex of
aged rats (3). These results suggest that the hippocampus is
more susceptible to the effects of ROS. It is thus likely that
green tea catechins exert a stronger antioxidative effect in the
hippocampus than in the cerebral cortex of rats.
The metabolism of green tea catechins has been studied in
various animals and in human subjects. Tea polyphenols can be
retained in the brain and can exert neuroprotective effects
simply by their ingestion (27). When EGCG, the most abun-
dant component in green tea catechin PE, is administered
orally, it is detected as EGCG or as its conjugates, or both, and
peaks 1–2 h postdose in the rat systemic circulation (28). EGCG
administered orally is rapidly absorbed and distributed into the
plasma, liver, and brain (8). EC metabolites (epicatechin glu-
curonide and 39-O-methylated epicatechin glucuronide) form
after oral ingestion of EC by rats and gain entry into the brain
(29). Furthermore, labeled EGCG orally administered to rats
has demonstrated wide distribution of radioactivity in their
organs, including the brain (30). Green tea catechins admin-
istered orally are thus absorbed by and retained in the brain,
and their antioxidative and neuroprotective effects could
ultimately result in beneficial effects on an age-related decline
in spatial cognition. Additionally, green tea catechins might be
a prophylactic means of preventing neurodegenerative diseases
such as Alzheimer’s disease which is associated with oxidative
damage and neurotoxicity. There may be questions concerning
whether the amount of intake of green tea catechins used in
this study could be proportionately represented to benefit hu-
man health. A green tea polyphenol extract (100 mg EGCG)
ingested 3 times a day for 7 d significantly decreased plasma
FRAP levels in humans (17). In this study, an increase in
plasma FRAP levels was related to the acquisition of higher
reference memory–related learning ability (Table 4). Therefore,
long-term administration of an amount of PE that could induce
antioxidative effects may protect against age-related declines in
memory and learning ability in humans.
In the process of aging, LPO accumulates and induces
disorders of cellular functions (31). Aging also leads to a decline
in spatial memory–related learning ability (32). Changes in the
ability may be associated with the degeneration of cholinergic
neurons in the hippocampus (33) because these neurons are the
key structure for spatial memory learning. Interruption of hip-
pocampal pathways causes crucial memory deficits in the radial
arm maze task (34). Therefore, the effects of long-term admin-
istration of PE on memory and oxidative stress may be even
greater in aging rats. Further studies are required to clarify the
protective effect of green tea catechins on aging-related mem-
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1The number of RME and WME in block 10 shown in Figure 1 was
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CATECHINS IMPROVE SPATIAL COGNITION ABILITY
by guest on May 30, 2013