Vous êtes sur la page 1sur 5

Journal of Ethnopharmacology 104 (2006) 144148

Protective effect of Polygonum multiorum Thunb on amyloid

-peptide 25-35 induced cognitive deficits in mice
Min-Young Um, Won-Hee Choi, Ji-Yun Aan, Sung-Ran Kim, Tae-Youl Ha
Food Function Research Division, Korea Food Research Institute, Seongnam 463-746, Republic of Korea
Received 9 January 2005; received in revised form 5 August 2005; accepted 27 August 2005
Available online 10 October 2005

Amyloid protein (A) may be neurotoxic during the progression of Alzheimers disease by eliciting oxidative stress. This study was designed
to determine the effect of Polygonum multiorum Thunb water extract (PWE) on A25-35-induced cognitive deficits and oxidative stress in mice.
Mice were fed experimental diets comprising either 0.5 or 1% PWE for 4 weeks, and then received a single intracerebroventricular (i.c.v.) injection
of A25-35 (10 g/mouse). Behavioral changes in the mice were evaluated using passive avoidance and water-maze tests. The consumption of PWE
significantly ameliorated the cognitive deficits caused by i.c.v. injection of A25-35. The A25-35 treatment accelerated the lipid peroxidation, and
PWE attenuated the A-induced increase in brain levels of thiobarbituric acid reactive substances. There was an increase in glutathione peroxidase
activity in PWE-treated groups. The acetylcholinesterase activity in the brain and serum was lower in PWE supplemented groups than in the only
A-injected group. These findings suggest that PWE exerts a preventive effect against cognitive deficits induced by A25-35 accumulation in
Alzheimers disease, and that this effect is mediated by the antioxidant properties of PWE.
2005 Elsevier Ireland Ltd. All rights reserved.
Keywords: Amyloid protein; Antioxidative capacity; Cognitive deficits; Polygonum multiorum Thunb

1. Introduction
Alzheimers disease (AD) is characterized by progressive
cognitive function deficits due to the presence of numerous
senile plagues and neurofibrillary tangles in brain regions
(Yankner, 1996). Amyloid (A) peptide is a major component
of these plagues (Golde et al., 1992; Yan et al., 2004). The accumulating evidences suggest that oxidative stress is involved in
the mechanism of A-induced neurotoxicity (Behl et al., 1992;
Yamada et al., 1999; Zhu et al., 2004). The levels of lipid peroxidation, protein carbonyl, and 8-hydroxyl-2-deoxyguanosine are
higher in the brains of AD patients than in aged-matched control
brains (Sayre et al., 1997; Smith et al., 1997; Morishima et al.,
2001). Antioxidants, such as Vitamin E, Ginkgo biloba, and fer-

Abbreviations: A, amyloid protein; AChE, acetylcholinesterase; AD,

Alzheimers disease; GPx, glutathione peroxidase; i.c.v., intracerebroventricular; MDA, malondialdehyde; PBS, phosphate buffered saline; PM, Polygonum
multiorum Thunb; PWE, Polygonum multiorum Thunb water extract; SOD,
superoxide dismutase; TBARS, thiobarbituric acid reactive substances
Corresponding author. Tel.: +82 31 780 9054; fax: +82 31 780 9225.
E-mail address: tyhap@kfri.re.kr (T.-Y. Ha).
0378-8741/$ see front matter 2005 Elsevier Ireland Ltd. All rights reserved.

ulic acid have been used in attempts to treat/prevent AD (Sano

et al., 1997; Christen, 2000; Yan et al., 2001). The mechanisms
underlying the preventive effect of antioxidants against AD are
unclear, but there is accumulating evidence that oxidative stress
contributes to neurotoxicity caused by A in vitro and in vivo
(Stackman et al., 2003; Tamagno et al., 2003).
Furthermore, it was reported that A deposition causes selective neuronal loss and is related to dysfunction and degeneration
of basal forebrain cholinergic neurons. The activity of acetylcholinesterase (AChE), responsible for acetylcholine hydrolysis, has been shown to be increased within and around amyloid
plagues (Atack et al., 1983). An increase in the AChE activity
promotes the assembly of A into fibrils, and it has been suggested that AChE plays a pathogenic role in AD by influencing
the process leading to A toxicity (Melo et al., 2003).
Polygonum multiorum Thunb (PM), the root of a Korean
medicinal herb, has been used for a long time as an antiaging
agent. Recent studies have demonstrated that PM exerts hypocholesterolemic, antitumor, and vasorelaxant effects (Zhang et
al., 1983; Xiao et al., 1993). The efficacy of PM in treating
chronic disorders may be mediated by its antioxidative properties. Chen et al. (1999) identified that gallic acid, catechin,

M.-Y. Um et al. / Journal of Ethnopharmacology 104 (2006) 144148

and 2,3,5,4 -tetrahydroxystilbene-2-O--d-glucoside in the

ethyl acetate fraction of PM extracts showed strong antioxidant
activities. Chan et al. (2002) showed that PM ethanol extract
supplemented groups had a lower percentage of lipofuscin and
a lower malondialdehyde (MDA) concentration in the brain. In
screening study of AChE inhibitory activity and neuroprotective
effect from some medicinal plants used in oriental medicines,
we found out that PM water extract (PWE) showed a potent protective effect against A-induced neuronal cell death and AChE
inhibitory activity in vitro. This result in the preliminary study
prompts us to investigate whether PWE can exhibit protective
effect on cognitive deficits in mice. We examined the behavioral
changes, AChE activity, level of lipid peroxidation, and antioxidant enzyme activities to evaluate effect of PWE on cognitive
deficits and oxidative stress induced in A-treated mice.
2. Materials and methods
2.1. Preparation of PWE
The roots of Polygonum multiorum Thunb, family Polygonacease, originated from Korea were purchased from Kyungdong Oriental medicine market (Seoul, Korea), and identified
by Professor Y.M. Park, Department of Life Science, Cheongju
University. Voucher specimens (KFRI-PM03002) were preserved in Korea Food Research Institute. Dried PM roots were
cut into small pieces and extracted three times with 10 volumes
of distilled water at 100 C for 3 h. The water extract was filtered with filter paper (Whatman No. 2, USA). The supernatants
were concentrated under reduced pressure with a vacuum rotary
evaporator. The concentrated extracts were freeze-dried. Finally,
11.1 g of the dried extract was obtained from 100 g of the roots
of PM and stored at 20 C until use.
2.2. Animals and intracerebroventricular (i.c.v.) injection
of A25-35
Male ICR mice (5-week-old; Bio Genomics, Korea) were
used in the experiments. The mice were housed in a room maintained at 23 1 C with a 12-h light/12-h dark cycle and fed
for 4 weeks ad libitum. The experimental diet was based on
the AIN76 formula, and comprised either 0.5 or 1% PWE.
The A25-35 peptide was dissolved in PBS. An i.c.v. injection
of A25-35 (10 g/mouse) was performed using the procedure
established by Laursen and Belknap (1986). In brief, each mouse
was injected at the bregma with a 50 l Hamilton microsyringe
fitted with a 26-gauge needle, the tip of which was adjusted to be
inserted by 2.4 mm. The i.c.v. injection volume was 10 l. Control animals were injected with PBS. Fifty mice were randomly
divided into five groups. All animal procedures were approved
by Institutional Animal Care and Use Committee of Korea Food
Research Institute.


illuminated and one dark, equipped with a grid floor and shock
generator. The day after A25-35 injection, mice were trained
in the passive avoidance task. During the training trial, each
mouse was placed in the lighted compartment, and as soon as
it entered the dark compartment the door was closed, and it
received an inescapable shock (0.3 mA, 3 s). The next day, the
mouse was again placed in the lighted compartment, and the
time until it returned to the dark compartment was measured as
the step-through latency (with a maximum of 300 s).
2.4. Water-maze test
The water maze was slightly modified from the Morris water
task. The experimental apparatus consisted of a circular water
tank (diameter 100 cm; height 35 cm) containing water at 23 C
to a depth of 15 cm and rendered opaque by the addition of powdered milk. A platform was positioned inside the tank with its
top submerged 2 cm below the water surface in the target quadrant of the maze. After several trials, the test was conducted on
the day of injection of A peptide. In each training trial, the time
required to escape onto the hidden platform was recorded. The
number of times the platform was not found was also recorded.
2.5. Measurement of AChE activity
AChE activity in the brain was measured using the method
of Ellman et al. (1961). Acetylthiocholine iodide was used as a
substrate. The hydrolysis of acetylthiocholine was determined
by monitoring the formation of the yellow 5-thio-2-nitrobenzoic
acid at a wavelength of 412 nm. Protein concentration was determined by the method of Lowry et al. (1951). Serum AChE
activity was assayed with cholinesterase kit from Sigma Chemical (St. Louis, MO, USA) following a modified version of the
method of Rappaport et al. (1959).
2.6. Measurement of lipid peroxide levels and antioxidant
enzyme activity
Lipid peroxidation in the brain was determined by measuring the formation of thiobarbituric acid reactive substances
(TBARS) according to the method of Ohkawa et al. (1979).
A standard curve was obtained using 1,1,3,3-tetramethoxypropane. Catalase activity was measured using the method of
Aebi (1974). Brain homogenate was reacted with hydrogen peroxide, and the decomposition of hydrogen peroxide was determined spectrophotometrically at 240 nm. Superoxide dismutase
(SOD) activities were assayed according to Marklund and Marklund (1974). Glutathione peroxidase (GPx) activity was measured according to Lawrence and Burk (1976). The decrease in
NADPH was recorded at 340 nm and is expressed here using a
molar extinction coefficient of NADPH of 6.22 mM1 cm1 .
2.7. Statistics

2.3. Passive avoidance test

Passive avoidance was tested using a two-compartment
shuttle chamber (256000 series, TSE Systems, Germany), one

Statistical analysis was performed using one-way analysis of

variance, with Duncans multiple test used for group comparison
with P < 0.05.


M.-Y. Um et al. / Journal of Ethnopharmacology 104 (2006) 144148

3. Result
3.1. PWE improves cognitive decits in A25-35-treated
It was suggested previously that the i.c.v. injection of A2535 causes memory deficits and lowers choline transferase in
hippocampus (Tang et al., 2002; Stepanichev et al., 2004). In the
present study, an i.c.v. injection of 10 g of A25-35-induced
cognitive dysfunction as assessed by passive avoidance and Morris water-maze tests. Changes in the step-through latency in
passive avoidance are shown in Fig. 1. There was no significant difference between the normal and normal PBS groups
(i.c.v. injection of PBS), but significantly reduced step-through
latency in the A25-35-injected control group (25.3% reduction
compared to normal, P < 0.05). This result confirmed that cognitive deficits induced by A i.c.v. were not attributable to the
i.c.v. injection itself. As shown in Fig. 1, step-through latency
was increased up to 2.5-fold by consumption of the 1% PWE diet
(P < 0.05). As shown in Fig. 2, injection of A25-35 increased
the escape latency and error frequency in the Morris water-maze
test. Treatment of mice with PWE for 4 weeks attenuated the
increase in the escape latency almost to that in the normal group,
but the change was not dose dependent. Changes in error frequency in each group showed a similar pattern to the escape

Fig. 2. Effect of PWE treatment on performance in the water-maze task by

A25-35-treated mice. Escape latency (A) and error frequency (B) were determined. Values are means S.E.M. (n = 10; * P < 0.05 compared to controls;
# P < 0.05 compared to normals).

3.2. Effect of PWE on AChE activity in the brain and serum

3.3. Effect of PWE on lipid peroxide levels in the brain
To determine the effect of PWE on AChE, we evaluated
AChE activity in the brain and serum (Table 1). Exposure to
A25-35 had no significant effect on AChE activity in brain,
but 0.5% PWE resulted in the reduction of AChE activity. In the
group consuming 1% PWE, the AChE activity was significantly
decreased compared to the control group. The activity of AChE
in serum was significantly higher in the control group than in
the normal group (21.0%, P < 0.05). In the group consuming 1%
PWE, the activity of AChE in serum was significantly lower than
that in the control group (25.3% reduction compared to control,
P < 0.05).

Lipid peroxide levels in the brain of A25-35-treated mice

are shown in Fig. 3. Injection of A25-35 into the cerebral ventricle increased lipid peroxide levels in the brain. PWE slightly
reduced the lipid peroxide (TBARS) levels in the brain of A2535 injected mice.
3.4. Effect of PWE on antioxidant enzyme activity in the
The effect of PWE on specific activities of catalase, SOD,
and GPx in the brain is shown in Table 2. Treatment with
A25-35 did not alter the activity of catalase in the brain. However, the activity of catalase was decreased in the PWE-treated
Table 1
Effect of PWE treatment on acetylcholinesterase activity in the serum and brain

Fig. 1. Protective effect of PWE on A25-35-induced cognitive deficits in mice.

The learning and memory performance was assessed by the passive avoidance test. Values are means S.E.M. (n = 10; * P < 0.05 compared to controls;
# P < 0.05 compared to normal).


Brain (M/(min mg protein))

Serum (Rappaport units/ml)

0.5% PW
1% PW

17.0 2.2 ab
17.9 0.9 a
18.4 0.4 a
15.0 0.5 b
14.8 0.3 b


27.8 b
8.6 b
11.7 a
8.3 b
2.2 b

(1) Values are means S.E.M. (n = 10). (2) One Rappaport unit is that amount
of cholinesterase that will liberate 1 mol of acetic acid from acetylcholine in
30 min at 25 C and pH 7.8 under the conditions of this test. (3) AChE activities are expressed as the amount of 5-thio-2-nitro-benzoic acid produced by
the hydrolysis of substrate. (4) Values with different letters within a row are
significantly different at = 0.05 by Duncans multiple-range test.

M.-Y. Um et al. / Journal of Ethnopharmacology 104 (2006) 144148

Fig. 3. Effect of PWE on TBARS levels in brain tissue of mice treated with
A25-35 (* P < 0.05 compared to controls; # P < 0.05 compared to normals).
Table 2
The effect of PWE on specific activities of catalase, SOD, and GPx in brain

Catalase (units/
(min mg protein))

SOD (units/
(min mg protein))

GPx (nmol/
(min mg protein))

0.5% PW
1% PW

2.96 0.42 n.s.

3.31 0.28
3.37 0.37
2.34 0.16
2.27 0.20

8.94 1.48 n.s.

9.33 0.47
8.88 0.97
6.67 0.16
8.01 0.37

34.81 7.67 ab
35.87 3.43 a
26.97 1.34 ab
24.68 1.10 ab
34.16 5.78 b

(1) Values are mean S.E.M. (n = 10). (2) Values with different letters within a
column are significantly different at = 0.05 by Duncans multiple-range test.
(3) n.s., not significant.

group, with the lowest activity exhibited in mice consuming 1%

PWE. The SOD activities did not differ significantly between the
groups. The activity of GPx in brain tissue was lower in A2535-treated mice than in normal mice. However, the activity of
GPx in brains of mice consuming 1% PWE was increased up to
the normal level.
4. Discussion
The present study has revealed a neuroprotective effect of
PM on A-induced cognitive deficits in mice. Memory associated behavior did not differ between the PBS-injected and
normal groups. Wang et al. (2001) similarly demonstrated that
i.c.v. injection of A25-35-induced impairment of memory as
assessed by passive avoidance and Morris water-maze tests. A
has the potential to induce oxidative stress in the brain (Behl and
Sagara, 1997). Moreover, it has been reported that A induces
the production of hydrogen peroxide and lipid peroxide in hippocampal neurons of the rat brain (Yatin et al., 2000). Jhoo et
al. (2000) showed the induction of 4-hydroxy-2-nonenal and 8hydroxy-2 -deoxyguanosine (a marker of oxidative damage to
DNA) immunoreactivities following infusion of A1-42 in rat
brain. In the present study, we found a significantly increased
level of TBARS in mice brain after a single injection with A2535. Furthermore, imbalances in each antioxidant enzyme were
also observed. Kim et al. (2003) demonstrated that continuous i.c.v. infusion of A1-42 in rat resulted in a significant
decrease in protein expression of SOD, GPx, and glutathioneS-transferase- in rat brain, from which they suggested that


A1-42 impairs antioxidant capacity. We found that consumption of a diet containing PWE ameliorated cognitive deficits
in A25-35-injected mice. Especially, the data show that the
step-through latency in passive avoidance increased in a dosedependent manner, but not in the water-maze test. Also, consumption of PWE decreased the escape latency almost to normal
levels. It is possible that neuroprotection plays a role in the
favorable effect of PWE on A25-35-induced cognitive deficits.
Antioxidants, such as -tocopherol and ferulic acid protect
against learning and memory deficits induced by A (Yamada et
al., 1999; Yan et al., 2001). The AChE activity has been shown to
be increased within and around amyloid plaques in Alzheimers
brain (Ulrich et al., 1990). The enhancement of AChE activity
induced by A25-35 is mediated by oxidative stress (Melo et al.,
2003). The AChE activity in the brain and serum was increased
in mice treated with A25-35 when compared with the normal
in our experiment. In addition, the A25-35-induced increase in
AChE was attenuated by PWE consumption.
PM is a medicinal plant that has antioxidant properties in
vitro (Ryu et al., 2002) and delays aging responses in vivo
(Chiu et al., 2002) involving oxidative stress. Also, previous
studies have shown that PM ethanol extract suppressed lipid
peroxidation in the mitochondria of rat heart (Chen et al., 1999).
Chan et al. (2002) demonstrated that PM ethanol extract significantly improved learning and memory deficits in SAMP8
(a murine AD model), and lowered lipofuscin percentages and
MDA concentrations in hippocampus, and increased total thiol
concentrations. Catalase, SOD, and GPx are involved in the
reduction in reactive oxygen species and peroxides produced in
living organisms as well as in the detoxification of certain compounds of exogenous origin, and thus play a primary role in the
maintenance of a balanced redox status (Kweon et al., 2003).
Treatment of mice with PWE for 4 weeks decreased TBARS
level and increased GPx activity in the brain, while having no
significant effect on catalase and SOD activity. These findings
can be attributed to GPx exhibiting a higher sensitivity to lipid
peroxidation than catalase or SOD. Therefore, we suggest that
accumulation of lipid peroxides by A was reduced by PWE via
antioxidative mechanisms.
In conclusion, we suggest that PWE markedly improves
cognitive deficits induced by A25-35, and that this effect is
mediated by the antioxidant properties of PWE. Future studies
should determine the specific components in PWE responsible
for preventing cognitive impairment.
Aebi, H., 1974. In: Bergmeyer, H.U. (Ed.), Catalase. Methods of Enzymatic
Analysis. Academic Press, New York and London, pp. 637684.
Atack, J.R., Perry, E.K., Bonham, J.R., Perry, R.H., Tomlinson, B.E., Blessed,
G., Fairbairn, A., 1983. Molecular forms of acetylcholinesterase in senile
dementia of Alzheimer type: selective loss of the intermediate (10S) form.
Neuroscience Letters 40, 199204.
Behl, C., Davis, J., Cole, G.M., Schubert, D., 1992. Vitamin E protects nerve
cells from amyloid beta protein toxicity. Biochemical and Biophysical
Research Communications 186, 944950.
Behl, C., Sagara, Y., 1997. Mechanism of amyloid beta protein induced
neuronal cell death: current concepts and future perspectives. Journal of
Neural Transmission. 49, 125134.


M.-Y. Um et al. / Journal of Ethnopharmacology 104 (2006) 144148

Chan, Y.C., Cheng, F.C., Wang, M.F., 2002. Beneficial effects of different Polygonum multiorum Thunb. extracts on memory and hippocampus morphology. Journal of Nutritional Science and Vitaminology 48,
Chen, Y., Wang, M., Rosen, R.T., Ho, C.T., 1999. 2.2-Diphenyl-1picrylhydrazyl radical-scavenging active components from Polygonum
multiorum Thunb. Journal of Agricultural and Food Chemistry 47,
Chiu, P.Y., Mak, D.H., Poon, M.K., Ko, K.M., 2002. In vivo antioxidant action of a lignan-enriched extract of Schisandra fruit and an
anthraquinone-containing extract of Polygonum root in comparison with
schisandrin B and emodin. Planta Medica 68, 951956.
Christen, Y., 2000. Oxidative stress and Alzheimer disease. American Journal
of Clinical Nutrition 71, 621S629S.
Ellman, G.L., Courtney, K.D., Andres, V.J., Featherstone, R.M., 1961. A
new and rapid colormetric determination of acetylcholinesterase activity.
Biochemical Pharmacology 7, 8895.
Golde, T.E., Estus, S., Younkin, L.H., Selkoe, D.J., Younkin, S.G., 1992.
Processing of the amyloid protein precursor to potentially amyloidogenic
derivatives. Science 255, 728730.
Jhoo, W.K., Kim, H.C., Yamada, K., Im, D.H., Shin, E.J., Park, S.J., 2000.
Prolonged exposure to -amyloid protein enhances 4-hydroxy-2-nonenal
modifies proteins in the rat brain. AbstractsSociety for Neuroscience
26, 1020.
Kim, H.C., Yamada, K., Nitta, A., Olariu, A., Tran, M.H., Mizuno, M., Nakajima, A., Nagai, T., Kamei, H., Jhoo, W.K., Im, D.H., Shin, E.J., Hjelle,
O.P., Ottersen, O.P., Park, S.C., Kato, K., Mirault, M.E., Nabeshima, T.,
2003. Immunocytochemical evidence that amyloid beta (1-42) impairs
endogenous antioxidant systems in vivo. Neuroscience 119, 399419.
Kweon, S.H., Kim, Y., Choi, H.M., 2003. Grape extracts suppress the formation of preneoplastic foci and activity of fatty acid synthase in rat liver.
Experimental and Molecular Medicine 35, 371378.
Laursen, S.E., Belknap, J.K., 1986. Intracerebroventricular injections in mice.
Some methodological refinements. Journal of Pharmacological Methods
16, 355357.
Lawrence, R.A., Burk, R.F., 1976. Glutathione peroxidase activity in
selenium-deficient rat liver. Biochemical and Biophysical Research Communications 71, 952958.
Lowry, O.H., Rosebrough, N.J., Farr, A.L., Randall, R.J., 1951. Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry
193, 265275.
Marklund, S., Marklund, G., 1974. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide
dismutase. European Journal of Biochemistry 47, 469474.
Melo, J.B., Agostinho, P., Oliveira, C.R., 2003. Involvement of oxidative
stress in the enhancement of acetylcholinesterase activity induced by amyloid beta-peptide. Neuroscience Research 45, 117127.
Morishima, Y., Gotoh, Y., Zieg, J., Barrett, T., Takano, H., Flavell, R., Davis,
R.J., Shirasaki, Y., Greenberg, M.E., 2001. Beta-amyloid induces neuronal
apoptosis via a mechanism that involves the c-Jun N-terminal kinase
pathway and the induction of Fas ligand. Journal of Neuroscience 21,
Ohkawa, H., Ohishi, N., Yagi, K., 1979. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry 95,
Rappaport, F., Fischl, J., Pinto, N., 1959. An improved method for the estimation of cholinesterase activity in serum. Clinica Chimica Acta 4, 227230.
Ryu, G., Ju, J.H., Park, Y.J., Ryu, S.Y., Choi, B.W., Lee, B.H., 2002. The
radical scavenging effects of stilbene glucosides from Polygonum multiorum. Archives of Pharmacol Research 25, 636639.
Sano, M., Ernesto, C., Thomas, R.G., Klauber, M.R., Schafer, K., Grundman,
M., Woodbury, P., Growdon, J., Cotman, C.W., Pfeiffer, E., Schneider,

L.S., Thal, L.J., 1997. A controlled trial of selegiline, alpha-tocopherol,

or both as treatment for Alzheimers disease. The Alzheimers Disease
Cooperative Study. New England Journal of Medicine 336, 12161222.
Sayre, L.M., Zelasko, D.A., Harris, P.L., Perry, G., Salomon, R.G., Smith,
M.A., 1997. 4-Hydroxynonenal-derived advanced lipid peroxidation end
products are increased in Alzheimers disease. Journal of Neurochemistry
68, 20922097.
Smith, M.A., Richey Harris, P.L., Sayre, L.M., Beckman, J.S., Perry, G.,
1997. Widespread peroxynitrite-mediated damage in Alzheimers disease.
Journal of Neuroscience 17, 26532657.
Stackman, R.W., Eckenstein, F., Frei, B., Kulhanek, D., Nowlin, J., Quinn,
J.F., 2003. Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimers disease by chronic Ginkgo biloba
treatment. Experimental Neurology 184, 510520.
Stepanichev, M.Y., Zdobnova, I.M., Zarubenko, I.I., Moiseeva, Y.V., Lazareva,
N.A., Onufriev, M.V., Gulyaeva, N.V., 2004. Amyloid-beta(25-35)induced memory impairments correlate with cell loss in rat hippocampus.
Physiology and Behavior 80, 647655.
Tamagno, E., Robino, G., Obbili, A., Bardini, P., Aragno, M., Parola, M.,
Danni, O., 2003. H2 O2 and 4-hydroxynonenal mediate amyloid betainduced neuronal apoptosis by activating JNKs and p38MAPK. Experimental Neurology 180, 144155.
Tang, F., Nag, S., Shiu, S.Y., Pang, S.F., 2002. The effects of melatonin
and Ginkgo biloba extract on memory loss and choline acetyltransferase
activities in the brain of rats infused intracerebroventricularly with betaamyloid 1-40. Life Science 71, 26252631.
Ulrich, J., Meier-Ruge, W., Probst, A., Meier, E., Ipsen, S., 1990. Senile
plaques: staining for acetylcholinesterase and A4 protein: a comparative
study in the hippocampus and entorhinal cortex. Acta Neuropathologica
80, 624628.
Wang, X.Y., Chen, J., Zhang, J.T., 2001. Effect of ginsenoside Rg 1 on
learning and memory impairment induced by beta-amyloid peptide(2535) and its mechanism of action. Yao Xue Xue Bao 36, 14.
Xiao, P.G., Xing, S.T., Wang, L.W., 1993. Immunological aspects of Chinese
medicinal plants as antiageing drugs. Journal of Ethnopharmacology 38,
Yamada, K., Tanaka, T., Han, D., Senzaki, K., Kameyama, T., Nabeshima,
T., 1999. Protective effects of idebenone and alpha-tocopherol on betaamyloid-(1-42)-induced learning and memory deficits in rats: implication
of oxidative stress in beta-amyloid-induced neurotoxicity in vivo. European Journal of Neuroscience 11, 8390.
Yan, J.J., Cho, J.Y., Kim, H.S., Kim, K.L., Jung, J.S., Huh, S.O., Suh, H.W.,
Kim, Y.H., Song, D.K., 2001. Protection against beta-amyloid peptide toxicity in vivo with long-term administration of ferulic acid. British Journal
of Pharmacology 133, 8996.
Yan, J.J., Kim, D.H., Moon, Y.S., Jung, J.S., Ahn, E.M., Baek, N.I., Song,
D.K., 2004. Protection against beta-amyloid peptide-induced memory
impairment with long-term administration of extract of Angelica gigas
or decursinol in mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry 28, 2530.
Yankner, B.A., 1996. Mechanisms of neuronal degeneration in Alzheimers
disease. Neuron 16, 921932.
Yatin, S.M., Varadarajan, S., Butterfield, D.A., 2000. Vitamin E prevents
Alzheimers amyloid beta-peptide (1-42)-induced neuronal protein oxidation and reactive oxygen species production. Journal of Alzheimers
Disease 2, 123131.
Zhang, Z., Zhuang, Q.Q., Mei, M.Z., 1983. Effect of some drugs on plasma
and liver lipoprotein lipase activities and plasma cholesterol levels in rats.
Yao Xue Xue Bao 18, 468471.
Zhu, X., Raina, A.K., Lee, H.G., Casadesus, G., Smith, M.A., Perry, G.,
2004. Oxidative stress signalling in Alzheimers disease. Brain Research
1000, 3239.