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Journal of Ethnopharmacology 146 (2013) 294299

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Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jep

Ginsenosides Rg5 and Rh3 protect scopolamine-induced memory


decits in mice
Eun-Jin Kim a,b, Il-Hoon Jung a, Thi Kim Van Le a, Jin-Ju Jeong a, Nam-Jae Kim b, Dong-Hyun Kim a,b,n
a
Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 1, Hoegi, Dongdaemun-gu, Seoul 130-701, Republic of Korea
b
East-West Medical Research Institute, Kyung Hee University, 1, Hoegi, Dongdaemun-gu, Seoul 130-701, Republic of Korea

a r t i c l e i n f o a b s t r a c t

Article history: Ethnopharmacological relevance: Panax ginseng (family Araliaceae) is traditionally used as a remedy for
Received 2 November 2012 cancer, inammation, stress and aging.
Received in revised form Aim of study: To explore whether ginsenosides Rg5 and Rh3, the main constituents of heat-processed
27 December 2012
ginseng (the root of Panax ginseng), could protect memory decit.
Accepted 29 December 2012
Materials and methods: We isolated ginsenosides Rh3 and Rg5 from heated-processed ginseng treated
Available online 9 January 2013
with and without human feces, respectively. Then we investigated their protective effects on memory
Keywords: impairment using the passive avoidance, Y-maze and Morris water maze tasks in mice. Memory decit
Panax ginseng was induced in mice by the intraperitoneal injection of scopolamine.
Araliaceae
Results: Ginsenosides Rg5 or Rh3 increased the latency time reduced by scopolamine in passive
Ginsenoside Rg5
avoidance test. Treatment with ginsenoside Rg5 or Rh3 signicantly reversed the lowered spontaneous
Ginsenoside Rh3
Memory decit-protecting effect alteration induced by scopolamine in Y-maze task. Ginsenoisde Rg5 or Rh3 (10 mg/kg) signicantly
shortened the escape latencies prolonged by treatment with scopolamine on the last day of training
trial sessions in Morris water maze task. Furthermore, ginsenosides Rg5 and Rh3 inhibited acetylcho-
linesterase activity in a dose-dependent manner, with IC50 values of 18.4 and 10.2 mM, respectively. The
inhibitory potency of ginsenoside Rh3 is comparable with that of donepezil (IC50 9.9 mM). These
ginsenosides also reversed hippocampal brain-derived neurotrophic factor (BDNF) expression and
cAMP response element-binding protein (CREB) phosphorylation reduced by scopolamine. Of them,
ginsenoside Rh3 more potently protected memory decit.
Conclusions: Ginsenoside Rg5 and its metabolite ginsenoside Rh3 may protect memory decit by
inhibiting AChE activity and increasing BDNF expression and CREB activation.
& 2013 Published by Elsevier Ireland Ltd.

1. Introduction decits by increasing brain cholinergic activity with acetylcholi-


nesterase (AChE) inhibitors such as donepezil. However, number
Alzheimers disease (AD) is a progressive degenerative disease of drugs approved for the use of treatment of patients with
of the brain that is characterized by deterioration of memory and memory impairment is limited due to their side effects such as
cognitive function (Whitehouse et al., 1981; Eikelenboom et al., pain, nausea and vomiting (Cambell et al., 1978; Doody, 1999).
1994). A decrease in cholinergic function in the central nervous Ginseng (the root of Panax ginseng C.A. Meyer, Family Aralia-
system can result in a decline in memory and cognitive function ceae) is frequently used for diabetes, cancer, stress and allergic
with advanced age (Terry and Buccafusco, 2003; Sarter and Bruno, diseases as a traditional Chinese medicine in Asian countries. Heat
2004). Scopolamine, an anti-cholinergic drug, causes memory processes have been adopted for enhancing the pharmacological
impairments in healthy young humans that parallel the memory activities of ginseng, and these processes alter its chemical
impairments seen in non-demented drug-free elderly subjects compositions (Kwon et al., 2001; Bae et al., 2006). In particular,
(Tariot et al., 1996; Araujo et al., 2005). Scopolamine is increas- the heat-processed ginsengs, which have been frequently used in
ingly disruptive with increasing age and declining cognitive Asian countries for cancer, inammation, stress and aging,
status. Many attempts have been made to improve cognitive uniquely contains ginsenoside Rg5 as a main constituent (Fig. 1)
as main constituents (Kim et al., 2000; Kwon et al., 2001; Bae
n
et al., 2006). Ginsenoside Rg5 exhibits anticancer, antidermatitic,
Correspondence to: Department of Pharmaceutical Science, Kyung Hee
University, 1, Hoegi, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
anti-allergic, platelet anti-aggregating, and radical scavenging
Tel.: 82 2 961 0374; fax: 82 2 957 5030. activities (Lee et al., 1997; Shin et al., 2006; Kim et al., 2012).
E-mail address: dhkim@khu.ac.kr (D.-H. Kim). Related to the memory decit-protecting effects of ginsenosides,

0378-8741/$ - see front matter & 2013 Published by Elsevier Ireland Ltd.
http://dx.doi.org/10.1016/j.jep.2012.12.047
E.-J. Kim et al. / Journal of Ethnopharmacology 146 (2013) 294299 295

kit were purchased from Millipore (Billerica, MA, USA). Donepezil


hydrochloride monohydrate (DNZ; purity, 4 99%) was kindly
provided by WhanIn Pharmaceutical Co., Ltd. (Seoul, Korea).
Ginsenosides Rg5 (purity, 4 95%) and Rh3 (purity, 4 95%)
(Fig. 1A) were isolated by our previously reported method
(Shin et al., 2006).

2.2. Animals

Male ICR mice (2830 g) were purchased from Samtako


Biokorea (Seoul, Korea). All animals were fed on standard labora-
tory chow (Samyang Co., Seoul, South Korea), housed in wire
cages at 2472 1C and 50 710% humidity and allowed to water ad
libitum. All experiments were performed in accordance with the
National Institutes of Health and Kyung Hee University guides for
Laboratory Animals Care and Use, and approved by the Commit-
tee for the Care and Use of Laboratory Animals in the Kyung Hee
Medical Center, Kyung Hee University.

2.3. AChE activity assay

AChE activity was measured using Ellmans coupled enzyme


assay (Ellman et al., 1961). The reaction mixture consisted of
125 mL of 3 mM DTNB, 25 mL of 15 mM ATCh, 50 mL of 50 mM
Tris-HCl (pH 8.0), and 25 mL of test agents in a microplate. The
mixture was pre-incubated for 10 min, and then 25 mL AChE
(0.226 U/mL) was added before scanning at 405 nm for 10 min
Fig. 1. The structures of ginsenosides Rg5 and Rh3 (A) and their enhibitory effects in a microplate reader, Model Biotek mQuant MQX200 (Winooski,
on acetylcholinesterase activity (B). Inhibition is expressed as percent inhibition of VT, U.S.A.). Enzyme activity was calculated as a percentage
enzyme activity in comparison with the medium control, and presented as
mean 7 SEM (n 3).
compared to buffer without any inhibitor.

2.4. Passive avoidance task

ginsenoside Rg3 and ginsenoside Rg5/Rk1 mixture (1:1, w/w) Passive avoidance task was performed according to previously
isolated from heat-processed ginseng show memory enhancing described (Yang et al., 2009). The apparatus consists of a two-
effect in scopolamine-treated mice (Bao et al., 2005). Ginsenoside compartment acrylic box in which a lighted compartment
Rg3 isolated from red ginseng, and its metabolite ginsenoside (20  20  20 cm) is connected to a dark compartment
Rh2, as well as ginsenoside Rg1 also protected scopolamine- (20  20  20 cm) by an entrance hole (5  5 cm). Briey, in the
induced memory decit in mice (Yang et al., 2009; Fang et al., acquisition trial a mouse was placed in the lighted chamber, and
2012). However, when ginsenoside Rg5 was incubated with when the mouse entered the dark chamber, a 0.3 mA electrical
human feces, it was metabolized to ginsenoside Rh3 (Bao et al., shock of 2 s durations was delivered through oor grids. Ginseno-
2005; Shin et al., 2006). Nevertheless, the neuroprotective effect side Rg5, Rh3 (5, 10 and 20 mg/kg, p.o.) or donepezil (5 mg/kg,
of ginsenoside Rh3 has not been studied. p.o.) as a positive control were orally given 1 h before treatment
During a screening program for Chinese traditional medicines to with scopolamine. Memory impairment was induced by treat-
protect memory impairment, heat-processed ginseng and its main ment with scopolamine (1 mg/kg, i.p.) and the maze task was
constituent ginsenoside Rg5 potently protected scopolamine- performed 30 min after treatment with scopolamine. A retention
induced memory decit in mice. Therefore, we investigated the trial was performed 24 h after the acquisition trial, and latency
protective effect of ginsenoside Rg5 or its metabolite ginsenoside times to reenter the dark chamber were measured. The success
Rh3 against memory decit in scopolamine-treated mice. rate was then calculated as the number of mice that did not enter
the dark compartment divided by the total number of mice and
expressed as a percentage (%). The maximum entry latency time
2. Materials and methods allowed in the acquisition session and retention session was 180
and 300 s, respectively.
2.1. Materials
2.5. Y-maze task
() Scopolamine hydrobromide, acetylthiocholine (ATCh), 5,50 -
dithiobis-(2-nitrobenzoic acid) (DTNB), acetylcholine esterase Y-maze is a three-arm horizontal maze (40 cm-long and 3 cm-
(AChE, electric eel type VI-S) and dimethylsulfoxide (DMSO) wide with 12 cm-high walls) in which the arms are symmetrically
were purchased from Sigma (St. Louis, MO, USA.). Antibodies disposed at 1201 angles from each other. The maze oor and walls
against brain-derived neurotrophic factor (BDNF), cAMP response were constructed from dark opaque polyvinyl plastic as has been
element-binding protein (CREB), p-CREB and b-actin were pur- described previously (Joh et al., 2012). Mice were initially placed
chased from Santa Cruz Biotechnology (Santa Cruz, L.A. U.S.A.). within one arm, and the sequence (i.e., ACABC, etc) and number of
The protease inhibitor cocktail was purchased from Roche Applied arm entries were recorded manually for each mouse over 8 min
Science (Mannheim, Germany). Immobilon-P nylon membrane was period. An actual alternation was dened as entries into all three
from Millipore Co. (Billerica, MA, U.S.A.). Polyvinylidene diuoride arms on consecutive choices (i.e., ABC, CAB or BAC but not ABA).
(PVDF) membrane and enhanced chemiluminescence (ECL) detection Maze arms were thoroughly cleaned between tasks to remove
296 E.-J. Kim et al. / Journal of Ethnopharmacology 146 (2013) 294299

residual odors. Ginsenoside Rg5, Rh3 (5, 10 and 20 mg/kg, p.o.) or (ANOVA) followed by the StudentNewmanKeuls test for multi-
donepezil (5 mg/kg, p.o.) as a positive control were orally given ple comparisons. Latency in the Morris water maze task was
1 h before treatment with scopolamine. Memory impairment was analyzed using two-way ANOVA followed by Tukeys analysis
induced by treatment with scopolamine (1 mg/kg, i.p.) and the with the day as one variable and treatment as a second. Statistical
maze task was performed 30 min after treatment with scopola- signicance was set at p o0.05, po0.001 and po0.001.
mine. The percentage of alternations was dened according to the
following equation: % alternation[(number of alternations)/
(total arm entries 2)]  100. The number of arm entries served 3. Results
as an indicator of locomotor activity.
In the preliminary experiment, we found that red ginseng, of
2.6. Morris water maze task which main constituent is ginsenoside Rg3, and heat-processed
ginseng, of which main constituent is ginsenoside Rg5, potently
Morris water maze is a circular pool (90 cm in diameter and protect scopolamine-induced memory decit in mice. Of them,
45 cm in height) with a featureless inner surface (Morris, 1989). heat-processed ginseng more potently improved the memory
The circular pool was lled to a depth height of 30 cm with water decit. Therefore, we isolated ginsenoside Rg5 from heat-
(20 71 1C), in which 500 mL of milk was mixed. A white platform processed ginseng and its metabolite ginsenoside Rh3 and mea-
(6 cm in diameter and 29 cm in height) was centered in one of sured their AChE-inhibitory effects. Ginsenosides Rg5 and Rh3
four quadrants of the pool (southwest area) and submerged 1 cm inhibited AChE activity in a dose-dependent manner, with IC50
below the water surface so that it was invisible at water level. The values of 18.4 and 10.2 mM, respectively (Fig. 1B). The inhibitory
rst day of the experiment was dedicated to swimming training potency of ginsenoside Rh3 is comparable with that of donepezil
for 60 s in the absence of the platform. In the following days the (IC50 9.9 mM).
mice were given the training trial sessions of four trials each day Next, we investigated their protective effects against
for four consecutive days. During each trial, the mouses escape scopolamine-induced memory decit in the passive avoidance
latency, measured with a stop watch, were recorded. This para- task. The step-through latency of mice treated with scopolamine
meter was averaged for each session of trials and for each mouse. alone (control group) was signicantly shorter than that of
Once the mouse located the platform, it was permitted to remain vehicle-treated mice (normal group) (po0.001) (Fig. 2A). Treat-
on it for 10 s. If the mouse did not locate the platform within 60 s, ment with ginsenoside Rg5 or Rh3 (5, 10 and 20 mg/kg) increased
it was placed on the platform for 10 s. During this period, the
platform was located in a xed position. The animal was taken to
its home cage and was allowed to dry up under an infrared lamp
after each trial. The time interval between each trial was 30 s. On
the day following the last day of training, mice were given a probe
trial session which consisted of removing the platform from the
pool and allowing the mice to swim for 60 s in search of it. A
record was kept of the swimming time in the pool quadrant
where the platform had previously been placed. Ginsenoside Rg5,
Rh3 (5 and 10 mg/kg, p.o.) or donepezil (5 mg/kg, p.o.) as a
positive control was given 1 h before treatment with scopola-
mine. Memory impairment was induced by treatment with
scopolamine (1 mg/kg, i.p.) and the rst trial session was per-
formed 30 min after treatment with scopolamine.

2.7. Immunoblotting

The hippocampus tissues were isolated from mouse brain


within 30 min h after the passive avoidance test and stored at
80 1C until used in experiment. The hippocampus lysates were
prepared with ice-cold lysis RIPA buffer containing 50 mM Tris
HCl (pH 8.0), 150 mM sodium chloride, 1.0% Igepal CA-630
(NP-40), 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate,
1% phosphatase inhibitor cocktail and a protease inhibitor
cocktail. They were electrophoresed by sodium dodecyl sul-
fate-polyacrylamide gel electrophoresis and transferred to an
Immobilon-P nylon membrane. BDNF, p-CREB, CREB and b-actin
were analyzed using the corresponding antibodies as previously
reported (Hong et al., 2011). Immunodetection was carried out
using an ECL detection kit.

2.8. Statistical analysis


Fig. 2. Effects of ginsenosides Rg5 and Rh3 on scopolamine-induced memory
All values are expressed as means7SEM. For the passive decit in the passive avoidance (A) and Y-maze tasks (B). Ginsenoside Rg5, Rh3 (5,
avoidance task, data was analyzed by a KruskalWallis non- 10 and 20 mg/kg, p.o.) or donepezil (DNZ, 5 mg/kg, p.o.) was orally given 1 h before
parametric ANOVA test. If the results were signicant, each treatment with scopolamine. Memory impairment was induced by treatment with
scopolamine (1 mg/kg, i.p.) and the maze task was performed 30 min after
treatment group was compared using the Tukeys post hoc test. treatment with scopolamine. Values are expressed as mean 7 SEM (n 6).
For the Y-maze task, and the probe trial of the Morris water maze #
Signicantly different from normal group (]]]p o 0.001). nSignicantly different
task, data were analyzed by one-way analysis of variance from scopolamine-treated control group (nnpo 0.01 and nnnp o 0.001).
E.-J. Kim et al. / Journal of Ethnopharmacology 146 (2013) 294299 297

the latency time in a dose-dependent manner. Particularly,


ginsenoside Rh3 at a dose of 10 and 20 mg/kg was comparable
with that of donepezil (5 mg/kg) (p o0.001).
In the Y-maze task, the spontaneous alteration of control
group was signicantly reduced to 51% of the normal group
(p o0.001). Treatment with ginsenosides Rg5 or Rh3 (5, 10 and
20 mg/kg) signicantly reversed the lowered spontaneous altera-
tion induced by scopolamine (Fig. 2B). Ginsenosides Rg5 and Rh3
(20 mg/kg) signicantly increased the scopolamine-induced
reduction in spontaneous alteration to 78% (p o0.01) and 91%
(p o0.001) of normal group, respectively (p o0.01). The protec-
tive effect of ginsenoside Rh3 (5 and 10 mg/kg) against memory
decit in scopolamine-treated mice was more potent in passive
avoidance and Y-maze tasks than that of ginsenoside Rh5
(p o0.05), its potency is comparable with that of donepezil
(5 mg/kg) to 89% of normal group (p o0.001).
We also measured the effects of ginsenosides Rg5 and Rh3
using the Morris water maze task (Fig. 3). The control group
exhibited longer escape latencies throughout the training days
than did the normal group (po0.001). Ginsenoisdes Rg5 and Rh3
(10 mg/kg) signicantly shortened the escape latencies prolonged
by treatment with scopolamine on the last day of training trial
sessions (p o0.05 and p o0.01, respectively). Donepezil (5 mg/kg)
also signicantly reduced escape latencies on the 4th day of training
trial sessions (po0.05). On the day following the nal day of training
trial sessions, swimming times within the platform quadrant for the
control group were signicantly lower than those of the normal
Fig. 3. Effects of ginsenosides Rg5 and Rh3 on the escape latencies in the training
trial sessions (A) and on the swimming time in the probe trial session (B) in the group. However, treatment with ginsenoside Rg5, Rh3 or donepezil
Morris water maze test. Ginsenoside Rg5, Rh3 (5 and 10 mg/kg, p.o.) or donepezil signicantly increased the swimming time shortened by scopola-
(5 mg/kg, p.o.) as a positive control was given 1 h before treatment with scopolamine. mine (po0.05, po0.01 and po0.01, respectively).
Memory impairment was induced by treatment with scopolamine (1 mg/kg, i.p.) and Next, we investigated the effect of ginsenoside Rg5 or Rh3 on
the rst trail session was performed 30 min after treatment scopolamine. The training
trial and the probe trial sessions were performed for 4 days as described in Section 2.
hippocampal CREB phosphorylation and BDNF expression in mice.
Values are expressed as mean7SEM (n 6). ]Signicantly different from normal Treatment with scopolamine alone inhibited CREB phosphoryla-
group (##po0.01 and ###po0.001). nSignicantly different from scopolamine-treated tion and BDNF expression. However, treatment with scopolamine
control group (npo0.05 and nnpo0.01). in the presence of ginsenoside Rg5 or Rh3 inhibited the reduction

Fig. 4. Effects of ginsenosides Rg5 and Rh3 on the expressions of p-CREB, CREB and BDNF in the hippocampi of scopolamine-treated mice. Effects on CREB phosphorylation
and BDNF expression were detected by immunoblotting. Ginsenoside Rg5, Rh3 (5, 10 and 20 mg/kg, p.o.) or donepezil (DNZ, 5 mg/kg, p.o.) was orally given 1 h before
treatment with scopolamine. Memory impairment was induced by treatment with scopolamine (1 mg/kg, i.p.) 1 h after the nal administration of test agents and the
passive avoidance task was performed 30 min after treatment with scopolamine. Then mice were sacriced 30 min after passive avoidance task. Then the mice were
sacriced within 30 min and then the hippocampus tissues were isolated. The levels of BDNF, p-CREB and b-actin were measured by immunoblotting. Values are expressed
as mean 7 SEM (n 4). #Signicantly different from normal group in the level of BDNF, CREB or p-CREB (]P o0.05). nSignicantly different from scopolamine-treated
control group in the level of BDNF, CREB or p-CREB (nPo 0.05).
298 E.-J. Kim et al. / Journal of Ethnopharmacology 146 (2013) 294299

of CREB phosphorylation and BDNF expression by scopolamine Acknowledgements


(Fig. 4). No signicant difference in total CREB and b-actin levels
between mice given scopolamine with and without ginsenoside This work was supported by the Brain Korea 21 Project
Rg5 or Rh3 was found. in 2010.

4. Discussion
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