J Ginseng Res 39 (2015) 148e154

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Journal of Ginseng Research

journal homepage: http://www.ginsengres.org

Research article

Korean Red Ginseng protects dopaminergic neurons by suppressing

the cleavage of p35 to p25 in a Parkinsons disease mouse model
Ye Lee Jun, Chang-Hwan Bae, Dongsoo Kim, Sungtae Koo, Seungtae Kim*
Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Korea

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 18 June 2014
Received in Revised form
22 September 2014
Accepted 16 October 2014
Available online 1 November 2014

Background: Ginseng is known to have antiapoptotic, anti-inammatory, and antioxidant effects. The
present study investigated a possible role of Korean Red Ginseng (KRG) in suppressing dopaminergic
neuronal cell death and the cleavage of p35 to p25 in the substantia nigra (SN) and striatum (ST) using a
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsons disease mouse model.
Methods: Ten-week-old male C57BL/6 mice were injected intraperitoneally with 30 mg/kg of MPTP at
24-h intervals for 5 d, and then administered KRG (1 mg/kg, 10 mg/kg, or 100 mg/kg) once a day for 12
consecutive days from the rst injection. Pole tests were performed to assess the motor function of the
mice, dopaminergic neuronal survival in the SN and ST was evaluated using tyrosine hydroxylaseimmunohistochemistry, and the expressions of cyclin-dependent kinase 5 (Cdk5), p35, and p25 in the SN
and ST were measured using Western blotting.
Results: MPTP administration caused behavioral impairment, dopaminergic neuronal death, increased
Cdk5 and p25 expression, and decreased p35 expression in the nigrostriatal system of mice, whereas KRG
dose-dependently alleviated these MPTP-induced changes.
Conclusion: These results indicate that KRG can inhibit MPTP-induced dopaminergic neuronal death and
suppress the cleavage of p35 to p25 in the SN and the ST, suggesting a possible role for KRG in the
treatment of Parkinsons disease.
Copyright 2014, The Korean Society of Ginseng, Published by Elsevier. All rights reserved.

Keywords:
Cdk5
1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)
p25
p35
Panax ginseng

1. Introduction
Parkinsons disease (PD) is a typical neurological disorder that
causes dopaminergic neuronal death in the substantia nigra (SN)
resulting in striatal dopamine depletion and leads to impaired
motor functions such as tremor, bradykinesia, rigidity, postural
instability, and akinesia [1]. Although various proteins and gene
mutations have been related to PD, the exact mechanisms are still
unknown. Therefore, many studies have focused on nding therapeutics that suppress neuronal death to prevent the progression of
PD [2].
Cyclin-dependent kinase 5 (Cdk5), a serine/threonine cyclindependent kinase, plays an important role in neuronal functions
including neuronal development, migration, synaptic activity, and
cell survival [3]. In normal conditions, Cdk5/p35, by phosphorylating specic substrates, supports neuronal survival through

activation of the antiapoptotic protein Bcl-2 [4] and inhibition of

sustained extracellular signal-regulated kinase activation [5].
Whereas in insulated conditions, increased intracellular Ca2 activates calpain, which cleaves p35 to p25. P25 induces hyperactivation of Cdk5, which causes abnormal hyperphosphorylation
of cytoskeletal proteins in the cell body and consequently induces
neuronal death [2]. Therefore inhibition of the cleavage p35 to p25
would be therapeutically benecial in neurodegenerative diseases
such as PD.
Panax ginseng (ginseng), a commonly used medical herb in Asian
countries, has been used traditionally to increase vitality, promote
mental stability, and prevent aging [6], and recent studies have
reported that it has antiaging, antioxidant, anti-inammatory and
antiapoptotic effects [7,8]. Ginseng and its extracts also produce
neuroprotective effects in PD models [9]. Water extract of ginseng
suppressed 1-methyl-4-phenylpyridinium ion (MPP)-induced

* Corresponding author. Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Busandaehak-ro 49, Mulgeum-eup, Yangsansi, Gyeongsangnam-do, Korea.
E-mail address: kimst@pusan.ac.kr (S. Kim).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
1226-8453/$ e see front matter Copyright 2014, The Korean Society of Ginseng, Published by Elsevier. All rights reserved.
http://dx.doi.org/10.1016/j.jgr.2014.10.003

Y.L. Jun et al / Ginseng protects dopaminergic neurons

apoptosis in SH-SY5Y cells by elevating the Bax/Bcl-2 ratio and

suppressing the overproduction of reactive oxygen species [10],
ginseng extract G115 alleviated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral impairment and dopaminergic neuronal death in C57/BL6 mice [11], and ginsenoside
Rg1 showed neuroprotective effects by reducing iron levels in
MPP-treated MES23.5 cells [12] and in the SN of MPTP-treated
mice [13]. These results indicate that ginseng has therapeutic efcacies in PD, but its mechanisms are not yet fully understood.
Korean Red Ginseng (KRG) is steamed and dried for lengthy
preservation. Despite the reports concerning the neuroprotective
effects of ginseng, it remains unknown whether KRG retains these
effects because chemical alteration by heat can occur while processing KRG [14]. Moreover, there is little information regarding
whether KRG or ginseng is involved in the cleavage of p35 to p25. In
this study, we investigated whether KRG can alleviate MPTPinduced behavioral impairment and dopaminergic neuronal death
and suppress the cleavage of p35 to p25 in the SN and striatum (ST)
of mice.
2. Materials and methods
2.1. Animals
This study was approved by the Pusan National University
Institutional Animal Care and Use Committee (PNU-2013-0456)
Yangsan, Korea. Male C57BL/6 mice (10 wk old, weighing 20e23 g;
Orientbio Inc., Seongnam, Korea) were housed at room temperature (22  3 C) under a standard 12-h light/dark cycle (lights on at
07:00 h) with unlimited access to food and water. The animals were
handled in accordance with the current guidelines established in
the National Institutes of Health (NIH) Guide for the Care and Use of
Laboratory Animals (NIH Publication No. 85-23, 1985), and all efforts were made to minimize animal suffering and reduce the
number of animals used.
2.2. Group classication
Mice were randomly assigned to four groups: A saline-injected
group (Saline), an MPTP injected group (MPTP), an MPTP-injected
plus 1 mg/kg KRG-treated group (MPTPKRG1), an MPTP-injected
plus 10 mg/kg KRG-treated group (MPTPKRG10) and an MPTPinjected plus 100 mg/kg KRG-treated group (MPTPKRG100).
2.3. MPTP injection and medication
All mice except the Saline group received an intraperitoneal
injection of MPTP-HCl (30 mg/kg of free base; Sigma, St. Louis, MO,
USA) in normal saline at 24-h intervals for ve consecutive days.
The mice in the Saline group received an intraperitoneal injection
of vehicle on the same schedule [15].
The KRG extract used in this experiment was offered by the
Korea Ginseng Corporation (Daejeon, Korea). Briey, KRG was obtained from 6-yr-old roots of Panax ginseng Meyer. First, the ginseng
was steamed at 90e100 C under no pressure for 3 h and was dried
at 50e80 C. The KRG was extracted three times with circulating hot
water at 85e90 C for 8 h. The water content of the pooled extract
was 36% of the total weight, and the content of crude ginsenoside in
the KRG was analyzed by high-performance liquid chromatography
as follows; 6.92 mg/g of Rb1, 2.68 mg/g of Rb2, 3.24 mg/g of Rc,
0.94 mg/g of Rd, 1.40 mg/g of Re, 1.03 mg/g of Rf, 1.12 mg/g of Rg1,
1.23 mg/g of Rg2s, 1.03 mg/g of Rg3r, 1.98 mg/g of Rg3s, 0.89 mg/g of
Rh1, and other minor ginsenosides. The extract was diluted with
sterilized mineral water to appropriate concentrations. Two hours
after the MPTP or saline injection, mice in the KRG-treated groups

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received oral administration of the KRG extract (1 mg/kg, 10 mg/kg,

or 100 mg/kg) once a day for 12 consecutive days, and mice in the
Saline and the MPTP groups were also administered the same
amount of vehicle on the same schedule.
2.4. Behavioral test (pole test)
The pole test was performed by modifying the method established by Abe et al [16]. Mice (n 6 in each group) were positioned
head downwards near the top of a rough-surfaced wood pole
(10 mm in diameter; 50 cm in height), and the time taken to arrive
at the oor was recorded. The test was repeated three times at 30-s
time intervals, and behavioral change was evaluated according to
the average of the three descending times. The test was performed
1 d before MPTP administration (Day 0) and 2 h after feeding KRG
on Day 5 and Day 12.
2.5. Tyrosine hydroxylase-positive immunohistochemistry
Immediately after the last pole test on Day 12, mice (n 6 in
each group) were anesthetized with isourane and perfused with
4% paraformaldehyde (PFA) in 0.1M phosphate buffer. The brain
was quickly removed and postxed in 4% PFA for 48 h, washed in
0.1M phosphate buffer, and immersed in 30% sucrose solution for
storage at 4 C prior to sectioning. Frozen sections (40 mm) were cut
using a Leica CM3050S cryostat (Leica Microsystems, Wetzlar,
Germany).
Immunohistochemistry was performed as described previously
[17,18] on free-oating cryotome-cut sections that encompassed
the entire SN (level between AP 3.08 w 3.28 mm from the
bregma) and the ST (level between AP 0.38 w 0.98 mm from the
bregma). After incubation with 1% H2O2 in 0.05M phosphatebuffered saline (PBS) for 15 min, followed by 0.3% Triton X-100 and
3% normal blocking serum in 0.05M PBS at room temperature for
1 h, the sections were stained overnight at room temperature using
an antityrosine hydroxylase (TH) (1:1,000; Santa Cruz Biotechnology, Santa Cruz, CA, USA) primary antibody for dopaminergic
neurons. The next day, the sections were washed with 0.05M PBS,
incubated with Vectastain Elite ABC reagents (Vector Laboratories
Inc., Burlingame, CA, USA) at room temperature for 1 h, washed
with 0.05M PBS, and then incubated with a diaminobenzidine
(DAB) substrate kit (Vector Laboratories Inc.) for 5 min. After the
DAB reaction, the tissues were rinsed with 0.05M PBS, mounted on
gelatin-coated slides, air-dried, dehydrated, and coverslipped.
Histological pictures were taken using an Axio Scope.A1 microscope (ZEISS, Oberkochen, Germany) and an AxioCam ICc3 camera
(ZEISS). The survival of dopaminergic neurons was evaluated by the
number of TH-positive neuronal cells in the SN. An independent
observer, without knowing the expected results, manually counted
TH-positive neurons bilaterally in ve continuous SN sections, and
the cell counting was conrmed three times to validate the data.
For dopaminergic ber analysis, the mean value of optical density
(OD) in the ST was determined using Image-Pro Plus 6.0 (Media
Cybernetics, Silver Spring, MD, USA).
2.6. Western blot
Immediately after the pole test on Day 5 or Day 12, mice (n 6
in each group) were sacriced with CO2 gas; tissues of SN and ST
were then dissected rapidly and kept at 80 C until use. The tissues
were homogenized with protease inhibitor and RIPA buffer,
centrifuged for 20 min at 4 C at 12,000 rpm, and the supernatants
were separated. Equal amounts of protein (30 mg) from each sample
were separated on 12% SDSepolyacrylamide gels and transferred to
nitrocellulose membranes. The membrane was blocked with 5%

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for 1 h. After washing the membrane, bands were detected using

the enhanced chemiluminescence detection kit (Thermo Scientic,
Rockford, IL, USA). Then, these blots were reprobed with rabbit
monoclonal anti-b-actin antibody (1:1,000; Santa Cruz Biotechnology) as a loading control for all experiments. Quantication of
immunoreactivity corresponding to the total bands was performed
by densitometric analysis using an Image Quant LAS 4000 (Fujilm,
Tokyo, Japan).
2.7. Statistical analysis
All data are expressed as the mean  standard deviation and
analyzed by one-way analysis of variance (ANOVA) with the Neuman-Keuls post hoc test. All statistical testing was performed using
Prism 5 for Windows (GraphPad Software Inc., La Jolla, CA, USA)
and statistical signicance was set at p < 0.05.
Fig. 1. Results of time spent in the pole test. The time elapsed before the mice arrived
on the ground from the 50 cm-high pole was measured. Data are shown as
means  standard deviation. *p < 0.05 compared with the saline group. #p < 0.05 and
##
p < 0.01 compared with the MPTP group. KRG, Korean Red Ginseng; MPTP, 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPTP, MPTP-injected group; MPTPKRG,
MPTP-injected and KRG-treated group; Saline, saline-injected group.

bovine serum albumin in Tris-buffered saline containing 0.1%

Tween-20 for 1 h at room temperature and incubated overnight
with rabbit polyclonal anti-p35 or anti-Cdk5 antibodies (Santa Cruz
Biotechnology) that were diluted 1:1,000 in blocking solution
antibody at 4 C. Then the membrane was washed and incubated
with horseradish peroxidase-conjugated secondary antirabbit
antibody (1:2,000, Santa Cruz Biotechnology) at room temperature

3. Results
3.1. Effect of Korean Red Ginseng on MPTP-induced behavioral
impairment
To conrm the effect of KRG on behavioral impairment by MPTP,
the pole test was performed. Before MPTP injection, there was no
signicant difference in the descending time of all mice. On Day 5,
the descending time of mice in the MPTP group was signicantly
prolonged (39.13  12.89 s; p < 0.05) compared with the time of
those in the Saline group (11.35  4.11 s). All doses of KRG reduced
the descending time dose dependently (32.45  13.68 s,
22.87  11.91 s, and 14.08  8.56 s for the MPTPKRG1,

Fig. 2. Tyrosine hydroxylase (TH)-positive neurons in the nigrostriatal system. (A) Results of TH-immunostaining in the substantia nigra (SN) and the striatum (ST). (B) Number of
TH-positive neurons in the SN and optical densities in the ST. Scale bar, 200 mm. Data are shown as means  standard deviation. *p < 0.05. **p < 0.01 and ***p < 0.001 compared
with the saline group. #p < 0.05 compared with the MPTP group. KRG, Korean Red Ginseng; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPTP, MPTP-injected group;
MPTPKRG, MPTP-injected and KRG-treated group; Saline, saline-injected group.

Y.L. Jun et al / Ginseng protects dopaminergic neurons

151

Fig. 3. Validation of Cdk5, p35, and p25 expressions in the substantia nigra. (A) Changes in the protein expressions on Day 5 (left) and Day 12 (right). (B) Relative values of Cdk5,
p35, and p25 expressions. Data are shown as means  standard deviation (n 6 in each group). *p < 0.05 compared with the saline group. #p < 0.05 and ##p < 0.01 compared with
the MPTP group. Cdk5, cyclin-dependent kinase; KRG, Korean Red Ginseng; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPTP, MPTP-injected group; MPTPKRG, MPTPinjected and KRG-treated group; Saline, saline-injected group.

MPTPKRG10, and MPTPKRG100 groups, respectively). However,

only mice in the MPTPKRG100 group showed a signicant difference (p < 0.05) compared with those in the MPTP group. On
Day 12, mice in the MPTP group still descended signicantly slower
(18.00  5.86 s) compared with the Saline-injected mice
(8.57  1.63 s, p < 0.05). By contrast, KRG-treated mice showed
dose-dependently decreased descending times (13.57  3.56 s,
10.43  0.81 s, 7.54  1.67 s for the MPTPKRG1, MPTPKRG10 and
MPTPKRG100 groups, respectively) compared with mice in the
MPTP group, and 10 mg/kg and 100 mg/kg KRG-treated mice
showed a signicant difference (p < 0.05 and p < 0.01, respectively;
Fig. 1).

3.2. Effect of Korean Red Ginseng on MPTP-induced neuronal loss in

the SN and the ST
To evaluate the neuroprotective effect of KRG on MPTP-induced
neuronal death, the number of TH-positive neurons in the SN was
counted. Compared with the number in mice of the Saline group
(100.00  31.09%), those in mice of the MPTP (40.66  24.54%,
p < 0.001), MPTPKRG1 (46.76  24.82%, p < 0.01), and
MPTPKRG10 (59.54  24.91%, p < 0.05) groups were signicantly
reduced in the SN. However, the number in mice of the
MPTPKRG100 group (79.84  28.77%) was signicantly increased
compared with that in the MPTP group (p < 0.05).

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In addition, the OD of TH-positive bers in the ST was evaluated. After MPTP administration, the OD in the MPTP
(73.27  16.69%) group was signicantly reduced versus that in the
Saline group (100.00  27.58%, p < 0.05). The OD in KRG-treated
mice was dose-dependently increased versus that in mice of the
MPTP group (86.24  16.66%, 92.73  16.73%, 109.20  19.04% in
the MPTPKRG1, MPTPKRG10, MPTPKRG100 groups, respectively) compared with mice in the MPTP group, however, only
100 mg/kg KRG-treated mice showed a signicant difference
(p < 0.05; Fig. 2).

3.3. Changes of Cdk5, p35, and p25 expressions in the substantia

nigra
Cdk5, p35, and p25 expressions in the SN and the ST were
evaluated using Western blot analysis. On Day 5, Cdk5 expression in
the MPTP group was signicantly upregulated versus that in the
Saline group (p < 0.05), and this was signicantly suppressed by
10 mg/kg and 100 mg/kg KRG administration (p < 0.05 and p < 0.01,
respectively). MPTP administration signicantly suppressed p35
expression (p < 0.05) and enhanced p25 overexpression (p < 0.05),

Fig. 4. Validation of Cdk5, p35, and p25 expressions in the striatum. (A) Changes in the protein expressions on Day 5 (left) and Day 12 (right). (B) Relative values of Cdk5, p35, and
p25 expressions. Data are shown as means  standard deviation (n 6 in each group). *p < 0.05 compared with the saline group. #p < 0.05 and ##p < 0.01 compared with the MPTP
group. Cdk5, cyclin-dependent kinase 5; KRG, Korean Red Ginseng; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPTP, MPTP-injected group; MPTPKRG, MPTP-injected
and KRG-treated group; Saline, saline-injected group.

Y.L. Jun et al / Ginseng protects dopaminergic neurons

whereas 100 mg/kg KRG administration signicantly normalized

these changes (p < 0.05). On Day 12, there were no signicant
differences in Cdk5 and p25 expressions among the groups. However, p35 expression in the MPTP group was signicantly suppressed compared with that in the Saline group (p < 0.05), and this
was signicantly alleviated by 100 mg/kg KRG administration
(p < 0.05; Fig. 3).
3.4. Changes of Cdk5, p35, and p25 expressions in the ST
On Day 5, Cdk5 expression in the MPTP group was signicantly
increased versus that in the Saline group (p < 0.05), and this was
signicantly suppressed by 10 mg/kg and 100 mg/kg KRG administration (p < 0.05 and p < 0.01, respectively). MPTP administration
also signicantly suppressed p35 expression (p < 0.05) and
enhanced p25 overexpression (p < 0.05), whereas 100 mg/kg KRG
administration in the MPTP group signicantly normalized these
changes (p < 0.05). On Day 12, there was no signicant difference in
Cdk5 expression among the groups. However, signicant suppression of p35 (p < 0.05) and overexpression of p25 (p < 0.05) were
observed in the MPTP group compared with those in the Saline
group, and these were signicantly normalized by 10 mg/kg
(p < 0.05) and 100 (p < 0.01) mg/kg KRG administration (Fig. 4).

153

There are some limitations in this study. Behavioral impairment

has relevance to dopamine depletion by dopaminergic neuronal
death in MPTP-induced PD animal models [25] as well as in PD
patients [26], and an increase in dopamine efux without restoration of dopamine levels can also improve motor function in
MPTP-treated mice [25]. In this study, the descending time of mice
in the MPTPKRG10 group was restored although the TH-positive
neurons in the SN of the mice were signicantly destroyed on Day
12, which suggests that the behavioral improvement may be due to
an increase in dopamine content or dopamine efux by KRG. Wang
et al [13] reported that ginsenoside Rg1, an active component of
ginseng, upregulated the dopamine content in the ST of MPTPtreated mice. However, more rigorous study is needed to clarify our
supposition.
In conclusion, this study demonstrated that KRG alleviates
MPTP-induced behavioral impairment and dopaminergic neuronal
death in the SN and ST, suggesting that the effects may be mediated
by suppressing MPTP-induced inappropriate hyperactivation and
increase of Cdk5 in the nigrostriatal system, and that the suppression of the cleavage of p35 to p25 by KRG may play an
important role in suppressing Cdk5 hyperactivation. However, the
possibility remains that KRG may mitigate MPTP-induced behavioral impairment via other mechanisms. Despite this limitation, our
ndings suggest important clues for understanding the mechanism
of KRG in PD intervention.

4. Discussion
Conicts of interest
Despite reports concerning the neuroprotective effects of
ginseng, there is little information in studies relating to the action
of KRG in PD. Our study demonstrated that KRG can improve the
behavioral impairment, protect dopaminergic neurons from MPTPinduced neuronal death, and suppress the MPTP-induced overexpression of Cdk5 and cleavage of p35 to p25 in the SN and the ST.
To evaluate the effect of KRG on MPTP-induced behavioral
impairment, the pole test was performed because it is a precise
method that can perceive nigrostriatal dysfunction [19]. In addition,
we conrmed dopaminergic neuronal death in SN and ST because
MPTP induces persistent symptoms of PD by destroying dopaminergic neurons in the nigrostriatal system. We found that KRG
administration dose-dependently alleviated the behavioral
impairment and suppressed dopaminergic neuronal death in the
SN and ST, which suggests that KRG can alleviate MPTP-induced
behavioral impairment by suppressing dopaminergic neuronal
death in the nigrostriatal system.
Although the mechanism by which Cdk5 mediates neuronal cell
death in PD is not fully understood, it has been known that
hyperactivation of Cdk5 plays an important role in pathogenesis of
PD. Cdk5 is phosphorylated by p35 in normal conditions, which
support neuronal survival [20]. However, MPTP injection enhances
p25 levels by degradation of p35, which induces Cdk5 hyperactivity
[21]. The hyperactivation of Cdk5 is also observed in the brains of
PD patients [22], which causes abnormal hyperphosphorylation of
cytoskeletal proteins in the cell body [2] and impairment of the
cellular antioxidative defense [20], and consequently induces
neuronal death [2]. The increase of the Cdk5 level may also
contribute to the death activation process, observed in the nigrostriatal system of MPTP-treated mice [23,24]. In this study, MPTP
administration increased the Cdk5 levels and the cleavage of p35 to
p25 in the SN and the ST; however, KRG suppressed the MPTPinduced changes, which suggests that KRG may alleviate MPTPinduced dopaminergic neuronal death by suppressing the increase
of Cdk5 and the cleavage of p35 to p25 in the nigrostriatal system.
The Cdk5 level in mice of the MPTP group was returned to its basal
level on Day 12, which may represent a natural compensatory
mechanism against MPTP.

The authors declare that no competing nancial interests or

conicts of interest exist. The funders had no role in the study
design, data collection and analysis, and the decision to publish the
manuscript.
Acknowledgments
This work was supported by the National Research Foundation
of Korea grant funded by the Korea government (MSIP) (No. NRF2013R1A1A1005580) and by the Research Fund Program of
Research Institute for Basic Sciences, Pusan National University,
Korea, 2013, Project No. RIBS-PNU-2013-115.
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