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J Tradit Chin Med 2015 June 15; 35(3): 349-354

ISSN 0255-2922
2015 JTCM. All rights reserved.

REVIEW
TOPIC

Protein kinase-based neural signaling pathways for ginsenosides: a

retrospective review

He Wenbin, Zhang Junlong, Chen Naihong

aa
Accepted: March 27, 2014

He Wenbin, Chen Naihong, Department of Basic Medicine,

Shanxi University of Traditional Chinese Medicine (Shanxi
Key Laboratory of Chinese Medicine Encephalopathy, Higher Education Key Laboratory of Brain Science in Shanxi Province), Taiyuan 030024, China; Department of Pharmacology,
Institute of Materia Medica, Chinese Academy of Medical
Sciences & Peking Union Medical College (Key Laboratory of
Bioactive Substances and Resources Utilization, Ministry of
Education), Beijing 100050, China
Zhang Junlong, Department of Basic Medicine, Shanxi University of Traditional Chinese Medicine (Shanxi Key Laboratory of Chinese Medicine Encephalopathy, Higher Education
Key Laboratory of Brain Science in Shanxi Province), Taiyuan
030024, China
Supported by National Natural Science Foundation of China (the Study of Electrochemical Mechanism on the Common Syndrome Factors Concerning Alzheimer's Disease and
Parkinson's Disease, No. 81273629), (Prescription-syndrome
Effect of Dihuang Yinzi Treating Alzheimer Disease and Parkinson Disease Based on the Theory of Syndrome Factor, No.
81273898), and (Study on the Synergistic Mechanism of Polygala Tenuifolia and Acorus Gramineus Improving Memory
Through Modulating Synaptic Plasticity Molecular Network,
No. 81473375); Shanxi Scholarship Council of China (the
Study of Electrochemical Mechanism on the Common Syndrome Factors Concerning Brain Degenerative Diseases, No.
2013-134); Shanxi Provincial Project of International Science
Technology Cooperation (R&D of Screen System for Chinese
Medicines of Anti-Neuronal Apoptosis Based on the Modulation Mechanism of Neuroglial Cells, No. 2010081065)
Correspondence to: Prof. Chen Naihong, Department of
Basic Medicine, Shanxi University of Traditional Chinese
Medicine (Shanxi Key Laboratory of Chinese Medicine Encephalopathy, Higher Education Key Laboratory of Brain Science in Shanxi Province), Taiyuan 030024, China; Department of Pharmacology, Institute of Materia Medica, Chinese
Academy of Medical Sciences & Peking Union Medical College (Key Laboratory of Bioactive Substances and Resources
Utilization, Ministry of Education), Beijing 100050, China.
Chennh@imm.ac.cn; hewb@sxtcm.com
Telephone: +86-10-63165177
JTCM | www. journaltcm. com

Abstract
Ginsenosides are the main active components of
ginseng, which have been reported to target brain
tissues and produce multiple neuroprotective effects. Ginsenosides have been shown to improve
learning ability and memory in normal aged animals, and in an animal model of memory impairment. However, its underlying pharmacological
mechanisms are very complicated, especially with
regard to its effects on the activation of protein kinases in neurons. Previous reports have shown that
some protein kinases may be affected by ginsenosides, including protein kinase C, calcium/calmodulin-dependent protein kinase , c-Jun-N terminal
kinase, and protein tyrosine kinase. In this paper,
protein kinases that may underlie the mechanisms
of ginsenosides will be discussed.
2015 JTCM. All rights reserved.
Key words: Panax; Ginsenosides; Signal transduction; Protein kinase C; Calcium-calmodulin-dependent protein kinase type 2; JNK mitogen-activated
protein kinases; Protein-tyrosine kinases

INTRODUCTION
Ginsenosides are the main active components of Renshen (Radix Ginseng), which have been shown to target
neural tissues and produce multiple pharmacological effects.1 Since ginsenosides and the other components of
ginseng produce different effects, and a single ginsenoside may perform multiple actions in the same tissues,
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their pharmacological mechanisms are complicated.

There is extensive evidence on the beneficial effects of
ginseng and its components, particularly regarding its
effects on the central nerve system (CNS) in vivo and
in vitro.1 It has been demonstrated that ginsenosides
can improve learning and memory in normal aged animals, as well as in animal models of impaired memory.1
Although the neuroprotective mechanism of Ginseng
(Radix Ginseng) on the CNS is unclear, there is evidence to suggest that it may possibly be involved in
synaptic plasticity, the calcium cascade, and neuronal
apoptosis inhibition.1 Among all these mechanisms,
the most important effect of ginsenosides on synaptic
plasticity may involve its role in activating many different protein kinases. Therefore, several protein kinases
involved in the neural mechanism of ginsenosides will
be discussed below.

been suggested that the contributions of presynaptic

and postsynaptic processes to long-term potentiation
maintenance may possibly be determined by the differential distribution of PKC subtypes and substrates in
the hippocampal synaptic zones.5
The modulation of PKC subtypes induced by ginsenoside Rh2 (G-Rh2) during apoptosis has been investigated in human neuroblastoma SK-N-BE2 and rat glioma C6Bu-1 cells.6 G-Rh2-induced apoptosis in both
cell lines has been confirmed by DNA fragmentation,
by strand breaks in situ, and by characteristic morphological changes. During apoptosis in SK-N-BE2 cells,
PKC subtypes , and increase progressively with
prolonged treatment of G-Rh2, whereas PKC increases transiently at 3 and 6 h following treatment, and
PKC is gradually down-regulated 6 h after treatment.
In addition, when maximal apoptosis is achieved PKC
subtype markedly increases at 24 h following treatment. However, during apoptosis in C6Bu-1 cells, no
significant changes were found in PKC subtypes , ,
, , and . These results suggest a possible role of the
PKC subtype during apoptosis induced by G-Rh2 in
SK-N-BE2 cells, but not in C6Bu-1 cells, which raises
the possibility that G-Rh2 may induce apoptosis via
different pathways.
Ginsenoside Rh groups (G-Rh1, G-Rh2, G-Rh3, and
G-Rh4) have been isolated from Renshen (Panax ginseng), but their biochemical and pharmacological effects remain uncertain. The induction of differentiation by the Rh groups and the involvement of PKC in
ginsenoside-induced differentiation have been previously investigated. Differentiation was assessed by
Wright-Giemsa stain and nitroblue tetrazolium reduction. G-Rh2 and G-Rh3 were shown to induce differentiation of HL-60 cells morphologically and functionally into granulocytes, but G-Rh1 and G-Rh4 were
not. G-Rh2 and G-Rh3 cause cell cycle arrest at the
G1/S phase, consistent with their ability to induce differentiation in a decreasing order; retinoic acid >
G-Rh2 > G-Rh3. During differentiation by G-Rh2,
the Ca2 +/phospholipid-dependent PKC activity increases in both the cytosol and total cell extract, and the
Ca2 +/phospholipid-dependent phosphorylation of 38
and 200 kDa endogenous proteins increase; while phosphorylation of 60, 64, 66, and 97 kDa proteins occurs
by a Ca2 +/phospholipid-independent mechanism. Immunoblot analysis revealed that there was no significant change in the cytosolic PKC isoform; however, an
immunoreactive 60-kDa protein band with similar
mass to the PKC catalytic fragment was observed following treatment with G-Rh2. The isoform increased gradually with prolonged treatment. The isoform was not detected in the cytosol of untreated cells,
but a low level of the protein was detected 5 days after
treatment. Therefore, G-Rh2 and G-Rh3 may induce
differentiation of HL-60 cells into granulocytes, and
modulating PKC isoform levels may contribute to differentiation of HL-60 cells by G-Rh2.7

GINSENOSIDES AND THE PKC

SIGNALING PATHWAY
Protein kinase C (PKC) consists of a family of closely
related enzymes that are highly expressed in the CNS.
They respond to the second messengers [i.e., calcium
(Ca2+ ) and diacylglycerol (DAG)] and perform their actions at cell membranes. It has been shown that PKC
activation in the nervous system is associated with the
regulation of neurotransmitter release, ion channels,
cell growth and differentiation, and neural plasticity.2
PKC activation commences with an increase in intracellular Ca2 + concentration, which triggers the association
of PKC isozymes with the cell membrane, whereby
DAG interacts with PKC to stimulate enzyme activity.
PKC activation at the cellular membrane depends on
the duration and magnitude of the DAG signal. The
conversion of the enzyme into an effector-independent
form results in sustained activation after Ca2 + and
DAG signals dissipate, which may also result from the
association of PKC with the cell membrane.3 Researchers have suggested that long-term translocation of PKC
can be induced by the synergistic activation of a
DAG-dependent pathway triggering PKC, and the calcium-dependent pathway triggering calmodulin
(CaM) kinase. Memory lasting several days may be due
to the translocation of PKC to the plasma membrane
by altering ion channel properties; whereas long-term
memory may be due to the translocation of PKC to
the nuclear membrane, which induces a cellular change
by genomic regulation. It has been reported that PKC
plays a critical role in the formation of short, intermediate, and long-term associative memory.4 PKC activation is necessary for the maintenance of a long-term potentiation response, which has been determined by
both correlational evidence (measures of PKC activity,
protein F1 phosphorylation, and phosphatidylinositol
turnover) and by interventional evidence (application
of PKC inhibitors and activators). Additionally, it has
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The involvement of ginsenosides in the signal cascade

that stimulates cell growth has been investigated.8 Ginsenosides Rh1 and Rh2 inhibited cellular proliferation
in NIH 3T3 fibroblasts. Both Rh1 and Rh2 effectively
reduced phospholipase C activity, resulting in a decrease in the intracellular level of DAG, an endogenous
activator of PKC. Thus, intracellular PKC activity can
be reduced after treating cells with Rh1 or Rh2. It was
also found that the phosphorylation of myristoylated
alanine-rich C kinase substrate, one of the major substrates of PKC in cells, can be inhibited by ginsenosides. These results suggest that ginsenoside Rh1 or
Rh2 may exert antiproliferative effects by inhibiting
phospholipase C, which may produce the second messengers necessary for PKC activation.
G-Rh2 has also been shown to induce apoptosis in a variety of cell types.9 In the human hepatoma cell line
SK-HEP-1, G-Rh2-induced apoptosis is accompanied
by mitochondrial release of cytochrome c and activation of caspase-3. In addition, PKC activity is markedly increased in a lipid activator-independent manner,
with kinetics similar to PKC and poly-ADP-ribose
polymerase cleavage during the apoptotic process.
Pre-treatment of the cells with a caspase-3 specific inhibitor effectively prevents G-Rh2-induced proteolytic
activation of PKC . Moreover, the specific PKC inhibitor rottlerin blocks G-Rh2-induced proapoptotic
effects on cells, including the release of cytochrome c,
activation of caspase-3 activity, and proteolytic cleavage
and activation of PKC . These results suggest that
G-Rh2-induced apoptosis is functionally linked to mitochondrial dysfunction.

poxic stimulation reduced the death rate to 12% , and

significantly shortened the recovery time from hypoxia-related symptoms in the surviving animals. Rb1 also
significantly reduced lactate dehydrogenase release
from primary hippocampal neurons which were maintained at low oxygen concentration, indicating increased neuronal survival by Rb1. CaMK activity in
the hippocampal tissues of hypoxia-induced rats decreased to about 50% of that in the control animals.
However, pretreatment with Rb1 significantly elevated
Ca2 +-independent kinase activity when measured 48
h after hypoxic stimulation, suggesting that the calcium-independent CaMK activity may be involved in
the process of ginsenoside Rb1-mediated recovery of
neuronal cells after hypoxic damage.
In a previous study,12 data showed that the local activation of CaMK , which may have important roles in
stabilizing dendrite architecture, appeared as a result of
neural cells' exposure to Rb1. Rb1 at nanomolar concentrations transiently activated CaMK in primary
cultured rat hippocampal cells and NG108-15 cells.
Fluorescence intensity indicating CaMK activation
increased immediately after Rb1 exposure, and then returned to basal level quickly after Rb1 was washed out.
In addition, Rb1-induced CaMK activation was
completely blocked by the CaMK-selective inhibitor
KN-93, suggesting that the kinase activity observed
was CaMK activity.
The authors in that study also found that filopodia formation occurred rapidly in the case of Rb1.12 The
NG108-15 cells, as well as neurons in primary cultured rat hippocampal cells, exposed to Rb1 for 2 min
showed peripheral actin polymerization and microspike formation, which is essentially identical in morphology, size, and kinetic nature to filopodia. In a mature culture, generation of actin filaments was enhanced in almost all the neuritis, as well as in the neuronal cell bodies, whereas actin filaments of non-neuronal cells were unchanged. Filopodia formation was prevented by a CaMK inhibitor (KN-93), but not by a
PKA inhibitor (H-89). Therefore, the activity of CaMKII, but not PKA, is required for the formation of
F-actin and filopodia induced by Rb1. Thus, Rb1 improves synaptic plasticity-associated function and structure through the phosphorylation of CaMK , which
leads to the promotion of memory formation and
learning.

GINSENOSIDES AND THE CAMK

SIGNALING PATHWAY

CaMK is a widely distributed protein kinase, expressed in almost all tissues, especially in the brain.
The expression of the enzyme is precisely regulated in
the brain regions and during brain development. Although much has been learned about its activity-dependent synaptic modifications, which are thought to underlie memory storage, the mechanism by which these
modifications are made remains unclear. Neuronal
CaMK regulates important neuronal functions, including neurotransmitter synthesis, neurotransmitter
release, modulation of ion channel activity, cellular
transport, cell morphology and neurite extension, synaptic plasticity, learning and memory, and gene expression. Studies on this kinase have provided insight into
the molecular basis of learning and memory.10
Ginsenoside Rb1 has been shown to play an important
role in protecting neural cells from damage via CaMK
activity, as indicated by a study demonstrating its
neuroprotective effect on hypoxic injury in young
rats11. About 50% of the animals in that study died following exposure to hypoxic condition three times in
three consecutive days. Rb1 pretreatment prior to hyJTCM | www. journaltcm. com

GINSENOSIDES AND THE JNKS

SIGNALING PATHWAY
JNKs are essential regulators in the physiological and
pathological processes, and are involved in several diseases such as diabetes, atherosclerosis, stroke, and Parkinson's and Alzheimer's diseases. JNKs were first discovered to be involved in control of cell differentiation
and morphogenesis during dorsal closure. Several reports have shown that it becomes activated in response
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ROS followed by inhibition of JNK activity and the

expression of cleaved caspase-3.
During G-Rh2-induced apoptosis of SK-HEP-1 cells,
JNK1 activity is markedly up-regulated, which appears within 10-30 min post-treatment and is associated with SAPK/Erk kinase (SEK1) activity; thereafter, the sustained activation results in photolytic
cleavage of JNK1-related p21(WAF1/CIP1) but not
SEK1. This is supported by evidence showing that
early JNK1 activation effectively blocks the expression
of the dominant negative SEK1 mutant, but does not
alter the sustained activation phase or apoptosis. Additionally, later JNK1 activation can be suppressed by the
expression of p21D112N, an uncleavable mutant of
p21(WAF1/CIP1). Moreover, apoptosis is suppressed
by the stable over-expression of ectopic JNK1 but can
be enhanced by the expression of the dominant negative JNK1 mutant. Therefore, early SEK1-associated
JNK1 activation may act to prolong cell survival
against apoptosis-inducing agents, which serves as an
intervening checkpoint prior to the occurrence of apoptosis.17
During apoptosis activated by paclitaxel- or ginsenoside-Rh2 in SK-HEP-1 cells, JNK1 activity is rapidly
up-regulated and prolonged by specific mechanisms. In
cells expressing the dominant negative SEK1 mutant,
the early phase of JNK1 activation is prevented without inhibiting apoptotic cell death. However, the later
phase of JNK1 activation, which temporally coincides
with caspase-dependent cleavage of JNK1-associated
p21(WAF1/CIP1), is effectively prevented by expression of p21D112N, an uncleavable mutant of p21
(WAF1/CIP1), resulting in the prevention of apoptosis. Co-treatments of cells with rottlerin or with the
pan caspase inhibitor z-VAD-fmk also prevent later
JNK1 activation and apoptotic progression. Thus, the
later phase of JNK1 activation, which is linked to a caspase-dependent mechanism that requires PKC- activity, is associated with the induction of apoptosis, while
early JNK1 activation is not directly involved in apoptotic progression.18
It was reported that the ginseng saponin metabolite,
compound K (20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol, IH901), inhibited the growth of U937
cells through a caspase-dependent apoptosis pathway.19
Furthermore, compound K induces cell cycle arrest at
the G1 phase. Compound K-treated U937 cells
showed increased p21 expression, an inhibitory protein
of the cyclin-cdk complex, followed by the inactivation
of cyclin D and cdk4 protein which act at the early G1
phase, and the inactivation of cyclin E which acts at
the late G1 phase. Furthermore, the activation of JNK
and transcription factor AP-1, which is a downstream
target of JNK, was induced by compound K. These results suggest that compound K causes cell cycle arrest
at the G1 phase by increasing p21 expression and JNK
activation.

to the action of small GTPases. JNK signaling acts on

the transcription factors Jun and Anterior, which eventually control the expression of target genes. Important progress has been made regarding the coordination of JNK and decapentaplegic signaling during
dorsal closure, and the role of JNK in the control of
cell shape and possibly cell polarity via changes in the
cytoskeleton.13
The JNK signaling cascade mediates the neurotoxicity
of
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP). MPTP-induced nigrostriatal dopaminergic
degeneration can be attenuated by CEP-1347/
KT-7515, an inhibitor of JNK activation. JNK activation occurs after the exposure of SHSY5Y cells to the
mitochondrial complex I inhibitor, 1-methyl-4-phenyl- pyridinium (MPP + ), and it can be attenuated by
Rg1. In an in vivo study, it was found that pretreatment with Rg1 or N-acetylcysteine (NAC) attenuated
MPTP-induced phosphorylation of JNK and c-Jun
in the substantia nigra. However, this change was associated with the loss of dopaminergic neurons at different Rg1 doses. These results indicate that the JNK
signaling cascade plays an important role in dopaminergic neuron apoptosis induced by MPTP, and Rg1
can attenuate MPTP-induced activation of the JNK
signaling cascade. Further studies are needed to elucidate whether Rg1 influences the JNK pathway
through mechanisms other than antioxidation.
Recently, the effect of ginsenoside Rg1 on MPTP-induced substantia nigra neuronal lesions has been investigated. C57-BL mice were treated with MPTP to produce a Parkinson's disease-like syndrome. Different
doses of Rg1 (5, 10, and 20 mgkg 1d 1) or NAC
(300 mgkg 1d 1) were given 3 d prior to MPTP
treatment in the pretreatment groups. The results demonstrated that MPTP-induced substantia nigra neuronal damage in C57-BL mice can be attenuated by treatment with different doses of Rg1 or NAC. Rg1 or
NAC also prevented GSH reduction and T-SOD activation in the substantia nigra, and attenuated the phosphorylation of JNK and c-Jun following MPTP treatment. Thus, the antioxidant property of Rg1, along
with the blockade of JNK signaling cascade, may contribute to the neuroprotective effect of ginsenoside Rg1
against MPTP.14,15
The neuroprotective mechanism of Rg1 was also
demonstrated by its potent anti-apoptotic effect on
human SHSY5Y cells.16 The results showed that the
signaling pathway in MPP +-induced apoptosis might
originate from reactive oxygen species (ROS) and be
transmitted to JNK, and then to caspase-3. Both the
NAC-pretreated groups and the Rg1-pretreated
groups displayed inhibition of MPP +-induced apoptosis, as well as a decreased level of ROS, less JNK activity, and lower expression of cleaved caspase-3. The
protection by Rg1 may be mediated by removal of
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GINSENOSIDES AND THE PTK

SIGNALING PATHWAY

topanaxadiol-type ginsenosides and some protopanaxatriol-type saponins also showed significant effects on
PTK activation.
Ginsenoside Rb1 has been shown to exert beneficial effects on memory and learning, possibly through its actions on the cholinergic system.26 In situ hybridization
studies showed that Rb1 may increase the expression of
choline acetyltransferase and the PTK mRNAs in the
basal forebrain, and increase the expression of nerve
growth factor mRNA in the hippocampus. Other neurotrophins (brain-derived neurotrophic factor, neurotrophin-3), genes encoding neuropeptides (preproenkephalin, preprotachykinin), and amyloid protein precursor failed to show this effect.
The specificity of the effects of Rb1 on certain aspects
of the PTK signaling pathway was supported by the
above findings. However, PTKs usually induce two signal cascades, namely, the PLC-PKC and Ras protein
pathways. Therefore, the detailed mechanism involved
downstream of PTK signals needs to be further studied.

Protein tyrosine kinases (PTKs) play a crucial role in

many cell regulatory processes. More than 50 PTK receptors are known to be involved in the regulation of
cell growth, differentiation, chemotaxis, and actin reorganization. Therefore, the functional disturbance of
PTKs may give rise to many diseases. PTKs are enzymes that catalyze the transfer of the -phosphate
group of ATP to the hydroxyl groups of specific tyrosine residues in peptides. Although the phosphotransfer reactions catalyzed by various PTKs are similar in
their basic mechanisms, their biological functions have
a considerable degree of specificity. Most growth factor
receptors contain a cytoplasmic PTK domain, and ligand-mediated receptor dimerization leads to
cross-phosphorylation of tyrosine in the receptor's cytoplasmic domain, initiating the signaling cascade. PTK
receptors can be classified into subfamilies according to
their structural features. PTK receptors can be activated by ligand induced homo- or hetero-dimerization,
leading to receptor autophosphorylation on tyrosine
residues. There are also examples of constitutively active signal transduction molecules that are translocated
to act at the cell membrane by binding to autophosphorylated PTK receptors. In this way, the specific intracellular signal transduction pathways are initiated.
PTK receptors are internalized and deactivated by dephosphorylation, as well as by degradation in the cytoplasm or in the lysosomes after ligand binding and activation.20-22
PTK signaling pathways play important roles in ischemia/reperfusion (I/R) or hypoxia/reoxygenation (H/
R) injuries. Inhibition of PTK activation can protect
brain tissues against I/R- or H/R-induced damage. The
effects of ginsenoside-Rd on H/R-induced PTK activation were examined in an in vitro H/R model in cultured human umbilical vein endothelial cells (HUVEC). The results demonstrated that an increase in
PTK activation was induced after a 2-h reoxygenation,
which was dose-dependently inhibited by ginsenoside-Rd. In the study using cultured HUVEC, H/R
caused injury in gap junctional intercellular communication (GJIC) after a 2-h reoxygenation. The PKC inhibitor calphostin C partly blocked this injury, but the
PTK inhibitor genistein completely inhibited GJIC injury. Ginsenoside-Rd was also shown to be able to protect HUVECs from H/R-induced GJIC injury.23
In another study, 27 individual ginsenosides and aglycones were tested for their effects on PTK activation in
an in vitro H/R model using cultured HUVECs.24,25
The results demonstrated that PTK activation induced
by H/R was significantly inhibited by ginsenoside-Rb1, -Rd, -Ra1 and -Ro, among which ginsenoside-Rb1 was the most active compound and could
completely block PTK activation at a wide range of
concentrations. Except for the crude extracts, most proJTCM | www. journaltcm. com

SUMMARY
A protein kinase is an enzyme that modifies other proteins by chemically adding phosphate groups to them
(i.e. phosphorylation), which usually results in a functional change of the target protein (substrate), causing
a change in enzyme activity, or cellular location, or association with other proteins. Thirty percent of all cellular proteins may be modified by protein kinase activity, and the protein kinases are known to regulate a majority of the cellular pathways, especially those involved
in signal transduction. The human genome contains
about 500 protein kinase genes, constituting about 2%
of all the eukaryotic genes. Because protein kinases
have profound effects on cells, their activities are highly regulated. Protein kinases can be turned on or off by
phosphorylation (sometimes by autophosphorylation),
by binding of activator proteins, inhibitor proteins or
small molecules, or by controlling their location in the
cell relative to their substrates.
Ginsenosides and the other components of ginseng
have the ability to regulate the expression or activation
of protein kinases, including PKC, CaMK , JNKs,
and PTKs. However, the underlying mechanisms of
ginsenosides on these protein kinases and the other protein kinases, such as protein kinase A and MAP kinase,
remain unclear. Research into the regulatory effects of
ginsenosides on protein kinases may help in elucidating the mechanisms of the Chinese herb ginseng.

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June 15, 2015 | Volume 35 | Issue 3 |