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Beneficial effects of Panax ginseng for the treatment and prevention of
neurodegenerative diseases: past findings and future directions
Ki Hyun Kim, Dahae Lee, Hye Lim Lee, Chang-Eop Kim, Kiwon Jung, Ki Sung Kang
PII: S1226-8453(16)30269-X
DOI: 10.1016/j.jgr.2017.03.011
Reference: JGR 270
To appear in: Journal of Ginseng Research
Received Date: 16 November 2016
Accepted Date: 15 March 2017
Please cite this article as: Kim KH, Lee D, Lee HL, Kim C-E, Jung K, Kang KS, Beneficial effects of
Panax ginseng for the treatment and prevention of neurodegenerative diseases: past findings and future
directions, Journal of Ginseng Research (2017), doi: 10.1016/j.jgr.2017.03.011.
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Running title: Neuroprotective evidence of ginseng
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Beneficial effects of Panax ginseng for the treatment and prevention of neurodegenerative
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diseases: past findings and future directions
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Ki Hyun Kim
a,☆
, Dahae Lee
a,☆
, Hye Lim Lee
b
, Chang-Eop Kim
b
, Kiwon Jung
c,*
, Ki Sung Kang
b,*
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a
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea
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b
College of Korean Medicine, Gachon University, Seongnam 13120, Korea
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c
Institute of Pharmaceutical Sciences, College of Pharmacy, CHA University, Sungnam 13844,
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Korea
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☆
These authors contributed equally to the work described in this study.
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*
Corresponding authors:
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Tel.:82-31-881-7173; Fax: 82-31-850-9315: E-mail: pharmj@cha.ac.kr (Jung KW)
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Tel.: 82-31-750-5402; Fax: 82-31-750-5416; E-mail: kkang@gahon.ac.kr (Kang KS)
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ABSTRACT
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In recent years, several therapeutical drugs have been rationally designed and synthesized
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based on the novel knowledge gained from investigating the actions of biologically active chemicals
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derived from foods, plants, and medicinal herbs. One of the major advantages of these naturalistic
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chemicals is their ability to interact with multiple targets in the body resulting in a combined
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beneficial effect. Ginseng is a perennial herb (Araliaceae family), a species within the genus Panax,
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and a highly valued and popular medicinal plant. Evidence for the medicinal and health benefits of
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Panax ginseng and its components in preventing neurodegeneration has increased significantly in the
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past decade. The beneficial effects of Panax ginseng on neurodegenerative diseases have been
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primarily attributed to the antioxidative and immunomodulatory activities of its ginsenosides
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components. Mechanistic studies on the neuroprotective effects of ginsenosides revealed that they act
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not only as antioxidants but also as modulators of intracellular neuronal signaling and metabolism,
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cell survival/death genes, and mitochondrial function. The goal of the present paper is to provide a
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brief review of recent knowledge and developments concerning the beneficial effects as well as the
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mechanism of action of Panax ginseng and its components in the treatment and prevention of
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neurodegenerative diseases.
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KEYWORDS: Panax ginseng; Gginsenosides; Antioxidant; Neurodegenerative diseases
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1. Introduction
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1. 1. Classification, structures, and chemical properties of ginseng components
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Ginseng is a perennial herb (Araliaceae family), a species within the genus Panax, and a
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highly valued and popular medicinal plant [1]. The name “Ginseng” originates from the Chinese
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words “Jen Sheng” and means “man-herb” because of the human-like shape of the root or rhizome
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of the plant. The word Panax means “cure all” and describes the traditional belief that ginseng has
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properties that heal all bodily diseases. So far, 14 plants, including 12 species and two infraspecific
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taxa, have been classified under the genus Panax [2]. The three major commercial ginseng sorts are
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the Korean ginseng (Panax ginseng Meyer), the Chinese ginseng (Panax notoginseng (Burk.) F. H.
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Chen), and the American ginseng (Panax quinquefolius L.), and they have been used worldwide as
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herbal medicines for thousands of years [3].
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Korean ginseng (Panax ginseng Meyer) is a well-known medicinal herb cultivated in eastern
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Asian countries [4]. Panax ginseng is native to China and Korea but is now widely cultivated in other
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countries like Japan, Russia, the United States, and Canada. The root of the Korean ginseng has been
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traditionally used to treat various diseases, particularly as an adaptogen since it is suggested to
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normalize body functions and increase physical strength [5,6]. Because fresh ginseng tends to be
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easily degraded at room temperature, it has been traditionally processed into white ginseng through
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air-drying of the root, or into red ginseng through root steaming followed by drying [7-9]. In Korea,
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red ginseng and various processed ginseng products are used popularly as functional foods or
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nutritional supplements. Based on recent studies, red ginseng has been reported to have biological
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benefits while inducing fewer side effects compared to fresh and white ginseng [7,10-14]. In addition,
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Korean red ginseng is known to possess various biological activities including boosting the immune
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system, improving the blood circulation, enhancing memory, anti-fatigue effects, antioxidant effects,
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and positive effects on menopausal disorder [10-14].
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Korean ginseng is known to have various therapeutic benefits mediated by its well studied active
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components [15-21]. Indeed, Korean ginseng is reported to contain various functional constituents,
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including most notably ginseng saponins (also called ginsenosides), polyacetylenes, phenolic
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compounds, sesquiterpenes, alkaloids, polysaccharides, and oligopeptides [22].
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1.2. Ginsenosides
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First attempts to isolate ginsenosides happened in the 1960s [23,24] and most were identified
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from the Panax species. Ginsenosides are biosynthesized from 2,3-oxidosqualene, which leads to the
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formation of cycloartenol, dammarenediol-II, and β-amyrin by the action of three different enzymes.
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Dammarenediol-II and β-amyrin are eventually biotransformed into ginsenosides [2]. Based on their
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chemical structures, ginsenosides are typically divided into two groups: a four-ring dammarane-type
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and a five-ring oleanane-type. Dammarenediol-II is the precursor of the dammarane-type, including
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ginsenosides Rb1, Rb2, Re, and Rg1, which account for a significant portion of ginsenosides found in
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ginseng species. Oleanane-type, on the other hand, are biosynthesized from β-amyrin. However,
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oleanane-type ginsenosides such as Ro are rare and often undetectable
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n Panax ginseng.
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Dammarane-type ginsenosides are further classified into two groups: protopanaxadiols (PPD) and
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protopanaxatriols (PPT). Dammarenediol-II is hydroxylated into PPD, 3β,12β,20-trihydroxydammar-
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24-ene. Consequently, a number of ginsenosides are biosynthesized by the O-glycosylation of PPD,
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which involves the attachment of saccharides to carbon (C)-3 and/or C-20. PPD-type ginsenosides
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include Rb1, Rb2, Rc, Rd, Rg3, Rh2, and Rh3 (Fig. 1). Dammarenediol-II is further hydroxylated
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into PPT, 3β,6α,12β,20-tetrahydroxydammar-24-ene. A variety of ginsenosides are biosynthesized
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by O-glycosylation of PPT, which involves the linkage of saccharides to C-6 and/or C-20. Typically,
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the hydroxyl group at C-3 remains free in PPT-type ginsenosides. Typical PPT-type ginsenosides in
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Panax ginseng are Re, Rf, Rg1, Rg2, and Rh1 (Fig. 1). While most naturally occurring ginsenosides
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are of the (S)-configuration at C-20, some artifactual ginsenosides exist in two epimeric forms at the
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carbon. The pseudoginsenoside F11 belongs to the PPT group although the carbon chain at C-20 is
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replaced by a tetrahydrofuran ring (Fig. 1). Several new ginsenosides such as 25-OH-PPD and 25-
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OH–PPT were recently isolated from ginseng berries [25]. Four malonyl derivatives of ginsenosides
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Rb1, Rb2, Rc and Rd have also been reported [25]. The malonyl derivatives and ginsenosides Ro are
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also called “acidic” ginsenosides while the others are called “neutral” ginsenosides [26].
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Heat treatment induces deglycosylation of ginsenosides. As a result, red ginseng has relatively
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high concentrations of the less polar ginsenosides transformed from fresh ginseng ginsenosides. Red
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ginseng contains ginsenosides Rg2, Rg6, F4, 20(E)-F4, Rh1, Rh4, Rk3, Rg3, Rg5, Rz1, Rk1, Rg9,
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and Rg10, which are converted from the major ginsenosides Rb1, Rb2, Rc, Rd, Rg1, and Re [7].
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Generally, ginsenosides deglycosylation during the process of red ginseng production results in these
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conversions: [Rg1 → Rh1 → (Rh4, Rk3)], [Re →Rg2 → (F4, Rg6)], [Rf → (Rg9, 20Z-Rg9, Rg10)],
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and [(Rb1, Rc, Rb2, Rd) → Rg3 → (Rg5, Rk1, Rz1)] [7]. These results are consistent with the
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experimental evidence that the levels of the less polar ginsenosides such as Rg2, Rh1, and Rg3
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progressively increase, whereas the levels of the natural ginsenosides such as Rg1, Re, Rb1, Rc, and
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Rd progressively decrease during the heat-processed red ginseng production [27].
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1.3. Polyacetylenes
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Polyacetylenes are representative non-saponin components of ginseng. The first polyacetylene
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identified and extracted from Panax ginseng was panaxynol [28]. Since then, many polyacetylenic
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substances, including panaxydol and ginsenoynes A-E, have been identified and extracted from
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Panax ginseng (Fig. 2) [22]. Panaxytriol is a hydrated compound with an epoxy ring derived from
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panaxydol by heat and acid treatment (Fig. 2). These Panax ginseng polyacetylenes are believed to
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possess anti-cancer properties. However, their in vivo efficacy has not been determined due to their
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chemical instability.
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1.4. Phenolic compounds
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Phenolic compounds generally possess antioxidative and anti-cancer biological properties.
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However, phenolic compounds found in ginseng are relatively less investigated. More than 10
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phenolic compounds have previously been reported in fresh and/or processed ginseng (Fig. 2). These
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include salicylic acid, vanillic acid, ascorbic acid, p-coumaric acid, ferulic acid, caffeic acid, gentisic
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acid, p-hydroxybenzoic acid, maltol, cinnamic acid, protocatechuic acid, syringic acid, and quercetin
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[29]. A recent study revealed that chlorogenic acid, gentisic acid, p- and m-coumaric acid, and rutin
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are the major phenolic compounds in 3–6 year old ginseng fruit, leaves, and roots [30]. Korean
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ginseng, which is suggested to provide more health benefits than other ginseng species, usually
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contains more phenolic compounds than Chinese ginseng [31].
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1.5. Sesquiterpenes
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A number of sesquiterpene hydrocarbons as well as oxygenated sesquiterpenes have been
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identified as volatile constituents of the Panax ginseng. More than 15 sesquiterpenes have been
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identified as volatile constituents of the P. ginseng. These include sesquiterpene hydrocarbons like β-
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panasinsene, african-2-ene, β-elemene, calarene, (E)-β-farnesene, α-humulene, α-neoclovene, 2-epi-
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(E)-β-caryophyllene, β-neoclovene, β-selinene, and bicyclogermacrene and oxygenated
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sesquiterpenes like spathulenol, humulene epoxide II, ginsenol, hexadecanoic acid, and falcarinol
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(Fig. 2) [32,33].
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1.6. Alkaloids
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Alkaloids are another non-saponin component of Korean ginseng and include 1-
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carbomethoxy-β-carboline, N
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-formylharman, harman, norharman, perlolyrine, 4-methyl-5-
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thiazoleethanol, and spinacine (Fig. 2) [22]. Recently, a new indole alkaloid, ginsenine, with a seven-
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membered lactam unit, was isolated from Panax ginseng berries [34]. These alkaloids are minor
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components of Panax ginseng and their biological activities are also limited.
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1.7. Polysaccharides
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Korean ginseng contains various polysaccharides. The hypoglycemic glycans, panasans A-E,
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panaxans I-L, panaxans M-P, and panaxans Q-U have been isolated from the roots of Panax ginseng
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[3,35-37]. It has been recognized that the composition of the polysaccharides vary depending on
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strains and/or places of production [35,37]; however, acid hydrolysis, reduction, acetylation followed
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by gas-liquid chromatography of these glycans showed that they consist of diverse combination of
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neutral sugars including rhamnose, mannose, galactose, arabinose, galactose and glucose. In addition,
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the immunomodulating g1lycans, ginsenan PA and ginsenan PB, were identified in the Panax
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ginseng root [38]. These immunomodulating glycans are composed of L-arabinose, D-galactose, L-
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rhamnose, D-galacturonic acid, and D-glucuronic acid, but their exact structure is still unknown.
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Other immunomodulating glycans, such as acidic polysaccharide ginsenan S-IA and ginsenan S-II A,
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have also been identified. On the other hand, ginseng polysaccharides are mainly composed of
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neutral polysaccharides (starch-like glucans) and acidic substances (ginseng pectin) [39]. Ginseng
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pectins have been reported to show a wider range of pharmacological activities compared to neutral
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polysaccharides [40,41], and they are known to be composed of galacturonic acid, galactose, glucose,
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arabinose, rhamnose, glucuronic acid, and mannose [41], however their exact structure is also
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unknown.
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2. Basic and clinical evidences on the beneficial effects of Panax ginseng on neurodegenerative
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diseases
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2.1. Alzheimer's disease
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Alzheimer’s disease is a neurodegenerative disorder that affects the central nervous system
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(CNS) and results in a loss of memory and basic motor functions. It is one of the most common
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causes of mental deterioration in elderly people, and accounts for around 50–60% of the overall cases
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of dementia [42,43]. The major brain areas affected in Alzheimer’s disease include the cerebral
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cortex, locus coeruleus, nucleus basalis of Meynert, and hippocampus [44]. The pathological
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characteristics include extracellular deposits of amyloid β (derived from amyloid precursor protein)
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in senile plaques, intracellular formation of neurofibrillary tangles (containing an abnormally
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phosphorylated form of tau, a microtubule associated protein), and loss of neuronal synapses and
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pyramidal neurons [42,45].
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Since the exact mechanism underlying Alzheimer’s disease is not fully understood, current
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therapies are largely based on a number of theories/hypotheses regarding the pathogenesis of the
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disease. The cholinergic hypothesis of Alzheimer’s disease is based on the reported presynaptic
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deficits observed Alzheimer’s disease affected brains and on the role of the cholinergic system in
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animal and human behavior [42,46]. The most common treatment strategy in Alzheimer’s disease
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involves acetylcholine (ACh), an important neurotransmitter in cognition and memory processes, that
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is known to be decreased in Alzheimer’s disease. Treatment options include the use of ACh
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precursors, ACh-releasing agents, and acetylcholinesterase (AChE) inhibitors [47,48]. Other
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therapeutical interventions, although with fewer proven beneficial effects, also involve antioxidative
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agents that scavenge free radicals and anti-inflammatory agents that treat the amyloid β cascade [48].
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Basic and clinical evidence of the beneficial effects of Panax ginseng on Alzheimer’s disease
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are summarized in Table 1. In males Sprague-Dawley rats, Panax ginseng extracts have been
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reported to exert neuroprotective effects by ameliorating the advanced glycation end product-induced
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memory impairment and mitigating the Alzheimer-like pathophysiological changes through
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downregulation of the RAGE/NF-κB pathway [49]. Moreover, ginsenosides attenuated d-galactose-
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and AlCl
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-induced spatial memory impairment and Alzheimer-like pathophysiological changes in
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male Wistar rats through restoration of amyloid β formation, tau phosphorylation, and the function of
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various neurotransmitters including Glu, Asp, GABA, ACh, DA, Gly and 5-HT [50]. Ginsenosides
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are reported to improve memory loss in C57BL/6J mice with severe hippocampal damage and in
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aged SAMP8 mice (senescence-accelerated mouse) by upregulating plasticity-related proteins such as
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PSD-95, PKCγ and BDNF [51].
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Ginsenoside Rb1 protected against amyloid β-induced neurotoxicity in SH-SY5Y cells by
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regulating the CAP1, CAPZB, TOMM40, and DSTN proteins related to the actin cytoskeleton
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organization and by decreasing the levels of apoptotic proteins like PARP-1 and Bax [52]. The
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expression of BDNF, a key modulator of neuronal survival, activity, and synaptic transmission, and a
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key player in hippocampal-dependent learning and memory, was increased in male ICR mice treated
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with ginsenoside Rh1, resulting in enhanced survival of dentate gyrus cells. Ginsenoside Rh1 was
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also reported to protect newborn neurons from death during the neuronal differentiation process
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[53,54].
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Ginsenoside Rg5 improved cognition and amyloid β deposition in a Wistar rat model by
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increasing IGF-1 and BDNF levels and decreasing TNF-α and IL-1β as well as COX-2 and iNOS
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levels [55]. Ginsenoside Rg5 and Rh3 reversed scopolamine-induced memory deficits in male ICR
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mice by inhibiting AChE activity and increasing BDNF expression and CREB activation [56].
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Ginsenoside Rg1 reduced the mRNA and protein expressions of TLR3, TLR4, NF-κB, and TRAF-6
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and down-regulated the levels of TNF-α and IFN-β in a NG108-15 neuroglial cell line stimulated by
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amyloid β peptide 25–35 (Aβ25–35) [57]. Moreover, ginsenoside Rg1 attenuated okadaic acid-
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induced memory impairment in male Sprague-Dawley rats through the GSK3β/tau signaling pathway
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and the
prevention of amyloid β formation [58].
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The potential efficacy of a heat-processed form of ginseng on cognitive function and
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behavioral symptoms has been recently reported in a clinical study in patients with moderately severe
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Alzheimer’s disease. Indeed, ginseng-treated patients showed a significant improvement on the Mini-
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Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale (ADAS). Moreover,
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patients treated with higher ginseng doses (4.5 g/day) showed further improvements in their ADAS
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cognitive, ADAS non-cognitive, and MMSE scores as early as 12 weeks following treatment. This
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improvement was sustained over a follow-up period of 24 weeks [59]. However, the effects of
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ginseng on Alzheimer’s disease remain inconclusive as reported in a recent meta-analysis study
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including seven main databases for randomized clinical trials [60]. The main limitations of the
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available studies are small sample size, poor methodological qualities, and the absence of placebo
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controls [60].
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2.2. Parkinson’s Disease
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Parkinson's disease is a neurodegenerative disorder commonly affecting the elderly. It is
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characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc)
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as well as other regions of the CNS [61-65]. Dopaminergic degeneration is typically associated with
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the
presence of protein deposits, called Lewy bodies, in the neuronal cytoplasm and thread-like
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proteinaceous inclusions, called Lewy neurites, within neuronal neurites [66-68]. The main clinical
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symptoms include resting tremor, bradykinesia, rigidity, and
postural instability, which result in
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impaired movement and other neurological dysfunctions. The current understanding of the
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pathophysiology of Parkinson's disease largely stemmed from elegant neurochemical investigations
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in the 1950s-60s that demonstrated over 80% reduction in striatal dopamine along with the loss of
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SNpc dopaminergic neurons in most Parkinson's disease patients.
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While the pathogenic mechanism of human Parkinson's disease is still not fully understood,
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oxidative stress and cytotoxicity are thought to play an important role in the degeneration of
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dopaminergic neurons [63,64,69-74]. Mechanistically, it is known that dopamine neurotransmitter is
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chemically labile and its oxidation products, such as dopamine quinones and semi-quinones, are
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highly cytotoxic to neurons in general and dopaminergic neurons in particular [63,64,69]. Elevated
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formation of these neurotoxic intermediates contributes to neuronal damage and degeneration. This
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mechanistic hypothesis is supported by many in vitro as well as in vivo studies.
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Basic and clinical evidence of the beneficial effects of Panax ginseng on Parkinson's disease
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are summarized in Table 2. Extracts of Panax ginseng had neuroprotective effects on 1-methyl-4-
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phenylpyridinium ion (MPP+)-induced apoptosis in SH-SY5Y cells through decreasing the levels of
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apoptotic proteins like Bax, Bcl-2, cytochrome c, and cleaved caspase-3 [75]. In both in vivo
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(C57BL/6J mice) and in vitro (PC12 cells) models of Parkinson's disease, ginsenoside Rg1 exerted
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neuroprotective effects through the Wnt/β-catenin signaling pathway including Wnt-1, β-catenin,
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GSK-3β, and p-GSK-3β. Neuroprotective effects of ginsenoside Rg1 on MPP+-induced apoptosis in
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PC12 cells were also mediated through the decrease in apoptotic proteins levels including Bcl-xL and
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cleaved caspase-3 [76]. Ginsenoside Rd was also shown to exert neuroprotective effects on MPP+-
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induced apoptosis in SH-SY5Y cells by decreasing the levels of apoptotic proteins including P-Akt,
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Bax, and Bcl-2 [77].
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2.3. Brain Ischemia and Stroke
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Stroke is the third leading cause of death in the industrialized world and the leading cause of
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disability [78]. There are two mechanistically distinct modes of cerebral ischemia, namely global and
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focal ischemia. Global ischemia commonly develops after transient cardiac arrest. The typical
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histological picture following global ischemic insults is described by delayed neuronal death sparing
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glial cells. Under normothermic conditions, 10 minutes of global brain ischemia is lethal in humans.
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Focal ischemia occurs after transient or permanent flow reduction in the territory of a cerebral artery
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resulting from embolic or thrombotic vessel occlusion. The typical histological picture following
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focal ischemia is a pan-necrosis that includes all brain cell types [78].
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Basic and clinical evidence of the beneficial effects of Panax ginseng on stroke are
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summarized in Table 3. In male Sprague–Dawley rats, ginsenoside Rd has been reported to protect
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against ischemic cerebral damage by promoting clearance of extracellular glutamate through the up-
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regulation of GLT-1 expression via PI3K/AKT and ERK1/2 pathways [79]. Moreover, administration
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of ginsenoside Rd increased the expression of non-selective cation channels including TRPM7,
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ASIC1a, and ASIC2a [80], and decreased the levels of apoptotic proteins like CytoC, AIF, and
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caspase-3 [81]. Post-ischemic synthesis of two damaging enzymes, COX-2 and iNOS, were also
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significantly decreased by ginsenoside Rd [82]. Ginsenoside Rb1 was also reported to promote
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extracellular glutamate clearance by up-regulating GLT-1 expression via PI3K/AKT and ERK1/2
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pathways in male Sprague-Dawley rats [83].
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Although no prospective clinical trials are available for Panax ginseng, a multi-center,
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double-blinded and randomized controlled clinical trial of 140 Chinese patients demonstrated that a
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low dose of aspirin (50 mg per day) combined with notogiseng capsules (200 mg, three times a day)
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significantly ameliorated neurological deficits and improved daily life activities compared to patients
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treated with aspirin alone [84].
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2.4. Huntington's Disease
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Huntington's disease is a neurodegenerative disorder caused by a CAG repeat expansion in
284
the gene encoding for the huntingtin protein [85,86]. Clinical symptoms of
Huntington's disease
285
comprise adult-onset personality changes, generalized motor dysfunctions, and cognitive decline. The
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peak age of adult-onset Huntington's disease is between 35 and 50 years [85,87]. Commonly reported
287
symptoms include progressive weight loss, alterations in sexual behavior, and disturbances in the
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wake-sleep cycle that occur very early during the course of the disease possibly due to hypothalamic
289
dysfunction [88]. At later disease stages, characteristic symptoms include motor impairments,
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progressive dementia, and gradual impairment of mental processes involved in comprehension,
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reasoning, judgment, and memory [89,90]. Most affected patients eventually succumb to the disease
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due to aspiration pneumonia caused by swallowing difficulties [89].
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Basic evidence of the beneficial effects of Panax ginseng on Parkinson's disease are
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summarized in Table 4. In a cellular model of Huntington's disease with primary medium spiny
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striatal neuronal cultures, ginsenosides Rb1, Rc and Rg5 exerted protective effects on glutamate-
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induced apoptosis and were suggested as a potential treatment choice [91]. In a Sprague-Dawley rat
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model of Huntington's disease, PPT were reported to have neuroprotective effects on 3-nitropropionic
298
acid-induced oxidative stress in males. Oral administration of PPT resulted in marked improvements
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in body weight and locomotor activity. Beneficial effects of PPT were mediated by increasing the
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Nrf2 entry into the nucleus while enhancing the expression of HO-1 and NAD(P)H quinone oxidase 1
301
in the striatum [92].
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3. Concluding Remarks and Future Perspectives
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Oxidative stress and dysregulation of the inflammatory network are being recognized as
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important components in the pathogenesis of neurodegenerative diseases [93-95]. Oxidative stress
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has been linked to neuronal cell death associated with certain neurodegenerative conditions [96,97].
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Because of its high metabolic rate and relatively reduced capacity for cellular regeneration compared
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with other organs, the brain is believed to be particularly susceptible to the damaging effects of
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reactive oxygen species (ROS). An acute oxidative insult to brain tissue can amplify ROS generation,
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increase the accumulation of oxidized biomolecules, and promote oxidative stress [98]. Accumulation
311
of ROS in the brain stimulates the oxidation of lipids [99], protein [100], and DNA [101], which are
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characteristic changes of many neuronal pathologies.
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In the case of Parkinson’s and Alzheimer’s diseases, various indices of ROS damage have
314
been reported within specific brain regions that undergo selective neurodegeneration [102-104].
315
Many researchers in the neurodegenerative field are seeking ways to modulate or emulate the
316
protective effects of key enzymatic components that regulate oxidative stress, with the aim of
317
developing rational drugs or genetic therapies [105,106].
318
A growing number of studies have demonstrated the efficacy of ginseng components
319
extracted from its fruit, roots, and leaves in reducing or blocking neuronal death in various
320
experimental neurodegeneration models [56,60]. Ginseng components, particularly ginsenosides, are
321
capable of protecting neurons both in vitro and in vivo by modulating biological processes including
322
oxidative stress, excitotoxicity, apoptotic neuronal death, and the kinase and ubiquitin-proteasome
323
signaling pathways [20,107]. Indeed, ginsenosides are receiving increasing interest from consumers
324
as well as researchers because of their unique ability to prevent neurodegeneration [108,109].
325
Extensive research over the last 10 years has indicated that components derived from Panax ginseng
326
target ROS and therefore may prevent neurodegenerative diseases [20,110].
327
Evidence for the medicinal and health benefits of Panax ginseng and its components in
328
preventing neurodegenerative diseases is increasing [20,56,111-113]. The current clinical results did
329
not report any serious adverse effects of ginseng [60], but it may alter the blood haemostasis and
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anticoagulation with warfarin [108]. The beneficial effects of ginseng have been attributed to the
331
presence of ginsenosides that are powerful antioxidants and free iron scavengers. Mechanistic studies
332
on the neuroprotective effects of ginsenosides revealed that they act not only as antioxidant metal
333
chelators but also as modulators of intracellular neuronal signaling and metabolism, cell
334
survival/death genes, and mitochondrial function. It has been shown that ginsenosides modulate
335
caspase-dependent and caspase-independent programmed cell death. Indeed, several ginsenosides
336
significantly inhibit the activation of caspase-3, key apoptotic player, and are able to modulate
337
mitogen-activated protein kinases known to play an important role in neuronal apoptosis. However,
338
findings from clinical studies on ginseng for neurodegenerative diseases showed that the effects of
339
ginseng were still inconclusive. The main limitations of the available studies were small sample size,
340
poor methodological qualities, and absence placebo controls. Larger, well-designed clinical studies
341
are a prerequisite to successfully elucidate the effect of ginseng on neurodegenerative diseases.
342
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[106] Ye M, Chung HS, Lee C, Song JH, Shim I, Kim YS, Bae H. Bee venom phospholipase A2
607
ameliorates motor dysfunction and modulates microglia activation in Parkinson's disease
608
alpha-synuclein transgenic mice. Exp Mol Med 2016; 48: e244.
609
[107] Radad K, Moldzio R, Rausch WD. Ginsenosides and their CNS targets. CNS Neurosci Ther
610
2011; 17: 761-768.
611
[108] Nguyen CT, Luong TT, Kim GL, Pyo S, Rhee DK. Korean Red Ginseng inhibits apoptosis in
612
neuroblastoma cells via estrogen receptor β-mediated phosphatidylinositol-3 kinase/Akt
613
signaling. J Ginseng Res 2015; 39: 69-75.
614
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[109] Kim S, Kim MS, Park K, Kim HJ, Jung SW, Nah SY, Han JS, Chung C. Hippocampus-
615
dependent cognitive enhancement induced by systemic gintonin administration. J Ginseng
616
Res 2016; 40: 55-61.
617
[110] Kang KS, Ham J, Kim YJ, Park JH, Cho EJ, Yamabe N. Heat-processed Panax ginseng and
618
diabetic renal damage. J Ginseng Res 2013; 37: 379-388.
619
[111] González-Burgos E, Fernandez-Moriano C, Gómez-Serranillos MP. Potential neuroprotective
620
activity of Ginseng in Parkinson’s disease: a review. J Neuroimmune Pharmacol 2015; 10:
621
14-29.
622
[112] Ong WY, Farooqui T, Koh HL, Farooqui AA, Ling EA. Protective effects of ginseng on
623
neurological disorders. Front Aging Neurosci 2015; 7.
624
[113] Li N, Liu Y, Li W, Zhou L, Li Q, Wang X, He P. A UPLC/MS-based metabolomics
625
investigation of the protective effect of ginsenosides Rg1 and Rg2 in mice with Alzheimer's
626
disease. J Ginseng Res 2016; 40: 9-17.
627
628
629
630
631
632
633
634
635
636
637
638
639
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FIGURE LEGENDS
640
641
FIGURE 1. Structure of selected ginsenosides. (A) protopanaxadiols (PPD). (B) protopanaxatriols
642
(PPT). (C) derivatives of PPD and PPT. (D) other ginsenosides. Glc, β-D-glucose; Rha, α-L-
643
rhamnose; Ara(p), α-L-arabinose(pyranose); Ara(f), α-L-arabinose(furanose); Xyl, β-D-xylose;
644
GlcUA, β-D-glucuronic acid; mal, malonyl; Ac, acetyl.
645
646
FIGURE 2. Structure of selected non-saponin constituents. (A) polyacetylenes. (B) phenolic
647
compounds. (C) sesquiterpenes. (D) alkaloids.
648
649
650
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Table 1. Effects of Panax ginseng and its active ingredient on Alzheimer’s disease.
651
Active
ingredient
Taget
molecules
Cell lines
or animal strain (toxicants)
Effective doses
(treatment time)
References
Rg1 TNF-α, IFN-β,
iNOS, TLR3,
TLR4, NF-κB and
TRAF-6
NG108-15 cells (amyloid β
peptide 25-35, Aβ25-35)
8, 16 and 32
µg/mL (24h)
[57]
Rb1 CAP1, CAPZB,
TOMM40, DSTN,
PARP-1 and Bax
SH-SY5Y cells (amyloid β) 100 µM (24 h)
[52]
Panax
ginseng
extract
RAGE and NF-κB
Male Sprague-Dawley rats
(advanced glycation end
product)
0.25, 0.5 and 1
g/kg/day (30
days)
[49]
Ginseng total
saponin
Aβ, tau, Glu, Asp,
GABA, Ach, DA,
Gly and 5-HT
Male Wistar rats (d-
galactose with AlCl
3
)
2 g/kg/day (30
days)
[50]
Ginseng total
saponin
PSD-95, PKCγ
and BDNF
Female C57BL/6J mice
(aged mice: 12 months old)
0.056 and 0.112%
(w/v) (8 months)
[54]
Ginseng total
saponin
PSD-95, p-
NMDAR1, p-
CaMKII, p-PKA
Cβ, PKCγ, p-
CREB and BDNF
Male SAMP8 and SAMR1
mice (aged mice: 4 months
old)
100 and 200
mg/kg/day (7
months)
[51]
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Rh1 BDNF Male ICR mice (aged mice:
6 months old)
10 mg/kg/day (3
months)
[53]
Rg5 TNF-α, IL-1β,
IGF-1, BDNF,
COX-2, iNOS
and Aβ
Wistar rats (streptozotocin)
10 and 20
mg/kg/day (28
days)
[55]
Rg5 and Rh3 BDNF and CREB Male ICR mice
(scopolamine) 10 mg/kg (1h) [56]
Rg1 GSK3β and tau Male Sprague-Dawley rats
(okadaic acid)
20 mg/kg/day (25
days)
[58]
652
653
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Table 2. Effects of Panax ginseng and its active ingredient on Parkinson’s disease.
654
Active
ingredient
Taget
molecules
Cell lines
or animal strain (toxicants)
Effective doses
(treatment time) References
Panax
ginseng
extract
Bax, Bcl-2, cytochrome c
and cleaved caspase-3
SH-SY5Y cells (1-methyl-
4-phenylpyridinium ion,
MPP
+
)
0.2 mg/mL (60
h) [75]
Rg1 Wnt-1, β-catenin, GSK-
3β and p-GSK-3β,
cleaved caspase-3 and
Bcl-xL
PC12 cells (MPP
+
) 20 µM (24 h) [76]
Rd Bax, Bcl-2 and P-Akt SH-SY5Y cells (MPP
+
) 1 and 10 µM
(72 h) [77]
Rg1 Wnt-1, β-catenin, GSK-
3β and p-GSK-3β
Male C57BL/6J mice (1-
methyl-4-phenyl-1,2,3,6-
tetrahydropyridine, MPTP)
5, 10 and 20
mg/kg/day (15
days)
[76]
655
656
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Table 3. Effects of Panax ginseng and its active ingredient on brain ischemia and stroke.
657
Active
ingredient
Taget
molecules
Cell lines
or animal strain (toxicants)
Effective doses
(treatment time) References
Rb1 ERK1/2 C57BL/6J mice (aged
mice: 12 months old)
5 mg/kg/every 3
days (1 year) [83]
Rd GLT-1, PI3K/AKT
and ERK1/2
Male Sprague–Dawley rats
(middle cerebral artery
occlusion, MCAO)
30 mg/kg (1h) [79]
Rd TRPM-1, -2, -3, -4, -
5, -6, -7, ASIC1a,
ASIC2a, NR1,
NR2A and NR2B
Male Sprague–Dawley rats
(MCAO) 10 mg/kg (15 min) [80]
Rd CytoC, AIF, and
Caspase-3
Male Sprague–Dawley rats
(MCAO) 50 mg/kg (30 min) [81]
Rd COX-2 and iNOS Male Sprague–Dawley rats
(MCAO) 50 mg/kg (30 min) [82]
658
659
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Table 4. Effects of Panax ginseng and its active ingredient on Huntington's disease.
660
Active
ingredient
Taget
molecules
Cell lines
or animal strain (toxicants)
Effective doses
(treatment time) References
Protopanaxtriol
Nrf2, HO-1, NQO1
and PCNA
Male Sprague-Dawley
rats (3-nitropropionic
acid)
20 mg/kg (30 min) [92]
661
662
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664
665
666
667
668
669
670
671
672
673
674
Figure 1.
675
676
R
1
O
OH
H
H
H
R
2
O
H
3
12
20
A
HO
OH
H
H
H
R
2
O
H
3
12
20
B
OR
1
6
20(S)-protopanaxadiol (PPD)
R
1
= R
2
= H
20(S)-protopanaxatriol (PPT)
R
1
= R
2
= H
Ginsenoside Rb1: R
1
= Glc
2
-Glc, R
2
= Glc
6
-Glc
Ginsenoside Rb2: R
1
= Glc
2
-Glc, R
2
= Glc
6
-Ara(p)
Ginsenoside Rc: R
1
= Glc
2
-Glc, R
2
= Glc
6
-Ara(f)
Ginsenoside Rd: R
1
= Glc
2
-Glc, R
2
= Glc
Ginsenoside Rg3: R
1
= Glc
2
-Glc, R
2
= H
Ginsenoside Rh2: R
1
= Glc, R
2
= H
Ginsenoside Rb3: R
1
= Glc
2
-Glc, R
2
= Glc
6
-Xyl
Ginsenoside Ra1: R
1
= Glc
2
-Glc, R
2
= Glc
6
-Ara(p)
4
-Xyl
Ginsenoside Ra2: R
1
= Glc
2
-Glc, R
2
= Glc
6
-Ara(f)
2
-Xyl
Ginsenoside Ra3: R
1
= Glc
2
-Glc, R
2
= Glc
6
-Glc
3
-Xyl
Ginsen oside Rs3: R
1
= Glc
2
-Glc-Ac, R
2
= H
Malonyl-ginsenoside Rb1 : R
1
= Glc
2
-Glc
6
-mal, R
2
= Glc
6
-Glc
Malonyl-ginsenoside Rb2 : R
1
= Glc
2
-Glc
6
-mal, R
2
= Glc
6
-Ara(p)
Malonyl-ginsenoside Rc: R
1
= Glc
2
-Glc
6
-mal, R
2
= Glc
6
-Ara(f)
Malonyl-ginsenoside Rd: R
1
= Glc
2
-Glc
6
-mal, R
2
= Glc
Ginsen oside Rh1: R
1
= Glc, R
2
= H
Ginsen oside Rg1: R
1
= Glc, R
2
= Glc
Ginsen oside Rf: R
1
= Glc
2
-Glc, R
2
= H
Ginsen oside Re: R
1
= Glc
2
-Rha, R
2
= Glc
Ginsen oside F1: R
1
= H, R
2
= Glc
Ginsen oside R1: R
1
= Glc
2
-Xyl, R
2
= Glc
Ginsen oside Rg2: R
1
= Glc
2
-Rha, R
2
= H
R
1
O
OH
H
H
HH
OH
C
R
2
20(R)-ginsenoside Rh1: R
1
= H, R
2
= O-Glc
20(R)-ginsenoside Rg2: R
1
= H, R
2
= O-Glc
2
-Rha
20(R)-ginsenoside Rg3: R
1
= Glc
2
-Glc, R
2
= H
20(R)-ginsenoside Rs3 : R
1
= Glc
2
-Glc
6
-Ac, R
2
= H
R
1
O
OH
H
H
HH
R
2
Ginsen oside F4: R
1
= H, R
2
= O-Glc
2
-Rha
Ginsen oside Rh4: R
1
= H, R
2
= O-Glc
Ginsen oside Rg5: R
1
= Glc
2
-Glc, R
2
= H
Ginsen oside Rs4: R
1
= Glc
2
-Glc
6
-Ac, R
2
= H
R
1
O
OH
H
H
HH
R
2
Ginsen oside Rg6: R
1
= H, R
2
= O-Glc
2
-Rha
Ginsen oside Rk3: R
1
= H, R
2
= O-Glc
Ginsen oside Rk1: R
1
= Glc
2
-Glc, R
2
= H
Ginsen oside Rs5: R
1
= Glc
2
-Glc
6
-Ac, R
2
= H
RO H
H
D
Ginsen oside Ro: R = Glc UA
2
-Glc
COOGlc
HO
OH
H
H
HH
R
OH
OH
25-OH -PPT: R = OH
25-OH -PPD: R = H
HO
OH
H
H
HH
OGlc
2
-Rha
O
HO
20(R)-pseudoginsenoside F11
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677
678
679
680
681
682
683
684
685
686
687
Figure 2.
688
689
Panaxynol
Panaxydol
HO
O
HO
O
HO
Ginseno yne A
OH
Cl
HO
OH
OH
HO
O
HO
O
O
Ginsenoyne B
Ginsenoyne C
Ginsenoyne D
Ginsenoyne E
OH
OH
Panaxytriol
HO
A
OH
O
OH
Salicylic acid
OH
O
HO OCH
3
Vanillic acid
OH
OH
O
m-Coumaric acid
O
OOH
Maltol
B
Beta-panasinsene African-2-ene Beta-elemene Calarene
C
HH
H
H
Beta-selinene
H
HO
H
Spathulenol
O
Humulene epoxide II
OH
H
Ginsenol
N
HN
OCH
3
O
1-Carbomethoxy-beta-carboline
N
HN
Harman
N
S
OH
4-Methyl-5-thiazoleethanol
NH
H
N
N
COOH
Spinacine
D
