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Plant Adaptogens: Natural Medicaments for 21 st Century?

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This review is devoted to adaptogens, plant products capable of producing nonspecific responses in the human body, resulting in increasing the resistance against multiple stressors (physical, chemical or biological) and capable of having a normalizing effect to the human body. Adaptogens must be non-toxic, harmless, capable of not influencing normal body functions more than required, and capable of treating depression, a common neuropsychiatric illness, the importance of which is increasing by number of new patients every year. Number of plants are able to produce natural compounds, which meet the criteria of becoming adaptogens. The most known of them are used in traditional medicine for centuries. This review summarizes data from several most important plant sources of adaptogens, however, it does not cover the field of adaptogens in all its variability. Based on the literature search covering the two past decades, it is focused at several most important plant species and their products, and at their proven or potential pharmacological effects in treating several important diseases.
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zMedicinal Chemistry &Drug Discovery
Plant Adaptogens: Natural Medicaments for 21st Century?
Zu
¨lal O
¨zdemir+,[a, b] Uladzimir Bildziukevich+,[a, b] Martina Wimmerova
´+,[a, b] Anna Macu
˚rkova
´+,[c]
Petra Lovecka
´,*[c] and Zdene
ˇk Wimmer*[a, b]
This review is devoted to adaptogens, plant products capable
of producing nonspecific responses in the human body,
resulting in increasing the resistance against multiple stressors
(physical, chemical or biological) and capable of having a
normalizing effect to the human body. Adaptogens must be
non-toxic, harmless, capable of not influencing normal body
functions more than required, and capable of treating
depression, a common neuropsychiatric illness, the importance
of which is increasing by number of new patients every year.
Number of plants are able to produce natural compounds,
which meet the criteria of becoming adaptogens. The most
known of them are used in traditional medicine for centuries.
This review summarizes data from several most important plant
sources of adaptogens, however, it does not cover the field of
adaptogens in all its variability. Based on the literature search
covering the two past decades, it is focused at several most
important plant species and their products, and at their proven
or potential pharmacological effects in treating several impor-
tant diseases.
1. Introduction
Depression is a common neuropsychiatric illness characterized
by diverse psychosomatic signs and symptoms, namely
decreased interest in delightful stimuli, depressed or irritable
mood, insomnia or hypersomnia, weight loss or weight gain,
psychomotor agitation or retardation, exhaustion or low
energy, feelings of worthlessness or excessive guilt, decreased
ability to think or concentrate and even repeated thoughts of
death or suicide. Depression affects about 10% of the global
population. It goes up globally, and it is expected to become
one of the most serious disease in global burden of diseases by
the year 2030, because it already affects about 40% of people
over 85 years old.[1] Alzheimer’s and Parkinson’s diseases belong
among these types of neuropsychiatric illnesses as well.[2,3] The
currently available antidepressants face challenges, namely
refractoriness, absolute recovery, illness restoring, delay in
action development, sexual dysfunction, changes of body
weight or cardiovascular and gastrointestinal difficulty.[4,5] The
situation supports the investigation of novel antidepressants
with better efficacy and higher safety, because the current
therapy has serious limitations especially in terms of efficacy,
safety, tolerability and therapeutic success. The most recent
literature data revealed numerous preclinical reports support-
ing the role of several types of plant products as natural drugs
for treating depression with justification of involving them in
the antidepressant drug discovery programs.[6] Nature itself
offers different plant products for potential improvement of
human health. Plant products named adaptogens have
displayed beneficial effects on human health. These natural
substances enable the normalization of physiological responses
to various stressors, enhance work performance, and increase
the stress tolerance of the body.[7,8] In this review, attention has
been paid to several most important plant sources of
adaptogens, showing the basic adaptogen structures naturally
produced, and exploring the preclinical profile of plant-based
products (the plant secondary metabolites) as an arising
therapy for depression. Only those plants producing the most
important natural adaptogens are mentioned in this review,
i.e., plants either used for centuries in traditional medicine, or
capable of treating serious neuropsychiatric illnesses with
clearly recognized positive medical effects.
In general, the term adaptogen is used to describe a plant
species or a plant product, capable of producing (a) a
nonspecific response, i. e., increasing the power of resistance
against multiple (physical, chemical or biological) stressors; (b)
having a normalizing effect, irrespective of the nature of the
[a] Z. zdemir,+U. Bildziukevich,+M. Wimmerov,+Prof. Z. Wimmer
University of Chemistry and Technology in Prague, Faculty of Food and
Biochemical Technology
Department of Chemistry of Natural Compounds
Technick 5, 16628 Prague 6, Czech Republic
E-mail: zulalozdemr@gmail.com
vmagius@gmail.com
wimmerom@vscht.cz
wimmerz@vscht.cz
[b] Z. zdemir,+U. Bildziukevich,+M. Wimmerov,+Prof. Z. Wimmer
Institute of Experimental Botany, Academy of Sciences of the Czech Re-
public
Isotope Laboratory
Vden
ˇsk 1083, 14220 Prague 4, Czech Republic
E-mail: zulalozdemr@gmail.com
vmagius@gmail.com
wimmerova@biomed.cas.cz
wimmer@biomed.cas.cz
[c] A. Macu
˚rkov,+Prof. P. Loveck
University of Chemistry and Technology in Prague, Faculty of Food and
Biochemical Technology
Department of Biochemistry and Microbiology
Technick 5, 16628 Prague 6, Czech Republic
E-mail: macurkoa@vscht.cz
loveckap@vscht.cz
[+]The authors Z.., U.B., M.W. and A.M. contributed equally to this article.
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pathology and being non-toxic; and (c) being harmless and not
influencing normal body functions more than required.[9]
2. Ginsenosides
Panax ginseng is probably one of the earliest used plant in
traditional medicine, used over 5 000 years by human popula-
tions. Ginsenosides (Figure 1) belong among the target com-
pounds studied in ginseng plants. They belong to a group of
triterpene saponins with multiple medicinal effects, mainly anti-
aging, anti-oxidative, anti-cancer and adaptogenic.[10] They are
plant secondary metabolites, almost exclusively produced by
Panax plant species, in which they are major pharmacological
ingredients. Nature bounds saponine aglycones to one or more
sugar moieties to improve solubility of the compounds in
aqueous media, and, in other words, to improve their
bioavailability in the mammal bodies. Ginsenosides belong to
two basic groups of triterpenes, (a) dammarane-type and (b)
oleanane-type plant products. Besides these basic groups,
several minor ginsenosides were found in varieties of Panax
plants from China, Japan or Vietnam.
The global market of ginseng has reached about 2 3109
USD, based particularly on two ginseng species, P. ginseng and
P. quinquefolius, consumed in many countries around the world,
especially in China, South Korea, Canada, and the United States,
Zu
¨lal O
¨zdemir was born in Denizli (Babadag),
Turkey. She received her bachelor degree
from the Izmir Institute of Technology in
Turkey, and her master degree from the
University of Chemistry and Technology in
Prague, Czech Republic. She is a PhD student
in the Department of Chemistry of Natural
Compounds, University of Chemistry and
Technology in Prague, and she also works in
the Isotope Laboratory of the Institute of
Experimental Botany, Academy of Sciences of
the Czech Republic.
Uladzimir Bildziukevich was born in Minsk,
Republic of Belarus. He received his master
degree from the Belarusian State University
in Minsk, Republic of Belarus. He is a PhD
student in the Department of Chemistry of
Natural Compounds, University of Chemistry
and Technology in Prague, and he also works
in the Isotope Laboratory of the Institute of
Experimental Botany, Academy of Sciences of
the Czech Republic.
Martina Wimmerova
´was born in Prague,
Czech Republic. She studied High school of
food technology in Prague, Czech Republic.
Currently she works as research assistant in
the Department of Chemistry of Natural
Compounds, University of Chemistry and
Technology in Prague, and in the Isotope
Laboratory of the Institute of Experimental
Botany, Academy of Sciences of the Czech
Republic.
Anna Macu
˚rkova
´was born in Teplice, Czech
Republic. She received Ing. (MSc.) degree
from the University of Chemistry and Tech-
nology Prague in 2011 and now is complet-
ing her Ph.D. at the same university. Her
main interest in research is isolation of
bioactive substances from plants and testing
of antimicrobial, antioxidant, cytotoxic, he-
molytic, anti-inflammatory, anti-diabetic ac-
tivity and activity against microorganisms
growing in biofilms.
Assoc. Prof. Petra Lovecka
´, Ph.D. was born in
Prague, Czech Republic. She received Ph.D.
degree from University of Chemistry and
Technology Prague in 2007 and was pro-
moted to associate professor on 2015 in
Department of Biochemistry and Microbiol-
ogy. Her main interest in research is isolation
of bioactive substances testing of antimicro-
bial activity; study of cytotoxicity of antimi-
crobial peptides; study of toxicity, genotox-
icity and endocrine activity of xenobiotics;
bacterial degradation of microbial diversity
characterization.
Prof. Zdene
ˇk Wimmer, PhD. DSc. was born in
Prague, Czech Republic. He received his PhD.
degree (in 1978), and DSc. Degree (in 2001)
from the Institute of Organic Chemistry and
Biochemistry, Academy of Sciences of the
Czech Republic. He got his associate profes-
sor degree (in 2005), and was appointed as
full professor (in 2009) from the Masaryk
University in Brno, Czech Republic. At
present, he is a full professor in the Depart-
ment of Chemistry of Natural Compounds,
University of Chemistry and Technology in
Prague, Czech Republic. He is the head of the
Isotope Laboratory of the Institute of Exper-
imental Botany, Academy of Sciences of the
Czech Republic. His main research interest is
organic, medicinal and supramolecular
chemistry of natural products.
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and it seems to be the best-selling herbal medicine used mainly
as a tonic, antiaging and adaptogenic agent.[11]
Ginsenosides differ from each other in the number, linkage
position and type of sugar moiety. At present, more than 150
naturally occurring ginsenosides are known from Panax species,
and their symbols (cf. Table 1 attached to Figure 1) are
generally used.[12] The dammarane-type ginsenosides contain
three groups: protopanaxadiol (PPD, 1.1), protopanaxatriol
(PPT, 1.2), and ocotillol (1.3), each with characteristic genuine
aglycone moieties (Figure 1). PPD-group saponins, such as
ginsenosides Ra1, Ra2, Ra3, Rb1, Rb2, Rb3, Rc and Rd;
quinquenoside R1; Rs1 to Rs3, and malonylginsenoside Rb1,
Rb2, Rc, and Rd are glycosides and each contains an aglycone
with a dammarane skeleton, with sugar moieties attached to
the b-OH at C-3 and/or C-20. Ginsenosides Re, Rf, Rg1, Rg2,
Rh1, F1, and notoginsenosides R1 and R2 belong to the PPT-
group of saponins consisting of sugar moieties attached to the
a-OH at C-6 and/or b-OH at C-20 (Figure 1). Ocotillol group of
ginsenosides observed in other Panax species, such as P.
quinquefolius,P. japonicus, and P. vietnamensis have a five-
membered epoxy ring at C-20.[12] The oleanane-group (1.4) has
one identified ginsenoside Ro with minor amounts in P. ginseng
and it contains a pentacyclic structure with aglycone oleanolic
acid.[13] In addition, some other types of ginsenosides, such as
the panaxatriol-type and dammarenediol-type ginsenosides,
have also been identified in Panax species. The anticancer
activity of ginseng saponins negatively correlates with the
number of sugar molecules, number and position of hydroxyl
groups, and stereoselectivity, which is an important finding.[14]
Although triterpenoid saponins have been proven a
defensive role against pathogenic microbes and herbivores,[15]
the general knowledge about the physiological roles of
ginsenosides in plants is still very limited. For example, the
major ginsenosides, secreted in the rhizosphere, display
allelopathic effects on the soil fungal community. The possible
mechanism in blocking pathogen attacks consists in an
interaction of ginsenosides with sterols at the fungal mem-
brane, leading to damage of the membrane integrity.[16] On the
other hand, the antifungal properties of ginsenosides can be
reduced by enzymic degradation by pathogen-formed glyco-
sidases.[16] The degraded ginsenosides may subsequently serve
as allelopathic growth stimulators of more virulent root
pathogens, such as Fusarium spp., and Cylindrocarpon destruc-
tans.[17] Ginsenosides also display activity for controlling insects,
most probably by interfering with the receptor of insect
hormone ecdysteroid, and influencing the life cycle of
herbivorous insects by this way.[18]
Because ginsenosides have become important in the
pharmacology and medicine, investigation of their chemical
structure, medical activities, biosynthetic pathways and aug-
menting their production have received priority attention at
present time. The biosynthetic pathway of ginseng saponins
uses the same enzymes, both common and diversified ones, as
plant use for biosynthesis of triterpenes.[1]
As already stated above, ginseng saponins act as defense
molecules in plant stress and defense system and pathogen
identification, and were biosynthesized for this purpose. When
Figure 1. Structures of the most important ginsenosides
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discovering their beneficial effects on humans, the pharmaco-
logical efficacy of ginsenosides was subsequently based on
their structural features. The hydroxyl groups and sugar
moieties interact with membrane lipids. In the near future, the
medical effects of ginsenosides, such as crosstalk with hormone
signaling pathways, are expected to allow more detailed and
soft structural modifications for achieving improved beneficial
activities and functions of these natural plant products.
It has been found that among diverse ginsenosides in
ginseng extract, ginsenoside Rg3 (1.1-Rg3) significantly re-
duced the production of b-amyloid (Ab) in cells by about 80%,
and in transgenic mice by 31%. Ginsenoside Rg3 reduced Ab
levels by promoting Abdegradation, and by enhancing
neprilysin gene expression, which is a rate-limiting enzyme in
Abdegradation. Furthermore, ginseng reduced learning deficits
in the damaged or aging brains of rodents. Additionally,
ginsenoside Rg1 (1.1-Rg1) reduced the amount of accumulated
Aband improved cognitive performance in a transgenic mouse
model by activating the protein kinase A/cAMP response
element binding protein signaling pathway. Ginsenoside Rg1
also reduced Abproduction by modulating the b-amyloid
precursor protein (APP) process, which was accompanied by
augmenting cognitive function.[1] All those results prove
undoubtedly the advantage of application of adaptogenic
ginsenosides in human medicine.
Another ginsenoside, Re (1.2-Re), protected PC12 cells
against Ab-induced neurotoxicity. In addition, ginsenoside Rb1
(1.1-Rb1) reversed Ab-induced memory loss in rats by reducing
neuroinflammation markers in the hippocampus.
Ginsenoside Rb1 also displayed beneficial effects on spatial
learning by increasing synaptic density in the brain.[1]
P. ginseng extracts were studied in clinical trials for their
biological efficacy. However, the clinical trial results were
complicated by different extraction methods and even different
ginseng species used in the different trials. Clinical studies with
a placebo-controlled, double-blind, balanced, crossover design
have identified both positive and negative effects of gin-
seng.[19,20] These studies have reported significant benefits of
ginseng extracts on cognitive function. Another clinical trial
administered ginseng powder daily for 12 weeks to a group of
patients with Alzheimer’s disease as the treatment group and
to another group of patients with Alzheimer’s disease as a
placebo control group.[21] Cognitive performance was moni-
tored using the Mini-Mental State Examination (MMSE) score
and the Alzheimer’s Disease Assessment Scale (ADAS) during
12 weeks of ginseng treatment. The ginseng group showed
gradually improved MMSE and ADAS scores over the 12 weeks
of treatment, whereas the control group showed gradually
declined MMSE and ADAS scores, suggesting the beneficial
effect of ginseng extracts on cognitive function and memory
enhancement. However, the beneficial effect of ginseng extract
on memory declined gradually to the level of the control group
during a 12 weeks period without treatment.[21] More details on
Alzheimer’s and Parkinson’s diseases can be also found below
in the text, and summarize the most important results so far
achieved with treatment of these serious neurodegenerative
diseases, in which ginsenosides and other adaptogens may be
considered as important factors.
Table 1. Substituents R1to R4used in the structures in Figure 1
Structure Ginsenoside R1R2R3R4
PPD type Ra1 -Glc2-1Glc - -Glc6-1Ara(p)4-1Xyl -
Ra2 -Glc2-1Glc - -Glc6-1Ara(f)2-1Xyl -
Ra3 -Glc2-1Glc - -Glc6-1Glc3-1Xyl -
Rb1 -Glc2-1Glc - -Glc6-1Glc -
Rb2 -Glc2-1Glc - -Glc6-1Ara(p) -
Rb3 -Glc2-1Glc - -Glc6-1Xyl -
Rc -Glc2-1Glc - -Glc6-1Ara(f) -
Rd -Glc2-1Glc - -Glc -
Rg3 -Glc2-1Glc - -H -
Rh2 -Glc - -H -
F2 -Glc - -Glc -
Quinquenoside R1 -Glc2-1Glc6-Ac - -Glc6-1Glc6-Ac -
PPT type Re - -Glc2-1Rha -Glc -
Rf - -Glc2-1Glc -Glc -
Rg1 - -Glc -Glc -
Rg2 - -Glc2-1Rha -H -
Rh1 - -Glc -H -
F1 - -H -Glc -
Notoginsenoside R1 - -Glc2-1Xyl -H -
Notoginsenoside R2 - -Glc2-1Xyl -H -
Ocotilol type Majonoside R2 - -Glc2-1Xyl - -
Pseudogin F11 - -Glc2-1Rha - -
Oleanolic acid type Ro -Glc2-1Glc - - -Glc
RoA -Glc2-1Glc - - -Glc6-1Glc
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3. Saponins
Nature produces a wide variety of plants that have been used
as natural drug for various ailments and diseases since ancient
times. Ginsenosides as specific saponins, produced exclusively
by Panax species, were discussed in the previous part of this
review. Nevertheless, nature has produced numbers of different
saponins, and some of them with proven adaptogenic effect
are mentioned here.
The medical use of licorice (Glycyrrhiza glabra; glycyrrhizin,
2.1) and opium poppy latex (Papaver somniferum; papaverin,
2.2) were already reported from Mesopotamia[22,23] (Figure 2).
Generally, saponins have been named after their foaming ability
upon shaking in aqueous solution and are composed of
lipophilic aglycone (i. e. sapogenins) and hydrophilic glycone
(i.e. glycosides) structures.[6] They have been further classified
into steroidal and triterpenoid saponins, based on structural
differences. Both types are pharmacologically active and
reported to cause anti-inflammatory, antimicrobial (against
bacteria, fungi and viruses) and cytotoxic agents.[24] It is
important that increasing number of preclinical reports have
appeared, exhibiting the potential role of saponins in the
treatment of clinical depression. In this respect, saponins from
Areca catechu nut, Asparagus racemosus,Bupleurum falcatum,P.
ginseng,P. notoginseng,Trichopus zeylanicus and several other
plants, grown in China, demonstrated their antidepressant
effect against rodents using various behavioral patterns.[6]
Several active saponins, namely bacopasides (bacopaside I,
bacopaside II and bacopasaponsin C; 2.3; Figure 2) obtained
from Bacopa monnieri,[25,26] ginsenoside Rb3 (P. notoginseng)[27]
and a triterpenoid saponin isolated from dried root of Polygala
tenuifolia were also described as antidepressant agents in
rodents.[28] However, the literature data show that most of the
experimental work was made on crude extracts and identifica-
tion of the active saponin contents causing antidepressant
action needs to be explored in more details.[28] The similar
disadvantage of present status of knowledge was mentioned in
connection with ginsenosides above. Furthermore, the com-
pounds previously known to act as antidepressant agents,
display diverse chemical structures and, therefore, no clear
correlation has yet been established among them. Similarly,
there is a lack of literature data reporting the differential effects
of steroidal and triterpenoid saponins as antidepressants.
However, the structures of some of the active saponins,
possessing preclinical antidepressant potential, have already
been presented in the literature (Figure 2). Fortunately, during
the last decade an increase in preclinical reports has appeared
demonstrating the antidepressant potential of saponins.
Depression is a very complex disorder differing from other
serious diseases. Several hypotheses have been proposing its
pathogenesis. Literature data show that saponins are capable
of modulating various neurochemical pathways attributed to
the beginning stage of depression. The monoamine hypothesis
of depression stated that the low levels of monoamines
(noradrenaline, dopamine and serotonin) in the brain lead to
depression.[29] Currently, the action of most of the clinically
available antidepressants has been based on this hypothesis.[30]
Saponins have been capable of increasing the levels of
monoamine neurotransmitters in the brain.[31] However, the
mechanisms, i.e., monoamine oxidase inhibition or reuptake
inhibition, causing the aforementioned neurochemical effects,
need to be further investigated. The hypothalamus–pituitary–
adrenal axis (HPA axis) plays an important role in coping with
stress. However, its over-activity has been assigned to the
pathogenesis of depression.[32] The normalization of HPA axis is
essential for treating depression by standard antidepressant,
imipramine.[33] Similarly, saponins have also decreased the
serum corticosterone levels in animals that underwent olfactory
bulbectomy which results in a disruption of the limbic-
hypothalamic axis with the consequence of behavioral, neuro-
chemical, neuroendocrine and neuroimmune changes in
rodents, of which many corresponding or even identical
changes were seen in depressed patients.[34,35] It is still not clear
how bulbectomy in animals relates to depression in humans.
The hypothesis might simply result from a high intensity of
chronic stressor caused by chronic sensory deprivation. This
model showed high predictive validity as it mimicked the slow
starting stage of antidepressant action reported in clinical
studies: there was a response to chronic but not subchronic
antidepressant treatment, and no response to other drugs.
The neurotrophin hypothesis of depression stated that the
lower levels of neurotrophic factors (especially brain-derived
Figure 2. Structures of glycyrrhizin, papaverin and bacopaside
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neurotrophic factor, BDNF) was the basis of the pathogenesis
of depression[36] and was the target for newer antidepres-
sants.[37] Clinically used antidepressants, imipramine and tranyl-
cypromine, were reported to restore their levels.[38] Saponins
increased the expression of BDNF and nerve growth factor
(NGF) in the hippocampus of rat brain.[39–41] The saponins
reversed the corticosterone-induced decrease in hippocampal
BDNF levels by interfering in cAMP response element binding
(CREB) signaling pathway.[42] This reflected that the saponins
possess a potential of affecting synaptic plasticity, a critical
attribute for therapeutics.
The discovery of neurogenesis phenomenon in adult brain
has brought new ideas to the neuroscience.[43] The reduced
neurogenesis has been assigned to the pathogenesis of
depression and has become the target for future antidepres-
sant agents.[44] The clinically available antidepressant fluoxetine
is neurogenic.[45] In turn, the ginsenoside Rg1 augmented
neurogenesis in the hippocampus of mice, thereby supporting
its possible role as herbal antidepressant.[41] In addition, calcium
is important factor in the pathogenesis of mood disorders,[46]
while saponins were reported to inhibit intra-neuronal calcium
dynamics, and, thereby, they prevent excitotoxicity.[47,48] The
neuroprotective role of saponins was also supported by the
reported inhibition of stress-induced apoptosis in mice.[49] This
proven neurogenic and neuroprotective effect of saponins
seemed to be of priority importance in developing possible
ways of treating various other neurodegenerative disorders, as
well as the disorders as Alzheimer’s and Parkinson’s diseases.
Oxidative stress, i. e. an imbalance between oxidants and
antioxidants inside the body, has been linked with the
importance of depressive disorder,[50] and was also observed in
animal models of depression as chronic mild stress. The widely
used antidepressants, as well as saponins, reduce oxidative
stress.[26,34]
Saponins interfere with various neurochemical pathways
involved in the pathogenesis of depression (elevation of
monoamines neurotransmitters, HPA-axis normalization, neuro-
genesis enhancement, reduction in stress-induced apoptosis,
increase in BDNF and NGF levels, alleviation of oxidative stress),
which finding was reported, showing saponins-induced behav-
ioral improvements in animal models of depression.[6] Saponins
possess several unfavorable properties, such as large molecular
weight, hydrophilicity and biliary excretion, resulting in their
low bioavailability and low penetration ability into the central
nervous system.[51] Bioavailability of saponins is based on their
structures, gastrointestinal digestion and plant combination.[52]
Lipid-based formulations generally increase their bioavailabil-
ity.[53] Literature data also revealed that the metabolism of
saponins by intestinal flora result in metabolites that possess
higher ability to cross the membrane barriers of the body.[54] In
this respect, the intestinal metabolite of ginsenosides, i. e. 20(S)-
protopanaxadiol, exhibited antidepressant-like action in ro-
dents.[34] The metabolites of saponins are also important in
further investigations how to characterize their antidepressant
components and how to investigate them as therapeutic
agents. This investigation is of top importance for designing
strategy to improve both, bioavailability and penetration of the
blood–brain barrier.
Literature data revealed high numbers of behavioral and
neurochemical evidences supporting saponins as potential
natural antidepressant agents. Because saponins are natural
plant products, they could be economical source for treating
the depressive disorder. However, the majority of the papers
reported the results achieved with the crude total saponins
extracts and tested in rodents alone. Saponins, active constitu-
ents of many herbal preparations, are already in clinical use and
justified for evaluating for their effectiveness in depressed
subjects through proper clinical trials. The oral bioavailability
can be resolved by understanding their intestinal metabolism
allowing the ability to cross membrane barriers in the body.
There is enough scientific evidence for supporting the idea that
the plant-based saponins and their metabolites can serve as
leading structures and useful models for near future antide-
pressant drug discovery.
Regardless the emergent need for prevention and treat-
ment of neurodegenerative processes, Alzheimer’s disease and
other severe disorders of the central nervous system, therapeu-
tic and prophylactic potential of drugs is not yet sufficient.
Many unfavorable effects of the drugs, potentially capable of
improving cognitive function in patients with Alzheimer’s
disease, proved serious consideration on increasing adaptive
potential and activating self-defense of the body. It is clear that
endogenous defense systems of the brain can limit progression
of Alzheimer’s disease long after the appearance of the disease.
The factors causing activation of the self-defense mechanisms
include administration of natural adaptogens and various types
of adaptations, such as adaptation to dietary restrictions,
promotion of physical and mental activity, and adaptation to
hypoxia. Some data were presented, supporting a hypothesis
that non-drug activation of self-defense of the body can
prevent cognitive decline induced by neurodegenerative
processes in the brain by targeting key points of Alzheimer’s
disease pathogenesis.[6]
One of the pathological signs of Alzheimer’s disease is
senile plaques, and Abis its major constituent, surrounded by
dystrophic neurites and microglia and accumulating outside of
neurons. Abis a product of sequential proteolytic cleavage of
amyloid precursor protein by b-secretase and g-secretase.[55] Ab
accumulates in the brain of patients with Alzheimer’s disease
due to increased production or decreased clearance of Ab. The
overproduction of Abfound in patients with Alzheimer’s
disease who have genetic mutations in the amyloid precursor
protein is correlated with early appearance of the disease
(beginning in the 30s). An increased amount of Ab(soluble
monomeric form) in the brain self-aggregates into Aboligom-
ers (2 – 6 Abpeptides),[56,57] which are more toxic to cells than
the fibrous or monomeric form.[58] Therefore, the excess of toxic
Abis the major factor causing Alzheimer’s disease pathology
(amyloid hypothesis).[59]
Particularly, the levels of Aboligomers correlate with the
severity of cognitive impairment in the patients with Alz-
heimer’s disease and play a critical role in disease pathology.[60]
Aggregated Aboligomers lead to synaptic dysfunction due to
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oxidative stress and inflammation.[61,62] A recent study reported
that Abinduces neuronal death by binding to nerve growth
factor receptors, pan neurotrophin receptor (p75NTR), and
activation of downstream c-Jun N-terminal kinase signal.[63]
Activation of the N-methyl-d-aspartate (NMDA)-type glutamate
receptor (NMDAR) disrupts calcium homeostasis inducing
oxidative stress and synaptic loss. Aboligomers bind and
modulate presynaptic P/Q-type calcium channels at glutami-
nergic and GABA-ergic synapses and possibly impair P/Q
current, which is important for neurotransmission and synaptic
plasticity.[1]
Alzheimer’s disease represents 50–60% of dementia in
patients.[1] The prevalence rate of Alzheimer’s disease positively
correlates with age because it affects 40% of those over
85 years old. Acetylcholinesterase inhibitors, tacrine and done-
pezil, are the major Alzheimer’s disease therapeutics, available
on the market. New therapeutic agents capable of blocking the
disease-inducing mechanisms are, therefore, essential for future
success in treatment this disease. Diverse efforts have been
made so far, to discover agents against Alzheimer’s disease
from natural sources, represented by terpenoids, namely
ginsenosides, gingkolides, and cannabinoids as potential
agents. These compounds exhibit promising in vitro and in vivo
biological activities. Additionally, other terpenoids, including
cornel iridoid glycoside, oleanolic acid, tenuifolin, cryptotanshi-
none, and ursolic acid, have also been under investigation for
their in vitro and in vivo animal studies.[1]
In an effort to control the multifaceted nature of
Alzheimer’s disease progression, a series of multifunctional,
bivalent compounds containing curcumin (3.1), diosgenin (3.2)
and caprospinol (3.3) were designed, developed and subjected
to investigation[64] (Figure 3). Biological characterization of
these compounds for protective activity in MC65 cells was
confirmed. It demonstrated the importance of the structural
features of the compounds for the biological activity.
Diosgenin could serve as an optimal leading moiety,
displaying its non-steroidogenic activity along with other
reported beneficial effects.[65] These compounds were unable to
bind biometals, in contrast to curcumin. The change from more
traditional cholesterol/cholesterylamine to diosgenin could also
influence the overall conformation of the bivalent structures,
and changing the metal chelating properties. In contrary to this
lack of biometal chelation, these compounds retain their
protective activity. This finding further supported the use of
multifunctional, bivalent compounds in a viable strategy of
developing effective Alzheimer’s disease treatments. Based on
these results, development and optimization of the structures
may result in more potent neuroprotective agents.[65]
4. Withanolides and sitoindosides
Withania somnifera is known as the Indian ginseng.[66] It is
classified as a rejuvenation plant, expected to promote physical
and mental health and increases longevity. It has been used to
treat almost all disorders that affect the human health in
traditional medicine, because of displaying wide range of
biological activity. In this review, the pharmacological basis of
the use of W. somnifera in various central nervous system (CNS)
disorders is mentioned, particularly its indication in epilepsy,
stress and neurodegenerative diseases (Parkinson’s and Alz-
heimer’s disorders, tardive dyskinesia or cerebral ischemia), and
in the management of drug reliance.
Many pharmacological studies were done to describe
multiple biological properties of W. somnifera.[67] These studies
showed that the plant preparation has an effect on central
nervous system, and displays anti-inflammatory, anticancer,
antistress, immunomodulatory, adaptogenic, endocrine and
cardiovascular activity.[66] W. somnifera modulated the oxidative
stress markers of the body. It was described that the root
extract significantly reduced the lipid peroxidation and in-
creased the superoxide dismutase (SOD) and catalase activity,
thus possessing a free radical scavenging property.[67] The active
constituents of plant (withanone (4.1), withaferin A (4.2) and
sitoindosides VII–X (4.6); Figure 4) were reported to have an
antioxidant activity that may contribute at least in part to the
reported antistress, immunomodulatory, cognition facilitating,
anti-inflammatory and antiaging properties.[67] Besides, W.
somnifera preparations were reported to modulate the GABA-
ergic or cholinergic neurotransmission, accounting for various
CNS related disorders.[68] W. somnifera has also been used as an
adaptogen, antistress, antiepileptic and protective agent in
neurodegenerative and neuropsychiatric disorders.[68]
The major biochemical constituents of W. somnifera are
steroidal alkaloids and lactones, a class of constituents together
known as withanolides (steroidal lactones with ergostane
skeleton; 4.24.5; Figure 4). The withanolides are structurally
analogous to ginsenosides of P. ginseng. The withanolides have
a C28 steroidal skeleton with a C9 side chain, bearing a six-
membered lactone ring. So far, 12 alkaloids, 35 withanoloids
and several sitoindosides have been isolated and their
structures have been elucidated[67] (for the key structures cf.
Figure 4). The various alkaloids include withanine, somniferine,
Figure 3. Structures of curcumin, diosgenin and caprospinol
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somnine, somniferinine, withananine, pseudo-withanine, tro-
pine, pseudo-tropine, choline, cuscohygrine, isopelletierine,
anaferine and anahydrine. Two acylated steryl glucosides,
sitoindoside VII and sitoindoside VIII, and two glycowithano-
loids, sitoindoside IX or sitoindoside X, were isolated from the
roots.
Withaferin A has recently been reported as an inhibitor of
angiogenesis, and, therefore, a protective agent against certain
types of cancer.[69] Two glycowithanoloids (sitoindoside IX or
sitoindoside X) possessed antistress activity and augmented
learning ability and memory retention in both young and old
rats.[66] Additional steroidal lactones of the withanolide-type
have been isolated from the fruits of W. somnifera.[70] The
diverse active constituents present in different parts of the
plant seem to be responsible for the multiple medicinal
properties of W. somnifera.
W. somnifera has been declared to be a safe drug. In one of
the studies published,[70] a 2% suspension of total alkaloids
from the roots of W. somnifera prepared in 10% glycol using
2% of gum acacia as suspending agent was used to determine
acute toxicity. The extract had no strong effect on central
nervous system or autonomic nervous system in toxicity
studies. However, it affected spontaneous motor activity in still
higher doses. In another long-term study, W. somnifera was
administered to rats in their daily drinking water for 8 months,
while their body weight, general toxicity, well-being, number of
pregnancies, litter size, and progeny weight were monitored.
The liver, spleen, lungs, kidneys, thymus, adrenals, and stomach
were examined histopathologically and were normal. The rats
treated with W. somnifera showed weight increase in compar-
ison with the control group. The group receiving W. somnifera
was healthier in comparison with the control group (adapto-
genic effect). Subacute toxicity studies with W. somnifera
resulted in a proof of no toxicity patterns.[66] The extract of W.
somnifera leaves possessed antigenotoxic potential.[71,72] These
extensive toxicological studies demonstrated that the plant is
nontoxic in wide range of reasonable doses and it can be
assumed that the doses, in which its preparations are indicated
in humans, are expected to be very safe.[66]
W. somnifera preparations have potential therapeutic role in
almost every CNS related disorders. W. somnifera modulated
GABA-ergic, cholinergic and oxidative systems. The phytochem-
icals present in W. somnifera are responsible for overcoming
the excitotoxicity and oxidative damage.[72] The plant extract
inhibited the hydrogen peroxide-induced cytotoxicity and DNA
damage in human non-immortalized fibroblasts.[72] The active
components of W. somnifera, sitoindosides VII–X and withaferin
A (glycowithanolides), were extensively tested for antioxidant
activity against the major free-radical scavenging enzymes,
superoxide dismutase, catalase, and glutathione peroxidase
levels of frontal cortex and striatum of the rat brain. Active
glycowithanolides of W. somnifera administered once daily for
21 days caused an increase in concentration of all enzymes.[66]
Recently, withanolides were proven to display calcium antago-
nistic properties.[73] Withanolides inhibited acetylcholinesterase
(AChE) and butyrylcholinesterase (BChE) activities in a concen-
tration-dependent fashion with EC50 values ranging between
29.0 and 85.2 mM for AChE and BChE, respectively. Therefore, it
was proposed that the cholinesterase inhibitory potential of
withanolides, along with calcium antagonistic ability could
indicate withanolides as possible drugs for further investigation
to treat Alzheimer’s disease and associated problems and
related diseases.[73] Recent studies have also shown the anti-
Parkinson’s disease activity of W. somnifera, and that finding
indicated their possible ability to modulate dopaminergic
system in the brain.[74]
It has been found that immobilization stress for 14 h caused
85% degeneration of the cells (dark cells and pyknotic cells) in
the CA(2) and CA(3) subareas of hippocampal region as
compared to control rats. Control rats were maintained in
completely, non-stressed conditions. A pre-treatment with root
extract of W. somnifera significantly reduced (80%) the number
of degenerating cells in both areas, demonstrating the neuro-
protective effects of plant preparations.[75] Another polyherbal
drug, consisting of standardized extract of W. somnifera,
Figure 4. Structures of withanolides and sitoindosides
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Oscimum sanctum,Asparagus racemosus and Emblica officinalis,
is widely prescribed as antistress formulation in the Indian
national medicine.[76]
The protective effect of W. somnifera has been undoubtedly
proven. A multicomponent herbal drug, which contained W.
somnifera as one of the main components, exhibited protective
effect against haloperidol- or reserpine-induced catalepsy in
mice.[77] The anti-Parkinson’s disease effects of W. somnifera
extract were evaluated using 6-hydroxy dopamine (6-OHDA)-
induced effect in rats.[74] W. somnifera extract turned out all
parameters of oxidative stress (lipid peroxidation, reduced
glutathione content, activities of glutathione-S-transferase,
glutathione reductase, glutathione peroxidase, superoxide
dismutase and catalase) and dopaminergic D2 dopamine
receptor binding, and tyrosine hydroxylase expression signifi-
cantly in a dose-dependent manner, as compared to 6-OHDA
treated rats.[74] In human medicine, W. somnifera was effective
in patients having Parkinson’s disease.[78]
Another neurodegenerative disease, tardive dyskinesia, is a
syndrome characterized by repetitive involuntary movements,
usually involving the mouth, face and tongue and sometimes
limb and trunk musculature. The dopaminergic receptors
supersensitivity and the oxidative stress are pathophysiological
reasons in this motoric dysfunction. Despite the importance of
appearance of side effects due to neuroleptics application,
these drugs remain the most effective drugs in treatment of
schizophrenia and for management of behavioral disorders in
developmentally disabled patients.[79] The studies demonstrated
that chronic administration of the root extract of W. somnifera
for 4 weeks in reserpine treated animals reduced the appear-
ance of vacuous chewing movements and tongue protrusion,
which are the main behavioral symptoms of tardive dyskinesia.
W. somnifera root extract also eliminated reserpine-induced
retention deficit. The root extract dose dependently reduced
the lipid peroxidation and restored the decreased glutathione
levels according to the checked biochemical parameters. It also
reduced significantly the reserpine-induced decrease in brain
superoxide dismutase (SOD) and catalase levels in rats.[80]
Therefore, W. somnifera has represented a powerful tool in
successful treatment of neurodegenerative diseases in general.
W. somnifera has been extensively used for reducing stress
in the patients, and, it has been capable of acting as an
antistress drug. The effect of W. somnifera was observed in a
mouse model with chronic fatigue syndrome, which is an
illness characterized by persistent exhaustion. The authors[81]
described that mice were made tired by forcing them to swim
for 6-minute session on each day during 15 days. W. somnifera
and other antioxidants were administered daily before subject-
ing the animals to stress. Mean immobility period was
calculated on every day and compared with control animals. W.
somnifera produced a significant decrease of immobility time,
when compared with control group of stressed animals, and,
therefore, its tested extract displayed significant antistress
activity.[81]
The antistress activity was explained by the antioxidant
property of W. somnifera root extract. Chronic exhaustion
induced by forced swimming for 15 days induced a significant
increase of brain MDA (3,4-methylenedioxyamphetamine) levels
in comparison with non-treated mice, which indicated the
oxidation of proteins, DNA and lipids. As published,[66,81]
administration of W. somnifera in a dose of 100 mg/kg
significantly inverted the extent of lipid peroxidation. Antistress
property of W. somnifera in cold-water swim stress categorized
biologically active components of W. somnifera as potent
antistress and adaptogenic agent.[66]
The antioxidant activity of W. somnifera glycowithanolides
was also evaluated in chronic footshock-induced stress. The
stress procedure, given once daily for 21 days, induced an
increase in activity of superoxide dismutase and lipid perox-
idation, with concomitant decrease of activities of catalase and
glutathione peroxidase in both brain areas. Application of W.
somnifera extract in the doses of 10, 20 and 50 mg/kg orally 1 h
prior to the stress procedure for 21 days produced a dose-
related reversal of the stress effects.[82] The effect of W.
somnifera root extract was also seen in stress-induced neuronal
degeneration in rats. The ultrastructural study of neuronal cell
bodies in hippocampal sublayer was studied, and the inves-
tigation suggested the cytoprotective effect of W. somnifera in
improving degenerating characteristics in rat brain.[83]
Two glycosides, sitoindoside VII and sitoindoside VIII
isolated from the roots of W. somnifera, showed significant
antistress activity when tested in diverse spectrum of stress-
induced patterns. Similarly, sitoindoside IX and sitoindoside X
produced significant antistress activity in mice and rats and
augmented learning acquisition and memory retention in both
young and old rats. Nowadays, W. somnifera has been
successfully supplemented in different therapeutic formulations
for treating stress and related disorders.[84] Recently, an enzymic
procedure for the synthesis of sitoindosides was published by
our team.[85]
Withanoloids isolated from the W. somnifera inhibit acetyl-
cholinesterase and butylcholinesterase in a dose-dependent
manner. The cholinesterase inhibitory potential along with
calcium antagonistic ability has also made W. somnifera
possible drug for treating Alzheimer’s disease and associated
diseases.[73] Sitoindosides VII–X, and withaferin A, isolated from
aqueous methanol extract of the roots of W. somnifera is used
in Indian medicine to decrease cerebral functional deficits,
including amnesia, in geriatric patients. The effect of these
active products from W. somnifera was also investigated for
putative nootropic activity in an experimentally validated
Alzheimer’s disease model. The syndrome was induced by an
injury of the nucleus magnocellularis in rats by ibotenic acid. W.
somnifera significantly inversed both, ibotenic acid induced
cognitive deficit, and the reduction of cholinergic markers after
2 weeks of treatment. These findings validated the effect of W.
somnifera on promoters of learning and memory. Memory-
deficient mice showed neuronal atrophy and synaptic loss in
the brain, and the treatment with withanolide A induced
significant regeneration of both axons and dendrites, in
addition to the reconstruction of pre- and post-synapses in the
neurons, improving a memory process.[86] Withanolide from
root of W. somnifera induced neurite consequence in cultured
rat cortical neurons, and when orally administrated, it improved
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neuronal dysfunction in Alzheimer’s disease due to the effect
of its aglycone.[87] An in vitro study, application of methanolic
extract of W. somnifera root showed significant and dose-
dependent increase of the percentage of cells with neurites in
human neuroblastoma cells. It was also reported that oral
administration of the W. somnifera root withanolide signifi-
cantly improved memory deficits in Ab-injected mice to induce
dendritic and axonal atrophy and prevented loss of axons,
dendrites, and synapses in the cerebral cortex and hippo-
campus.[86,87] W. somnifera root extract also improved retention
of a passive avoidance task in a step-down paradigm in mice.
W. somnifera inverted the scopolamine induced disruption of
acquisition and retention, and decreased the amnesia produced
by acute treatment with electroconvulsive shock, and, there-
fore, displayed memory improving property.[88] The extract from
W. somnifera affected preferentially events in the cortical and
basal forebrain cholinergic signal transduction cascade. W.
somnifera induced an increase in cortical muscarinic acetylcho-
line receptor capacity that partly explained the cognition-
enhancing and memory-improving effects observed in animals
and humans.[89] W. somnifera also turned out the memory loss
that was induced by oxidative damage in consequence with
streptozotocin application.[90] Memory impairments in the
diabetics is associated with an increase of free-radical-mediated
oxidative damage and the administration of W. somnifera
displayed protective effects in decreasing diabetes-induced
memory loss due to its antioxidative mechanisms.[90]
5. Ginkgolides and bilobalide
Ginkgolides (5.15.3; Figure 5) and bilobalide (5.4; Figure 5) are
cyclic diterpenes of labdane type commonly isolated from
Gingko biloba. Extract of the plant leaves typically contains 24%
of flavonoid glycosides, 6% of terpenoids, and 5–10% of
organic acids.[91] The extracts were extensively evaluated for
their neuroprotective and adaptogenic effects,[92] and terpene
trilactones, ginkgolides, were identified as the major pharmaco-
logically active constituents in these extracts. A pre-treatment
of neuronal cells with ginkgolide A (5.1) and ginkgolide B (5.2)
protected neuronal cells from synaptic damage, evaluated by a
loss of synaptophysin, a pre-synaptic and synaptic marker.[93] An
increase of neuronal survival against Ab-induced toxicity was
also described.[94]
Ginkgolide B (5.2) rescued hippocampal neurons from Ab-
induced apoptosis by increasing the production of brain-
derived neurotrophic factor[95] and reduced apoptotic death of
neuronal cells in hemorrhagic rat brain.[96] In transgenic
Caenorhabditis elegans, ginkgolide A (5.1) reduced Ab-induced
adverse behavior, including paralysis.[97] Ginkgolide B (5.2)
inversed the Ab-induced reduction of ACh release from hippo-
campal brain slices, and caused substantial improvement in
learning and memory worsening by Ab.[98] Ginkgolide J (5.3)
was described as the most potent inhibitor of Ab-induced
hippocampal neuronal cell death among the ginkgolides in the
plant extract.[99] Additionally, bilobalide (5.4) reduced Ab-
induced synaptic loss and subsequently improved hippocampal
neurogenesis and synaptogenesis.[100] It also protected chick
embryonic neurons from apoptosis induced by serum depriva-
tion or staurosporine treatment.[101,102]
6. Triterpenes
Oleanolic acid (6.1; Figure 6) is a triterpene which was
identified as neuroprotective component in Aralia cordata
(Araliaceae).[1] A. cordata grows in eastern Asia, namely in China,
Japan, and Korea, and biological activities include adaptogenic,
anti-nociceptive (reflecting response of sensory nervous sys-
tem), antidiabetic, antioxidant, and anti-inflammatory activities,
reported in the literature.[1] Due to the antioxidant and anti-
inflammatory activities, extracts of A. cordata were tested for
their neuroprotective effect against Ab. An extract of A. cordata
protected neuronal death induced by Abin cultured rat cortical
neurons and improved Ab-induced memory deficit in
mice.[103,104]
Tenuifolin (6.2; Figure 6) is another triterpene with benefi-
cial (adaptogenic) effect in treatment of the Alzheimer’s
disease. It was isolated from Polygala tenuifolia (Polygalaceae),
which has been a well-known traditional Chinese medicine
plant, frequently used to improve cognitive function. An extract
of P. tenuifolia decreased the production of Abin in vitro
cultured cells.[105,106] Additional effort to identify the responsible
constituents in P. tenuifolia resulted in the isolation and
identification of tenuifolin.[106] It reduced Absecretion by
inhibiting b-secretase, the enzyme responsible for cleaving APP
to Ab. Tenuifolin also improved learning and memory in aged
mice by decreasing AChE activity accompanied by increased
neurotransmitters levels, such as norepinephrine and dopamine
levels.[107]
Figure 5. Structures of gingkolides and bilobalide
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Cryptotanshinone (6.3; Figure 6) is a labdane-type diter-
pene displaying anti-inflammatory, antioxidant, and anti-apop-
totic activities.[108–110] The compound was isolated from Salvia
miltiorrhiza. Cryptotanshinone easily crossed the blood-brain
barrier and affected cognitive function in mice, which indicates
its adaptogenic activity.[111] Furthermore, cryptotanshinone
reduced Abproduction by up-regulating a-secretase, which
cleaves APPs in the middle of the Absequence, due to which
Abproduction in vivo and in vitro by activating the PI3 K
pathway is made impossible.[112,113] In addition, cryptotanshi-
none protected neuronal cell damage by inhibiting Ab
aggregation.[114]
A screening effort to identify potent AChE inhibitors from
medicinal herbs resulted in the isolation of ursolic acid (6.4;
Figure 6) from Origanum majorana. Ursolic acid, other triter-
pene plant product, effectively inhibited AChE activity in a
dose-dependent and competitive / non-competitive manner.[115]
It also reduced Ab-induced oxidative damage, e. g., free radical
formation and lipid peroxidation in in vitro assay systems,[116]
and inhibited Abbinding to microglia. In the summary, it
reduced the production of pro-inflammatory cytokines and
neurotoxic reactive oxygen species and displayed a neuro-
protective effect against Ab, and integrated itself among
adaptogens.[117]
7. Plant ecdysteroids and steroid plant
hormones
Plant ecdysteroids (phytoecdysteroids; 7.17.7; Figure 7) are
natural polyhydroxylated compounds that have a steroid
skeleton, usually composed of either 27 carbon atoms or 28–29
carbon atoms, and, thus biosynthetically derived either from
cholesterol or from other plant sterols. The physiological roles
of ecdysteroids in plants have not yet been fully resolved, and
their occurrence is not universal within the plant families.
Nevertheless, they are present in various plant species in high
concentrations, including commonly consumed vegetables,
and they display a broad spectrum of pharmacological and
medicinal properties in mammals. Their effects include hepato-
protective, hypoglycemic and anabolic effects without andro-
genic side effects. Phytoecdysteroids caused an increase in
stress resistance by promoting vitality and improving physical
performance, and, therefore, they were described as plant
products with adaptogenic effect.[118]
Ecdysteroids were originally found in the animals to control
process of insect molting (insect ecdysis) and other metamor-
photic processes in insects.[119] Since the discovery of ecdyste-
roids, about 300 compounds have been identified in over 100
terrestrial plant families. 20-Hydroxyecdysone is the most
widely distributed plant product of this type. Plant ecdysteroids
differ from those isolated from animal sources, however, the
division is not strict, because some ecdysteroids are present
both, in animals and plants [(e.g., 20-hydroxyecdysone (7.1)
and ajugasterone C (7.2); Figure 7]. In addition to higher plants
(both angiosperms and gymnosperms), phytoecdysteroids
have also been discovered in algae, ferns and fungi (7.17.7;
Figure 7).[120] Evidence exists in the literature that most plant
species have the genetic capacity to produce phytoecdyste-
roids, although these plant products have been detected in
only a small proportion (5 – 6%) of 250 thousand of plant
species tested.[120] The inability to detect these compounds in
some species could be due to a suppression of gene tran-
scription,[120] insufficient purification during sample preparation
and/or instrumental limitations due to very low concentrations
of those plant products in the analyzed samples. This argument
is supported by the results found in Arabidopsis, considered as
phytoecdysteroid non-producing plant.[119] Phytoecdysteroid
detection in plant species will undoubtedly change, when
technical facilities with sufficient detection limits will be
developed and applied in those analyses. Recent studies also
indicated that the concentration of phytoecdysteroids may
relate to phylogenetic position.[120] For example, in the genus
Chenopodium, phytoecdysteroids are present in most of the
members of the subgenus Chenopodium, but no phytoecdyste-
roid has been identified in the subgenus Ambrosia so far.[120]
Figure 6. Structures of oleanolic acid, tenuifolin, cryptotanshinone and
ursolic acid
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Phytoecdysteroids clearly have diverse distribution, and
their roles in plants are still mostly unknown despite many
recent findings. Their most probable function has still been the
role of defense products biosynthesized against insect herbi-
vores, and, therefore, they have strong potential to be applied
in agriculture. In addition, they have important pharmacolog-
ical and medicinal characteristics that will attract more and
more attention in a near future. Plants and their products
become a major part of human diet in many countries. For
example, the numerous indications on their effectiveness,
nonandrogenic effects, adaptogenic effects and as elicitors of
anabolic effects on skeletal muscle resulted in possible
applications of phytoecdysteroids as natural drugs to support
resistance of people against stress, to increase muscle regener-
ation after damaging, and in consequence with sport perform-
ances. In addition, phytoecdysteroid constituents of many
more plants should be undoubtedly studied by using modern
analytical instruments with high performance to allow detec-
tion and identification of phytoecdysteroids present at low
concentrations to broaden general knowledge on their distri-
bution, profiles and roles in plants. Further analysis of the
origin(s) of isoprene or isoprenoid units used by nature in
phytoecdysteroids biosynthesis will also be soon required for
better understanding of natural biosynthetic pathways.[118]
8. Arbutin, bergenin, protocatechuic acid,
gallic acid, ellagic acid, quinic acid and
1,2,6-tri-O-galloylglucose
Bergenia crassifolia has been used as a medicinal and
ornamental plant for more than a century. Due to its rich and
varied chemical composition, of which arbutin (8.1), tannins
and bergenin (8.2) seem to be the most important products in
the topic of this review (Figure 8), the plant has been subjected
to the pharmacological studies.[9] More than 100 chemical
components have already been isolated and identified from
this plant species, including not only tannins, but also
benzanoids (hydroquinone), flavonoids, polysaccharides, ter-
penes, aldehydes, etc.
B. crassifolia appeared to meet the criteria of being involved
among adaptogens.[121] Adaptogenic effects of black and
fermented B. crassifolia leaves were studied in mice forced
swimming test, often used in such an investigation. It was
published that the swimming time of mice treated with
infusion of fermented leaves was increased in 2.2-folds in
comparison with the control mices. The adaptogenic effect was
accompanied by increasing glucose utilization and decreasing
lactate level by 92% compared with the control group. A
positive correlation between forced swimming capacity and
the content of arbutin (8.1) and protocatechuic acid (8.3) was
observed. Glucose and lactate utilization had a positive
correlation with the content of gallic acid (8.4), ellagic acids
(8.5) and hydroquinone (Figure 8). Other important compo-
nents in B. crassifolia are quinic acid (8.6) and 1,2,6-tri-O-
galloylglucose (8.7; Figure 8). All these plant products partici-
pated at hemostatic, astringent, anti-inflammatory and anti-
microbial effects, and are considered to be adaptogenic plant
products.[121,122] Additionally, it was found that infusions of B.
crassifolia leaves increased fat utilization during swimming,
resulted in a decrease of the mouse body weight.[122] The
running time in treadmill of rats treated with B. crassifolia
leaves extract increased in 30% in comparison with the control
Figure 7. Structures of several plant ecdysteroids
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group. The capacity of persistence in rats was subjected to
chronic exposure to cold. It was significantly improved after
supplementation with extract of B. crassifolia leaves. Stress
protective effect of extract was evaluated in rats in the model
of immobilization stress. Significant turnover in stress-induced
inhibition in adrenal weight, thymus involution and bleeding
from gastric red spots was observed after administration of B.
crassifolia leaves extract.[123] Activation of mitochondrial ATP-
dependent potassium channel (mitoKATP) and increase in ATP-
dependent K+transport in mitochondria were an essential
stage initiating the adaptive response of organism under
extreme conditions (e. g. hypoxia). Antihypoxic activity of
lyophilized and standardized water-soluble extract of Bergenia
was studied ex vivo.[123]
Besides adaptogenic effect, extracts of different parts of B.
crassifolia display anticancer, antimicrobial, antidiabetic, anti-
obesity, antihypertensive (hypotensive), antitussive, antioxidant,
diuretic, anti-inflammatory, immunomodulating, and gastro-,
hepato- and skin-protective effects. A synergic action of all
components found in B. crassifolia extracts, including flavo-
noids and other phenolic and volatile compounds, is undoubt-
edly responsible for broad effect scale of this medicinal
plant.[118]
9. Tyrosol and salidroside
Rhodiola is a genus of medicinal plants originated and grown in
Asia and Europe, and is used as adaptogen traditionally.
Rhodiola plants are rich in polyphenols. Tyrosol (9.1) and
salidroside (9.2) are the primary bioactive marker plant
products in the standardized extracts of Rhodiola rosea (Fig-
ure 9). Rhodiola plants display a spectrum of biological
activities, besides already mentioned adaptogenic effect, they
display antifatigue, antidepressant, antioxidant, anti-inflamma-
tory, anti-nociceptive, and anticancer activities, and they are
capable of modulating the immune function and of preventing
cardiovascular, neuronal, liver, and skin disorders.[124,125]
The genus Rhodiola consists of more than 200 species, of
which approximately 20, including R. rosea,R. alterna,R.
brevipetiolata,R. crenulata,R. kirilowi,R. quadrifida,R. sachali-
nensis, and R. sacra, have been used in traditional medicines in
Asia.[126] These plants grow mainly in the Himalayan belt, Tibet,
China, and Mongolia, but are also cultivated in Europe and
North America, and are available on the market as dietary
supplements.[127–130] R. rosea has been used for a long time in
Eastern Europe and Asia to improve physical and mental
performances (adaptogenic effect). It has also been used in
Eastern Europe and Asia as a traditional medicine to stimulate
the nervous system, decrease depression and tiredness,
improve work performance, and prevent high-altitude sickness,
mountain malhypoxia, and anoxia.[131] In Russia and Mongolia, it
has been used for treating long-term illness and weakness
caused by infection.[132] In addition, R. rosea displayed cardio-
vascular protection effects. In recent years, the root extracts of
R. rosea were used as drinks, food additives, and in commercial
pharmaceutical drugs available worldwide.[133]
Rhodiola plants also contain polyphenols, such as flavo-
noids, proanthocyanidines and cinnamyl alcohol, as well as
glycosides, organic acids, essential oils, sugars, fats, alcohols,
and proteins.[130] The polyphenol content of R. rosea is
approximately 40%.[134] Rosavin, rosarin, rhodionin, rhodiosin,
Figure 8. Structures of adaptogens from Bergenia crassifolia
Figure 9. Structures of tyrosol and salidroside
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rosin, cinnamyl alcohol, salidroside and tyrosol are the major
components of Rhodiola plants.[124] Salidroside (9.2) and its
aglycone, tyrosol (9.1), are the most important plant products
in R. rosea, and the content of these compounds are often used
as a criterion in evaluating the quality of crude drugs of R. rosea
(Figure 9).[135]
Researchers have categorized R. rosea as an adaptogen
because of its observed ability to increase resistance to various
chemical, biological, and physical stressors and its perform-
ance-improving effect in humans.[136–139] It was reported that
repeated administration of R. rosea extract, SHR-5, generated
an anti-exhaustion effect, due to which mental performance
(particularly the ability to concentrate) increased, and it also
reduced cortisol response to awakening stress in patients with
syndromes of burning out and tiredness.[140] The adaptogenic
and central nervous system activities of R. rosea were assigned
to its influence on the levels and activity of monoamines and
opioid peptides, such as b-endorphins.[128]
Application of an aqueous extract of R. imbricata (100 mg/
kg) provided maximum resistance to cold-hypoxia restraint
stress-induced hypothermia and accelerated recovery from the
stressor.[141] In addition, the aqueous extract of R. imbricata also
exhibited dose-dependent adaptogenic activity.[142] This inves-
tigation indicated that Rhodiola extracts were useful in treating
asthenic conditions, which develop after intense physical or
intellectual stress, including a decrease of work performance,
sleeping disorders, poor appetite, irritability, hypertension,
headaches and exhaustion.[142]
It was proven that intense exercises resulted in increasing
oxygen consumption, and caused oxidative stress as an addi-
tional result of increased reactive oxygen species produc-
tion.[143] Exogenous antioxidants are capable of preventing
oxidative damage. They are capable of purifying ROS generated
during exercises.[144] Salidroside (9.2) elevated exercise tolerance
and increased the liver glycogen levels of rats after exhaustive
swimming.[144] In addition, salidroside reduced malondialdehyde
levels and improved the activity of antioxidant enzymes, such
as catalase, superoxide dismutase, and glutathione peroxidase
in the liver tissue of rats.[144] The studies resulted in a proof of
ability of Rhodiola plants and its important plant constituents
to improve work performance and resistance to stress.[144]
10. Eleutherosides
Eleutherosides, the phenylpropanoid and lignin glycosides, are
the active ingredients accumulated in the roots and stems of
Eleutherococcus (formerly Acanthopanax) species, and in Eleu-
therococcus senticosus in particular (Figure 10). Syringin, known
as eleutheroside B (10.1), and (–)-syringaresinol-di-O-b-D-
glucopyranoside (eleutheroside E; 10.2), appeared as the most
important bioactive compounds that have been used as
adaptogens, besides their abundant antidiabetic and anticancer
properties. As the availability of Eleutherococcus species is
becoming increasingly limited because of its rare natural
distribution, the production of these compounds by biotechno-
logical means has become an attractive and important
alternative. In E. senticosus and other closely related species, E.
sessiliflorus,E. chiisanensis, and E. koreanum, organogenic
cultures were induced for the production of eleutherosides.[145]
These technologies were developed for a production of a
biomass and metabolites. Bioactive eleutherosides can also be
produced from embryogenic and adventitious root cultures of
E. sessiliflorus,E. chiisanensis, and E. koreanum.
E. senticosus is used as a traditional medicine in Russia,
China, Korea, and Japan.[146] It is known as Siberian ginseng,
and is widely used as an adaptogen,[146] immunomodulator,[147]
and insulin sensitizer.[148] The phenylpropanoid and lignan
glycosides, triterpenoid saponin glycosides, and polysacchar-
ides are major chemical constituents of E. senticosus.[149] The
plant also contains valuable essential oils, coumarins, and
flavones,[149] however, lignans syringin (eleutheroside B, 10.1)
and (–)-syringaresinol-di-O-b-D-glucoside (eleutheroside E,
10.2) appeared as the most active components among
phytochemicals present in E. senticosus.[149] Besides already
mentioned effects, E. senticosus has displayed also anti-
inflammatory, hepatoprotective, immunomodulatory, antiulcer,
anti-allergic, anti-irradiation, antifatigue, neuroprotective, anti-
oxidant, hypoglycemic, antisteatosis, antiviral and antibacterial
activity.[145] The total content of eleutherosides B and E was
found to be optimal in the dried rhizomes and roots. Old bark
and stems, aged 3 to 5 years, were also reported to possess
high content of these compounds.[150] Many clinical studies
have resulted in proving their immunomodulatory properties in
humans[151] without adverse drug interactions.[152] They are one
of the main ingredients of Chinese, Russian, and oriental
(Korean and Japanese) system of medicine and also a popular
tonic or adaptogen.[149] Eleutherosides have been known and
requested dietary supplements, and have also been included in
the European Pharmacopeia as medicine.[153] Since 1994, the
Dietary Supplements Health and Education Act (DSHEA) and
the Food and Drug Administration (FDA) regulation of the USA
allowed direct distribution of eleutherosides.[152] However, the
natural resources of this plant have been decreasing because
of overharvesting. As already mentioned above, this plant
Figure 10. Structures of eleutherosides
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belongs among rare species. Even if E. senticosus can be
cultivated in controlled conditions, its growth is slow and
propagation through seeds takes a long time due to the
prolonged seed dormancy. Therefore, cells and organs as well
as somatic embryos have been cultured in vitro for both
biomass accumulation and phytochemical production, which is
quite successful.[145]
11. 20-Hydroxyecdysone and plant sterols
Leuzea carthamoides, syn. Rhaponticum carthamoides, a peren-
nial herb, is also known as a maral root. For many centuries, it
has been used in traditional medicine of Siberia in cases of
exhaustion and common weakness after illness. At present, the
plant has been introduced to various regions of Central and
Eastern Europe, where its extracts have been used for their
adaptogenic and tonic properties in various dietary supple-
ments or nutraceutical preparations. The roots display healing
effect and have been used for production of tea-like beverages
and other products.
We have compared water and organic extracts and
tinctures from roots and leaves, infusion of the leaves and
infusion of the roots of L. carthamoides in terms of biological
activity and their composition of secondary metabolites.
Antimicrobial, antifungal, antioxidant and hemolytic activity
were tested for all samples. To determine the composition of all
of extracts, reversed-phase high-performance liquid chroma-
tography, phytochemical analysis, thin-layer chromatography
and mass spectrometry were used. The work investigated
whether the leaves and stems are really the waste or whether
they contain interesting substances that could be used.[154]
Phytochemical analysis showed that samples from roots
and leaves contain the similar structural groups of substances.
The antibacterial activity was tested against bacteria Escherichia
coli,Pseudomonas aeruginosa,Staphylococcus aureus and
Bacillus cereus. Further, the antifungal activity was tested
against yeasts Candida utilis,Geotrichum candidum and against
fungi Fusarium sporotrichoides,Spaerodes fimicola and Mucor
sp. The most sensitive microorganisms were bacteria B. cereus,
and S. aureus, yeast G. candidum and fungi S. fimicola and
Mucor sp. The most effective were the samples from the roots.
L. carthamoides has been intensively studied for its
adaptogenic effects. In general, biological activity and active
components composition of its extracts have often been
investigated.[155] Steroids, flavonoids, phenolic acids, lignans,
tanins, polyacetylenes, sesquiterpenic lactones and triterpenic
glycosides, plant sterols, and, based on a more detailed
analysis, proteins, amino acids and saponins were found based
on a detailed analysis.[154,155]
20-Hydroxyecdysone (7.1; Figure 7) is the most important
ecdysteroid isolated from this plant, present in roots, stems,
leaves and seeds. During more than 30 years of intensive
research on the chemistry of L. carthamoides, 50 various
ecdysteroids have been isolated and identified.[154,155] Several
sterols, such as b-sitosterol (11.1), stigmasterol (11.2), D7-
avenasterol (11.3), campesterol (11.4), and cholesterol (11.5)
were found in the roots. Cholesterol, stigmasterol, b-sitosterol,
and b-sitostanol (11.6) were found in the seeds (Figure 11).
Regarding L. carthamoides, various flavonoids or anthocyanins
were found in the roots, stems and leaves of the plant in
addition. Besides the flavonoids, a number of phenolic acids,
several lignans and tannins e. g. ellagic acid have also been
identified in this plant. For a detailed list of reported
constituents of L. carthamoides, a review paper[155] should be
consulted.
The results of a long-term pharmacological and clinical
investigation showed that the extracts, as well as compounds,
especially ecdysteroids, isolated from different parts of the
plant, display specific biological effects indicating adaptogenic
properties of L. carthamoides. These effects include immunosti-
mulation, ability to eliminate free radicals to prevent oxidizing
Figure 11. Structures of the most important plant sterols
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pathology, to increase protein biosynthesis and physical work
capacity along with endurance and performance, to improve
cardiovascular functions and mental work capacity. Similarity
between some of the described properties of the plant and
those described for ecdysteroids was observed.[156] Various
in vivo tests with animals and clinical tests proved a significant
positive effect of L. carthamoides extracts and ecdysteroid
constituents (especially of 20-hydroxyecdysone) on the increase
of protein synthesis and working capacity of tested subjects,
subsequently resulting in the development of several formula-
tions used to increase strength, persistence and promote
muscle growth of humans.[155] In the 1970s, the anabolic effect
of L. carthamoides was reported, and it has been subjected to a
number of experiments on laboratory animals, performed
mainly with mice or rats. According to the so far obtained
results it is evident that an application of 20-hydroxyecdysone,
isolated from L. carthamoides, at a dose of 5 mg/kg adminis-
tered to rats for 7 days is accompanied by an increase in the
weight of the liver, heart, kidneys and musculus tibialis
anterior.[155] Recently,[157,158] it was observed that intraperitoneal
injections of aqueous solutions of L. carthamoides extract and
20-hydroxyecdysone activated the biosynthesis of macromole-
cules (protein, RNA, and DNA) in organs of mice. In clinical
trials, several commercially available drug preparations (e. g.,
Ecdysten, Leveton or Prime Plus), taken orally for 20 days by
three separated groups of tested humans under conditions of
daily aerobic-anaerobic training, significantly diminished fat
content and increased the muscle mass in all groups of treated
individuals in comparison with the control group.[155]
12. Naphthodianthrones and phloroglucinols
Hypericum perforatum (St. John’s wort) has been used for
treating depression, mental disorders, wounds, peptic ulcers,
malaria, gout and arthritis, pulmonary complaints, bladder
troubles in suppression of urine, dysentery, worms, diarrhea,
hysteria and other hemorrhages and jaundice.[159] Generally, it
has been used in the traditional medicine for more than
3000 years.[160] Various compounds of the plant are known as
sedative, diuretic and expectorant according to their effects.
The flowers and the aerial parts are commonly used in the
preparations of traditional medicines. H. perforatum with
identified active compounds like hypericins, hyperforins is
being studied for its anti-depressant activity in both humans
and animals.[159]
The most important compounds found in Hypericum
species generally include naphthodianthrones [e. g. hypericin
(12.1) and pseudohypericin (12.3)], phloroglucinols [e. g. hyper-
forin (12.2) and adhyperforin (12.4)] and flavonoids (e. g.
quercetin, quercitrin, hyperoside and rutin) (Figure 12).[161]
Enormous scientific data generated from preclinical and
clinical studies support the medicinal use of H. perforatum
extracts and products.[162] Preclinical studies performed with H.
perforatum extract proposed non-selective monoamine oxidase
inhibition and neurotransmitter reuptake inhibition to be the
underlying mechanisms of its antidepressant effect. Hypericine
(12.1) is responsible for a non-selective monoamine oxidase
inhibition and/or competitive antagonism at corticotropin-
releasing factor receptors and/or augmentation of presynaptic
action potential duration by delayed rectifier potassium
currents, and it displays anti-Parkinsonian activity. Hyperforin
(12.2) controls antagonism at corticotropin-releasing factor
receptors and/or non-selective neurotransmitter reuptake in-
hibition by transient receptor potential protein channel-6
mediated membrane sodium gradient breakdown, and it is
active against dementia. Pseudohypericine (12.3) controls
hypothalamic-pituitary-adrenal axis hyperactivity by selective
antagonism at corticotropin-releasing factor receptors. Adhy-
perforin (12.4) non-selectively inhibits neurotransmitter uptake
by binding to serotonin and noradrenaline transporters. All
compounds display a number of additional effects.[162]
Figure 12. Structures of naphthodianthrones and phloroglucinols
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In the past decade, H. perforatum has become very popular
as an effective alternative treatment in weak/medium forms of
depression, as widely demonstrated by numerous preclinical
and clinical studies, cf. review,[160] and the references therein.
Even though pharmacological studies have mainly focused on
H. perforatum antidepressant activity, several studies have
documented other bioactivities produced by this herbal plant.
Preclinical studies on H. perforatum extracts highlighted
anxiolytic, sedative, nootropic, antischizophrenic and anticon-
vulsant activities, and it resulted beneficial in the treatment of
alcohol, nicotine, and caffeine addiction in experimental
animals.[163–164] Antibacterial, antiviral and anti-inflammatory
activity are also well documented.[160] Certain disadvantage of
H. perforatum, when administered together with certain
synthetic drugs, is the adverse effect of the H. perforatum
extract.[165] Nevertheless, the presented effects of the H.
perforatum extract, as well as those of hypericine and other
components found in this plant, result in qualifying this plant
among the adaptogenic plants improving the human health.
13. Conclusion
In this review, several plant sources of adaptogenic compounds
were mentioned, which are either generally important or have
local importance in the country of authors and neighboring
areas. The most important plant products capable of qualifying
themselves as adaptogens are shown in Figure 1–12, and their
pharmacological effects were mentioned. Nowadays, all those
mentioned plant products are considered as active constituents
of potential new drugs for treating depression and other
important neurodegenerative disorders.
Natural products are attractive sources for developing
agents for treating depression and other neurodegenerative
disorders, because they can provide diverse structural charac-
teristics and biological activities. Considering Alzheimer’s
disease, some AChE inhibitors and NMDA receptor antagonists
are the only medications approved by the FDA to treat patients
with this neurodegenerative disorder. Therefore, this review
discussed several diverse natural products which can be
developed as potential agents against Alzheimer’s disease. The
representative terpenoids with effects against Alzheimer’s
disease are ginsenosides from P. ginseng, ginkgolides and
bilobalide from G. biloba. The evaluation of biological activities
by in vitro cell based assays and in vivo animal studies indicate
the beneficial effects of these compounds against Alzheimer’s
disease. However, their clinical efficacy is still not fully under-
stood. Clinical trials should be designed to reflect diverse races,
dementia severity, and different doses of biologically active
compounds. Other compounds, such as oleanolic acid, tenuifo-
lin, cryptotanshinone and ursolic acid have outstanding neuro-
protective effects in in vitro assays. These compounds can exert
beneficial effects on central nervous system directly or
indirectly by acting on peripheral targets. Therefore, the
methods to deliver the bioactive compounds to the brain
efficiently should be considered to develop terpenoids as
agents against Alzheimer’s disease and other neurodegener-
ative disorders, or – in other words – agents displaying
adaptogenic effects.
Adaptogens seem to have all prerequisites to become
potential medicaments for 21st century. In turn, they will not
become medicaments for everyday or general application.
Acknowledgments
The authors appreciate a financial support through the grants
FV10599, FV20666 and FV30300 (MPO) and the grant TE01020080
(Bioraf; TAC
ˇR).
Conflict of Interest
The authors declare no conflict of interest.
Keywords: adaptogen ·Alzheimer’s disease ·neuropsychiatric
disease ·Parkinson’s disease
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Submitted: November 9, 2017
Revised: February 8, 2018
Accepted: February 12, 2018
Reviews
2214
ChemistrySelect 2018,3, 2196–2214  2018 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim
Wiley VCH Dienstag, 20.02.2018
1807 / 107375 [S. 2214/2214] 1
... Phytoecdysteroids of medicinal plants such as Panax ginseng, Eleutherococcus Senticosus, Rhaponticum Carthamoides, Rhodiola Rosea, and Schisandra Chinensis are widely known as adaptogens [3,4]. Phytoecdysteroids are known for the numerous and diverse biological activities associated with their anabolic, adaptogenic, antidiabetic, hypolipidemic, and hepatoprotective effects [5,6]. Thus far, these results have positioned phytoecdysteroids as effective agents against several acute and chronic pathological conditions [7]. ...
Article
Full-text available
Increasing the ability of the human body to adapt in conditions of physical or emotional stress is promising from the standpoint of the use of preventive nutrition containing functional food ingredients (FFI) with proven effectiveness in complex physiological in vivo studies. In this work, we developed FFI from spinach leaves (Spinacia oleracea L.) with a high content of polyphenols and adaptogens—phytoecdysteroids. Using in vivo models of increased physical activity and immobilization-induced emotional stress, we evaluated the nonspecific resistance of rats in response to the addition of the developed FFI to the diet. In the acute toxicity experiment, we found no signs of FFI toxicity up to 5000 mg/kg body weight. As a result of the daily 26-day consumption of FFI, we observed an anxiolytic effect in physiological studies. FFI prevented an increase in the content of biogenic amines in the blood, the main markers of the stress system, and had a positive effect on the lipid metabolism of the rats. The obtained results demonstrate a “smoothing” effect on the body’s reaction in response to induced stress conditions.
... Although already isolated from several hundred plant species [2,3], however, it is most often isolated from olive tree (Olea europaea) [1]. Oleanolic acid (1), despite its low bioavailability, also displays a broad spectrum of pharmacological activity, and it is considered to be an adaptogen [4]. It has a protective effect on the human liver, where it acts against serious liver injuries and against hepatitis [1], and it containing compounds [28][29][30][31][32]. ...
Article
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Background: Oleanolic acid is a natural plant adaptogen, and tryptamine is a natural psychoactive drug. To compare their effects of with the effect of their derivatives, tryptamine and fluorotryptamine amides of oleanolic acid were designed and synthesized. Methods: The target amides were investigated for their pharmacological effect, and basic supramolecular self-assembly characteristics. Four human cancer cell lines were involved in the screening tests performed by standard methods. Results: The ability to display cytotoxicity and to cause selective cell apoptosis in human cervical carcinoma and in human malignant melanoma was seen with the three most active compounds of the prepared series of compounds. Tryptamine amide of (3β)-3-(acetyloxy)olean-12-en-28-oic acid (3a) exhibited cytotoxicity in HeLa cancer cell lines (IC50 = 8.7 ± 0.4 µM) and in G-361 cancer cell lines (IC50 = 9.0 ± 0.4 µM). Fluorotryptamine amides of (3β)-3-(acetyloxy)olean-12-en-28-oic acid (compounds 3b and 3c) showed cytotoxicity in the HeLa cancer cell line (IC50 = 6.7 ± 0.4 µM and 12.2 ± 4.7 µM, respectively). The fluorotryptamine amide of oleanolic acid (compound 4c) displayed cytotoxicity in the MCF7 cancer cell line (IC50 = 13.5 ± 3.3 µM). Based on the preliminary UV spectra measured in methanol/water mixtures, the compounds 3a-3c were also found to self-assemble into supramolecular systems. Conclusions: An effect of the fluorine atom present in the molecules on self-assembly was observed with 3b. Enhanced cytotoxicity has been achieved in 3a-4c in comparison with the effect of the parent oleanolic acid (1) and tryptamine. The compounds 3a-3c showed a strong induction of apoptosis in HeLa and G-361 cells after 24 h.
... Withania somnifera, and it shows anti-neoplastic immunomodulatory and anti-stress activity (Alam et al. 2012;Özdemir et al. 2018). It was the best-docked molecule obtained for the cluster 2. It showed hydrophobic interaction with Phe490 of the Spike protein. ...
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The S-glycoprotein (Spike) of the SARS-CoV-2 forms a complex with the human transmembrane protein angiotensin-converting enzyme 2 (ACE2) during infection. It forms the first line of contact with the human cell. The FDA-approved drugs and phytochemicals from Indian medicinal plants were explored. Molecular docking and simulations of these molecules targeting the ACE2-Spike complex were performed. Rutin DAB10 and Swertiapuniside were obtained as the top-scored drugs as per the docking protocol. The MD simulations of ligand-free, Rutin DAB10-bound, and Swertiapuniside-bound ACE2-Spike complex revealed abrogation of the hydrogen bonding network between the two proteins. The principal component and dynamic cross-correlation analysis pointed out conformational changes in both the proteins unique to the ligand-bound systems. The interface residues, His34, and Lys353 from ACE2 and Arg403, and Tyr495 from the Spike protein formed significant strong interactions with the ligand molecules, inferring the inhibition of ACE2-Spike complex. Few novel interactions specific to Rutin-DAB10 and Swertiapuniside were also identified. The conformational flexibility of the drug-binding pocket was captured using the RMSD-based clustering of the ligand-free simulations. Ensemble docking was performed wherein the FDA-approved database and phytochemical dataset were docked on each of the cluster representatives of the ACE2-Spike. The phytochemicals identified belonged to Withania somnifera, Swertia chirayita, Tinospora cordifolia and Rutin DAB10, fulvestrant, elbasvir from FDA. Supplementary information: The online version contains supplementary material available at 10.1007/s11696-021-01680-1.
... Vesicular self-assembly of molecules from renewable sources in aqueous solvents is rare. Plant metabolites with diversified structures and functional groups offer new opportunities to study their self-assembly process, as they are available in renewable sources without extensive synthetic research [175]. Triterpenoid pentacyclic acids are attractive candidates due to their relatively rigid structures with the length exceeding 1 nanometer. ...
Article
The importance of natural raw materials has grown recently because of their ready availability, renewable nature, biocompatibility and controllable degradability. One such group of plant-derived substances includes the triterpenoid acids, terpenic compounds consisting of six isoprene units, a carboxyl group and other functional groups producing various isomers. Most can be easily extracted from different parts of the plant and modified successfully. By themselves or as aglycones (genins) of triterpene saponins, they have potentially useful pharmaceutical activity. This review focuses on the supramolecular properties of triterpenoid acids with regard to their subsequent use as biocompatible nanocarriers. The review also considers the current list of pentacyclic triterpene acids for which molecular self-assembly has been confirmed without the need for structural modification.
... Thousands of scientific articles and books were published about adaptogenic plants in previous years (Baranov, 1982;Zhuravlev and Kolyada, 1996;Panossian et al., 1999;Davydov and Krikorian, 2000;Barnaulov. 2001;Panossian, 2003;Panossian and Wagner, 2005;Panossian and Wikman, 2008;2009;Asea et al., 2013;Panossian, 2017;Panossian et al., 2018a,b;Ö zdemir et al., 2018;Panossian and Brendler, 2020;Gerontakos et al., 2020). ...
Article
Ethnopharmacological relevance Herbal medicine in Russia has a long history starting with handwritten herbalist manuscripts from the Middle Ages to the officinal Pharmacopoeia of the 21st century. The "herbophilious" Russian population has accumulated a lot of knowledge about the beneficial effects of local medicinal plants. Yet, for a long time, Russian traditional and officinal herbal medicine was not well known to the international audience. In our previous comprehensive review, we discussed the pharmacological effects of specific plants included in the 11th edition of the Pharmacopoeia of the USSR, which was also for a while used in Russia. The 14th edition of the Russian Federation’s State Pharmacopoeia was implemented in 2018. Aim of the review The aims of the present review are: (i) to trace the evolution of medicinal plant handling from handwritten herbalist manuscripts to Pharmacopoeias; (ii) to describe the modern situation with regulatory documents for herbal medicinal products and their updated classification; (iii) to summarize and discuss the pharmacology, safety, and clinical data for new plants, which are included in the new edition of the Pharmacopoeia. Methods New medicinal plants included in the 14th edition of the Russian Federation’s State Pharmacopoeia were selected. We carefully searched the scientific literature for data related to traditional use, pharmacological, clinical application, and safety. The information was collected from local libraries in Saint-Petersburg, the online databases E-library.ru, Scopus, Web of Science, and the search engine Google scholar. Results Investigating the evolution of all medicinal plants referred to in the Russian Pharmacopoeias led us to the identification of ten medicinal plants that were present in all editions of civilian Russian Pharmacopoeias starting from 1778. In the 14th edition of the modern Russian Pharmacopoeia, medicinal plants are described in 107 monographs. Altogether, 25 new monographs were included in the 14th edition, and one monograph was excluded in comparison to the 11th edition. Some of the included plants are not endemic to Russia and do not have a history of traditional use, or on the other hand, are widely used in Western medicine. For 15 plants, we described the specificity of their application in Russian traditional medicine along with the claimed dosages and indications in officinal medicine. The pharmacology, safety, and clinical data are summarized and assessed for nine plants, underlining their therapeutic potential and significance for global phytopharmacotherapy. Conclusions In this review, we highlight the therapeutical potential of new plants included in the modern edition of the Russian Pharmacopoeia. We hope that these plants will play an imperative role in drug development and will have a priority for future detailed research.
... The biological and healing effects of plants appear due to their secondary metabolites, which protect plants from the effects of the external environment. Knowledge about the medicinal effects from traditional medicine has resulted in a great interest in determining the plant metabolites that display biological effects for their expected applications-not only for the preparation of medicinal products, but also for their use as food supplements or biopesticides [2][3][4][5]. ...
Article
Full-text available
Magnolia plants are used both as food supplements and as cosmetic and medicinal products. The objectives of this work consisted of preparing extracts from leaves and flowers of eight Magnolia plants, and of determining concentrations of magnolol (1 to 100 mg·g−1), honokiol (0.11 to 250 mg·g−1), and obovatol (0.09 to 650 mg·g−1), typical neolignans for the genus Magnolia, in extracts made by using a methanol/water (80/20) mixture. The tested Magnolia plants, over sixty years old, were obtained from Průhonický Park (Prague area, Czech Republic): M. tripetala MTR 1531, M. obovata MOB 1511, and six hybrid plants Magnolia × pruhoniciana, results of a crossbreeding of M. tripetala MTR 1531 with M. obovata MOB 1511. The identification of neolignans was performed by HRMS after a reversed-phase high-performance liquid chromatography (RP-HPLC) fractionation of an extract from M. tripetala MTR 1531. The highest concentrations of neolignans were found in the flowers, most often in their reproductive parts, and obovatol was the most abundant in every tested plant. The highest concentrations of neolignans were detected in parent plants, and lower concentrations in hybrid magnolias. Flower extracts from the parent plants M. tripetala MTR 1531 and M. obovata MOB 1511, flower extracts from the hybrid plants Magnolia × pruhoniciana MPR 0271, MPR 0151, and MPR 1531, and leaf extract from the hybrid plant Magnolia × pruhoniciana MPR 0271 inhibited growth of Staphylococcus aureus.
... Pharmacologic assessment of adaptogens involves exposure to altered environmental surroundings, radiation, toxic substances, starvation, fear, and chronic diseases. Also, the most important feature of adaptogens is the ability to increase resistance to both physical and emotional stress (Özdemir et al., 2018;Wal et al., 2019). P. longum has also been evaluated for combating stress. ...
Article
Ethnopharmacological relevance: Piper longum, commonly referred as 'Pippali', has found its traditional use in India, Malaysia, Singapore and other South Asian countries as an analgesic, carminative, anti-diarrhoeic, immunostimulant, post childbirth to check postpartum hemorrhage and to treat asthma, insomnia, dementia, epilepsy, diabetes, rheumatoid arthritis, asthma, spleen disorder, puerperal fever, leprosy etc. AIM OF THE REVIEW: This review offers essential data focusing on the traditional use, phytochemistry and pharmacological profile of Piper longum thereby identifying research gaps and future opportunities for investigation on this plant. Materials and methods: This systematic survey was accomplished as per the PRISMA guidelines. The information was collected from books, and electronic search (PubMed, Science Direct, Lilca and Scielo) during 1967-2019. Results: Many phytochemicals have been identified till date, including alkaloids as its major secondary metabolites (piperine and piperlongumine), essential oil, flavonoids and steroids. These exhibit a wide range of activities including anti-inflammatory, analgesic, anti-oxidant, anti-microbial, anti-cancer, anti-parkinsonian, anti-stress, nootropic, anti-epileptic, anti-hyperglycemic, hepatoprotective, anti-hyperlipidemic, anti-platelet, anti-angiogenic, immunomodulatory, anti-arthritic, anti-ulcer, anti-asthmatic, anthelmintic action, anti-amebic, anti-fungal, mosquito larvicidal and anti-snake venom. Conclusion: Amongst various activities, bioscientific clarification in relation to its ethnopharmacological perspective has been evidenced mainly for anti-amebic, anthelminthic, anti-tumor and as contraceptive and hypoglycemic herb. However, despite traditional claims, insufficient scientific validation for the treatment of insomnia, dementia, epilepsy, rheumatoid arthritis, asthma, spleen disorder, puerperal fever and leprosy, necessitate future investigations in this direction. It is also essential and critical to generate toxicological data and pharmacokinetics on human subjects so as to confirm its conceivable bio-active components in the body.
... Araliaceae Used for regulating body disorders, improving the circulatory system, to treat fatigue, for promoting blood circulation for removing blood stasis, invigorating the stomach and for diuresis and so on [13,87] Eleutheroside, acanthopanax senticosus polysaccharide, etc. [13,87] Withania somnifera Indian ginseng Solanaceae Used for strengthening; nourishing;its anti-ageing, antistress, antioxidation, anti-tumor, anti-anxiety, anti-inflammatory, anti-depression properties; immune regulation; improving cognitive function and so on [19] Withanolides and other steroid esters and withanine and other alkaloids [88] Pfaffia paniculata ...
Article
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Abstract Modern studies have shown that adaptogens can non-specifically enhance the resistance of human body under a wide range of external stress conditions with a multi-targeted and multi-channel network-like manner, especially by affect the immune-neuro-endocrine system and the hypothalamic–pituitary–adrenal axis. This review article draws the attention to the relationships of adaptogens, tonics from traditional Chinese medicine (TCM) and ginseng-like herbs worldwide, which all have similar plant sources and clinical applications. To clarify the sources and pharmacological mechanisms of these plant-originated adaptogens, which will provide useful information for the utilization of adaptogens to improve the human health. Meanwhile, the TCMs and the world-wide ginseng-like herbs from each region’s ethnopharmacology will be beneficial modernization and globalization.
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The Amazon Forest is known all over the world for its diversity and exuberance, and for sheltering several indigenous groups and other traditional communities. There, as well as in several other countries, in traditional medical systems, weakness, fatigue and debility are seen as limiting health conditions where medicinal plants are often used in a non-specific way to improve body functions. This review brings together literature data on Ampelozizyphus amazonicus, commonly known in Brazil as “saracura-mirá” and/or “cerveja de índio”, as an Amazonian adaptogen, including some contributions from the authors based on their ethnographic and laboratory experiences. Topics such as botany, chemistry, ethnopharmacological and pharmacological aspects that support the adaptogen character of this plant, as well as cultivation, market status and supply chain aspects are discussed, and the gaps to establish “saracura-mirá” as an ingredient for the pharmaceutical purposes identified. The revised data presented good scientific evidence supporting the use of this Amazonian plant as a new adaptogen. Literature data also reveal that a detailed survey on natural populations of this plant is needed, as well as agronomical studies that could furnish A. amazonicus bark as a raw material. Another important issue is the lack of developed quality control methods to assure its quality assessment.
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The target diosgenin–betulinic acid conjugates are reported to investigate their ability to enhance and modify the pharmacological effects of their components. The detailed synthetic procedure that includes copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (click reaction), and palladium-catalyzed debenzylation by hydrogenolysis is described together with the results of cytotoxicity screening tests. Palladium-catalyzed debenzylation reaction of benzyl ester intermediates was the key step in this synthetic procedure due to the simultaneous presence of a 1,4-disubstituted 1,2,3-triazole ring in the molecule that was a competing coordination site for the palladium catalyst. High pressure (130 kPa) palladium-catalyzed procedure represented a successful synthetic step yielding the required products. The conjugate 7 showed selective cytotoxicity in human T-lymphoblastic leukemia (CEM) cancer cells (IC50 = 6.5 ± 1.1 µM), in contrast to the conjugate 8 showing no cytotoxicity, and diosgenin (1), an adaptogen, for which a potential to be active on central nervous system was calculated in silico. In addition, 5 showed medium multifarious cytotoxicity in human T-lymphoblastic leukemia (CEM), human cervical cancer (HeLa), and human colon cancer (HCT 116). Betulinic acid (2) and the intermediates 3 and 4 showed no cytotoxicity in the tested cancer cell lines. The experimental data obtained are supplemented by and compared with the in silico calculated physico-chemical and absorption, distribution, metabolism, and excretion (ADME) parameters of these compounds.
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Hypericum perforatum L. is an ethnomedicine with a popular remedial legacy; especially of antidepressant and wound healing properties. Rigorous preclinical and clinical research conducted in last sesqui-decade has revealed newer facets of its therapeutic activities against psychiatric, metabolic and neoplastic disorders. Most of such curative effects are imparted synergistically by hypericin, hyperforin and flavonoids; but their action mechanisms remain ambiguous. Concomitant administration of St. John’s Wort formulation and cytochrome P450 substrate drug is limited by the episodes of herb–drug interactions; nevertheless, adverse drug reaction rate of H. perforatum remains only 2%. In present review, we aim to highlight the ‘evidence-based’ therapeutic potential of aforementioned phytopharmaceutical, which would accelerate the contemporary pharmaceutical development of this traditional phytomedicine.
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Main conclusion The present review summarises current knowledge of phytoecdysteroids’ biosynthesis, distribution within plants, biological importance and relations to plant hormones. Plant ecdysteroids (phytoecdysteroids) are natural polyhydroxylated compounds that have a four-ringed skeleton, usually composed of either 27 carbon atoms or 28–29 carbon atoms (biosynthetically derived from cholesterol or other plant sterols, respectively). Their physiological roles in plants have not yet been confirmed and their occurrence is not universal. Nevertheless, they are present at high concentrations in various plant species, including commonly consumed vegetables, and have a broad spectrum of pharmacological and medicinal properties in mammals, including hepatoprotective and hypoglycaemic effects, and anabolic effects on skeletal muscle, without androgenic side-effects. Furthermore, phytoecdysteroids can enhance stress resistance by promoting vitality and enhancing physical performance; thus, they are considered adaptogens. This review summarises current knowledge of phytoecdysteroids’ biosynthesis, distribution within plants, biological importance and relations to plant hormones.
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Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-secretase, coupled with the recent identification of β-secretase, has provided discrete biochemical targets for drug screening and development. Alternate and novel strategies for inhibiting the early mechanism of the disease are also emerging. The progress reviewed here, coupled with better ability to diagnose the disease early, bode well for the successful development of therapeutic and preventative drugs for this major public health problem.
Article
Ethnopharmacological relevance: Hypericum perforatum L. (Hypericaceae), popularly called St. John's wort (SJW), has a rich historical background being one of the oldest used and most extensively investigated medicinal herbs. Many bioactivities and applications of SJW are listed in popular and in scientific literature, including antibacterial, antiviral, anti-inflammatory. In the last three decades many studies focused on the antidepressant activity of SJW extracts. However, several studies in recent years also described the antinociceptive and analgesic properties of SJW that validate the traditional uses of the plant in pain conditions. Aim of the review: This review provides up-to-date information on the traditional uses, pre-clinical and clinical evidence on the pain relieving activity of SJW and its active ingredients, and focuses on the possible exploitation of this plant for the management of pain. Materials and methods: Historical ethnobotanical publications from 1597 were reviewed for finding local and traditional uses. The relevant data on the preclinical and clinical effects of SJW were searched using various databases such as PubMed, Science Direct, Scopus, and Google Scholar. Plant taxonomy was validated by the database Plantlist.org. Results: Preclinical animal studies demonstrated the ability of low doses of SJW dry extracts (0.3% hypericins; 3-5% hyperforins) to induce antinociception, to relieve from acute and chronic hyperalgesic states and to augment opioid analgesia. Clinical studies (homeopathic remedies, dry extracts) highlighted dental pain conditions as a promising SJW application. In vivo and in vitro studies showed that the main components responsible for the pain relieving activity are hyperforin and hypericin. SJW analgesia appears at low doses (5-100mg/kg), minimizing the risk of herbal-drug interactions produced by hyperforin, a potent inducer of CYP enzymes. Conclusion: Preclinical studies indicate a potential use of SJW in medical pain management. However, clinical research in this field is still scarce and the few studies available on chronic pain produced negative results. Prospective randomized controlled clinical trials performed at low doses are needed to validate its potential efficacy in humans.
Article
Naturally occurring acylated β-sitosteryl glucosides have been investigated for their novel properties. The synthetic protocol based on the literature data was improved and optimized. The main improvement consists in employing systems of ionic liquids combined with organic solvents in lipase-mediated esterification of (3β)-stigmast-5-en-3-yl β-D-glucopyranoside to get (3β)-stigmast-5-en-3-yl 6-O-acyl-β-D-glucopyranosides. Maximum yields of these products were achieved with Candida antarctica lipase B immobilized on Immobead 150, recombinant from yeast, in absolute THF and in the presence of either ionic liquid [1-butyl-3-methyl imidazolium tetrafluoroborate ([BMIM]BF4) or 1-butyl-3-methyl imidazolium hexafluorophosphate ([BMIM]PF6)] employed. Pharmacological activity of (3β)-stigmast-5-en-3-yl 6-O-acyl-β-D-glucopyranosides was studied in tests on MCF7 tumor cell lines; the compounds displayed moderate activity which was higher than the activity of β-sitosterol. Supramolecular characteristics were discovered at (3β)-stigmast-5-en-3-yl 6-O-dodecanoyl-β-D-glucopyranoside that formed supramolecular polymer through multiple H-bonds in a methanol/water system (60/40). Its formation was confirmed by the independent UV-VIS measurements during certain time period, by variable temperature DOSY-NMR measurement in deuteriochloroform, and visualized by transmission electron microscopy (TEM) and atomic force microscopy (AFM) showing chiral helical structures and complex superassembly systems based on fibrous supramolecular polymer. In contrary, no such properties have been observed for the other two (3β)-stigmast-5-en-3-yl 6-O-acyl-β-D-glucopyranosides under the given experimental conditions.
Article
Amyloid beta protein (Abeta) increases free radical production and lipid peroxidation in PC12 nerve cells, leading to apoptosis and cell death. The effect of ursolic acid from Origanum majorana L. on Abeta-induced neurotoxicity was investigated using PC12 cells. Pretreatment with isolated ursolic acid and vitamin E prevented the PC12 cell from reactive oxygen species (ROS) toxicity that is mediated by Abeta. The ursolic acid resulted in decreased Abeta toxicity assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and trypan blue assay. Thus, treatment with these antioxidants inhibited the Abeta-induced neurotoxic effect. Therefore, these results indicate that micromolar Abeta-induced oxidative cell death is reduced by ursolic acid from Origanum majorana L.
Article
Systematic reviews and meta-analyses represent the uppermost ladders in the hierarchy of evidence. Systematic reviews/meta-analyses suggest preliminary or satisfactory clinical evidence for agnus castus (Vitex agnus castus) for premenstrual complaints, flaxseed (Linum usitatissimum) for hypertension, feverfew (Tanacetum partenium) for migraine prevention, ginger (Zingiber officinalis) for pregnancy-induced nausea, ginseng (Panax ginseng) for improving fasting glucose levels as well as phytoestrogens and St John's wort (Hypericum perforatum) for the relief of some symptoms in menopause. However, firm conclusions of efficacy cannot be generally drawn. On the other hand, inconclusive evidence of efficacy or contradictory results have been reported for Aloe vera in the treatment of psoriasis, cranberry (Vaccinium macrocarpon) in cystitis prevention, ginkgo (Ginkgo biloba) for tinnitus and intermittent claudication, echinacea (Echinacea spp.) for the prevention of common cold and pomegranate (Punica granatum) for the prevention/treatment of cardiovascular diseases. A critical evaluation of the clinical data regarding the adverse effects has shown that herbal remedies are generally better tolerated than synthetic medications. Nevertheless, potentially serious adverse events, including herb-drug interactions, have been described. This suggests the need to be vigilant when using herbal remedies, particularly in specific conditions, such as during pregnancy and in the paediatric population. Copyright © 2016 John Wiley & Sons, Ltd.
Article
In an effort to combat the multifaceted nature of Alzheimer's disease (AD) progression, a series of multifunctional, bivalent compounds containing curcumin and diosgenin were designed, synthesized, and biologically characterized. Screening results in MC65 neuroblastoma cells established that compound 38 with a spacer length of 17 atoms exhibited the highest protective potency with an EC50 of 111.7±9.0nM. A reduction in protective activity was observed as spacer length was increased up to 28 atoms and there is a clear structural preference for attachment to the methylene carbon between the two carbonyl moieties of curcumin. Further study suggested that antioxidative ability and inhibitory effects on amyloid-β oligomer (AβO) formation may contribute to the neuroprotective outcomes. Additionally, compound 38 was found to bind directly to Aβ, similar to curcumin, but did not form complexes with the common biometals Cu, Fe, and Zn. Altogether, these results give strong evidence to support the bivalent design strategy in developing novel compounds with multifunctional ability for the treatment of AD.