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REVIEW
Rhodiola rosea L. and Alzheimer’s Disease: From
Farm to Pharmacy
Seyed Fazel Nabavi,
1
Nady Braidy,
2
*Ilkay Erdogan Orhan,
3
Arash Badiee,
4
Maria Daglia
5
and
Seyed Mohammad Nabavi
1
*
1
Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
2
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
3
Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, Turkey
4
Deputy of Food and Drug, Mazandaran University of Medical Sciences, Sari, Iran
5
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Italy
Rhodiola rosea L. (roseroot) is a common member of the family Crassulaceae, known as one of the most impor-
tant popular medicinal plants in the northern region of Europe. The roots of R. rosea possess a wide range of
pharmacological activities such as antioxidant, antiinflammatory, anticancer, cardioprotective, and neuroprotec-
tive effects that are because of the presence of different phytochemicals such as phenols and flavonoids. In ad-
dition, the presence of salidroside, rosavins, and p-tyrosol are responsible for its beneficial effects for the
treatment of on depression, fatigue, and cognitive dysfunction. A plethora of studies report that R. rosea has po-
tent neuroprotective effects through the suppression of oxidative stress, neuroinflammation, and excitotoxicity in
brain tissues and antagonism of oncogenic p21-activated kinase. However, to our knowledge, no review articles
have been published addressing the neuroprotective effects of R. rosea. Therefore, the present article aims at
critically reviewing the available literature on the beneficial effects of R. rosea on as a therapeutic strategy for
the treatment of Alzheimer’s disease and other neurodegenerative diseases where oxidative stress plays a major
role in disease development and progression. We also discuss the cultivation, phytochemistry, clinical impacts,
and adverse effects of R. rosea to provide a broader insight on the therapeutic potential for this plant. Copyright
© 2016 John Wiley & Sons, Ltd.
Keywords: Neurodegeneration; Neuroinflammation; Neurotoxicity; Oxidative stress; Rhodiola rosea.
INTRODUCTION
Alzheimer’s disease (AD) is one of the most common
debilitating age-related neurodegenerative disorders,
which causes dementia in the elderly. It is associated
with progressive cognitive impairment and dementia,
eventually leading to complete incapacity and death
(Birks, 2006; Reitz et al., 2011). Ageing represents the
main risk factor for developing AD (Lindsay et al.,
2002). However, cardiovascular diseases, obesity, diabe-
tes, traumatic brain injury, cigarette smoking, and alcohol
abuse are other important risk factors of major concern.
AD was first reported in a 51-year-old woman who suf-
fered from progressive dementia, by the German psychi-
atrist and neuropathologist, Alois Alzheimer, in 1907
(Berchtold and Cotman, 1998). Since then, while exten-
sive progress has been made in AD research, the exact
etiology and pathogenesis of the disease remain unclear.
Although AD remains untreatable, it has been reported
that mental stimulation and exercise training can delay
cognitive impairment in patients who suffer from AD.
Histopathologically, AD is characterized by the pres-
ence of extracellular amyloid plaques containing aggre-
gated amyloid beta (Aβ) peptides and intracellular
neurofibrillary tangles containing hyperphosphorylated
tau protein. A wealth of evidence has shown that
marked increases in oxidative stress are present in the
AD brain in addition to the well-established pathology.
Increased production of reactive oxygen species (ROS)
and reactive nitrogen species (RNS) induces oxidative
stress and cell death in neural tissues of the brain.
ROS and RNS are well known to induce oxidative dam-
age to biological macromolecules, including proteins
and lipids resulting in the cross-linking of cytoskeletal
biological macromolecules (Yu, 1994; Stadtman and
Berlett, 1997; Toyokuni, 1999; Patel et al., 2000). In
addition, accelerated production of ROS and RNS leads
to oxidative injuries to RNA and DNA leading to a
variety of mutations and cell death. With respect to the
high metabolic activity as well as high levels of polyun-
saturated fatty acids and low levels of antioxidant
enzymes and non-enzymatic antioxidants, the brain is
highly susceptible to oxidative stress. Because of
regional differences in total brain antioxidant activity,
it is likely that selective regional susceptibilities for oxi-
dative stress exist in the brain.
Pathological evidence has shown that oxidative stress
plays a crucial role in both the initiation and progression
of AD. It has been reported that in AD, cholinergic neu-
rons in the forebrain are highly vulnerable to oxidative
* Correspondence to: Nady Braidy, Centre for Healthy Brain Ageing,
School of Psychiatry, University of New South Wales, Sydney, Australia;
Seyed Mohammad Nabavi, Applied Biotechnology Research Center,
Baqiyatallah University of Medical Sciences, Tehran, Iran, P.O. Box
19395-5487.
E-mail: n.braidy@unsw.edu.au (Nady Braidy); Nabavi208@gmail.com
(Seyed Mohammad Nabavi)
PHYTOTHERAPY RESEARCH
Phytother. Res. 30: 532–539 (2016)
Published online 11 January 2016 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/ptr.5569
Copyright © 2016 John Wiley & Sons, Ltd.
Received 05 October 2015
Revised 07 December 2015
Accepted 12 December 2015
stress (Yankner, 1996; Gibbs and Aggarwal, 1998). In
addition, increased levels of F
2
-isoprostanes, a marker
for lipid peroxidation in the neuronal tissues, have been
reported in multiple regions of the brain and cerebrospi-
nal fluid of patients with AD (Praticò et al., 1998;
Montine et al., 2005). Furthermore, in the neural tissues,
oxidative stress is associated with increasing in the level
of protein carbonyls that can induce DNA damage. The
levels of protein carbonyls and 3-nitrotyrosine and
markers of oxidative damage to DNA and RNA, such
as 8-hydroxydeoxyguanosine, are higher in AD brains
compared with age-matched controls (Butterfield and
Kanski, 2001). As well, the activities of several endoge-
nous antioxidant enzymes such as superoxide dismutase
(SOD) and catalase have been observed in both the cen-
tral nervous system and peripheral nervous system tissues
of AD patients (Pratico and Sung, 2004). Elevations in
oxidative stress markers have also been reported in mild
cognitive impairment, an intermediate state between nor-
mal ageing and dementia (Ansari and Scheff, 2010). This
suggests that oxidative damage in AD may commence
prior to the onset of the disease. Therefore, oxidative
stress may represent an early alteration during the devel-
opment of the disease.
Neuroinflammation also appears to play a prominent
role in the pathogenesis of AD. Microglial cells, the resi-
dent immune cells of the brain, have been shown to be re-
cruited to AD-associated Aβplaques and in close
proximity to neurofibrillary tangles (Rogers et al., 1988;
Griffin et al., 1989). Increased levels of several inflamma-
tory molecules have been reported, including complement
compounds, cytokines, macrophage colony-stimulating
factor, transforming growth factor-α, C-reactive protein,
S100β, and arachidonic acid (Hensley, 2010). These
inflammatory markers are capable of producing ROS
and RNS, which are elevated in the AD brain and amply
evidenced. Despite this, the exact role of the primacy
and consequences of neuroinflammation as an initiator
or accelerator of AD remains unclear. Current research
suggests that neuroinflammation represents an early and
continuous feature in AD that is amenable to pharmaco-
logical exploitation.
Glutamate neurotoxicity has also been thought to
play critical roles in the pathophysiology of AD and
other neurodegenerative disorders, including hypoxic-
ischemic brain injury, epileptic seizures, and Parkinson’s
disease. L-glutamate (L-glu) is the most abundant excit-
atory neurotransmitter in the central nervous system
(CNS). It plays a crucial role in the neurological pro-
cesses including cognition, learning, and memory
(Collingridge and Lester, 1989). However, hyperactiva-
tion of glutaminergic receptors, under pathophysiologi-
cal conditions, induces neuronal damage and cell death
via apoptosis and energy restriction, known as
excitotoxicity (Olney et al., 1971). Therapeutic strate-
gies that attenuate L-glu-induced excitotoxicity are
potential candidates for the treatment of AD.
Dendritic spine defects are a common feature in AD
and human developmental mental retardation syn-
dromes (Fiala et al., 2002). While it is likely that
dendritic spine defects occur secondarily to upstream
deficits in mental retardation, the exact significance of
dendritic spine defects in AD pathology was strength-
ened by the recent finding that the genes associated with
mental retardation are linked to the X chromosome
(Ramakers, 2002). These studies identified a clustering
of proteins in the postsynaptic pathways modulating
spine actin assembly and disassembly and spine mor-
phogenesis (Kichina et al., 2010). Most important are
p21-activated kinases (PAKs), which represent a down-
stream signaling effector of the Rho/Rac family of small
GTPases (Kichina et al., 2010). PAKs have been shown
to be involved in multiple signal transduction pathways
in mammalian cells (Maruta, 2014). For instance,
PAK1 has been shown to be decreased in the hippocam-
pus from postmortem AD brain, accompanied by
relocalization of activated PAKs to the membrano-
cytoskeletal fractions (Zhao et al., 2006). A recent study
showed that a dominant-negative form of PAK1 sensi-
tizes, while the wild-type form ameliorated toxicity
induced by cytotoxic Aβoligomers in cultured primary
neurons (Zhao et al., 2006). Dominant-negative PAK1
has been shown to antagonize other PAK isoforms,
following expression in mouse forebrain-affected
synapse morphology and consolidation of long-term
memory (Hayashi et al., 2004).
In respect to this, much attention has been paid to an-
tioxidants as a therapeutic strategy for the treatment of
AD (Choi et al., 2012; Feng and Wang, 2012; Galasko
et al., 2012; Mecocci and Polidori, 2012). Plants and
plant products are rich sources of natural polyphenolic
antioxidants such as flavonoids, which can scavenge free
radicals while demonstrating potent antiinflammatory
properties and low adverse effects (Nabavi et al.,
2012b; Nabavi et al., 2013b; Nabavi et al., 2014; Nabavi
et al., 2015c). At present, there are numerous scientific
evidences regarding the beneficial effects of natural
products in human diseases (Nabavi et al., 2012a;
Nabavi et al., 2013a; Nabavi et al., 2015a; Nabavi et al.,
2015b; Nabavi et al., 2015d). Rhodiola rosea L. is an
important plant species from the genus Rhodiola.Itis
most abundant in Eastern Europe and Asia where it is
used as a traditional medicine for a variety of different
ailments (Brown et al., 2002; Panossian et al., 2010).
The aim of this paper is to critically review the scientific
evidence regarding the beneficial effects of R.rosea in
AD and lay foundation for its future research.
RHODIOLA ROSEA L.
Rhodiola rosea L. (roseroot, golden root, or Arctic root)
is a genus of herbaceous perennial plants that belongs to
the family Crassulaceae (Rohloff, 2002; Ming et al.,
2005). Rhodiola species grow wild in high-altitude areas
as well as other cold parts of continental Asia, Europe,
and America (Brown et al., 2002; De Bock et al.,
2004). In continental Asia, the genus Rhodiola is abun-
dant in the Altai Mountains located between Mongolia
and Siberia regions (Furmanowa et al., 1995; Galambosi,
2006). In the continental Europe, it is widely distributed
in Iceland and the British Isles between Scandinavia and
several mountains such as Pyrenees, Alps, Carpathian
as well as other mountains in the Balkan area (Brown
et al., 2002; Wiedenfeld et al., 2007; Panossian et al.,
2010). In addition, some varieties of Rhodiola have
been found in different high-altitude regions of Alaska,
Canada as well as other mountains of the North American
continent (Brown et al., 2002). It is an herbaceous
perennial flowering member of the genus Rhodiola that
has a wide range of medicinal effects in the traditional
533RHODIOLA ROSEA L. AND ALZHEIMER’S DISEASE
Copyright © 2016 John Wiley & Sons, Ltd. Phytother. Res. 30: 532–539 (2016)
medicine. It is widely distributed in the Arctic and moun-
tainous area of the Europe and Asia and traditionally
used for treatment of human diseases especially mental
diseases (Adaptogen, 2001; Brown et al., 2002). In addi-
tion to R.rosea, there are over 200 species from the genus
Rhodiola (Platikanov and Evstatieva, 2008) of which at
least 20 species (such as Rhodiola alterna S.H. Fu,
Rhodiola brevipetiolata (Fröd.) S.H. Fu, Rhodiola
crenulata (Hook.f. & Thomson) H.Ohba, Rhodiola
kirilowii (Regel) Maxim., Rhodiola quadrifida (Pall.)
Fisch. & C.A.Mey, Rhodiola sachalinensis Boriss., and
Rhodiola sacra (Prain ex Raym.-Hamet) S.H. Fu) are
known to have different medicinal effects in traditional
medicine (Adaptogen, 2001; Brown et al., 2002; Goldstein
et al., 2008; Li et al., 2009).
RHODIOLA ROSEA L. CULTIVATION
Up till now, cultivation experiments have been
performed in Russia, Sweden, Poland, Finland, and
Germany (Galambosi, 2006; Platikanov and Evstatieva,
2008; Galambosi et al., 2009; Kylin, 2010; Adamczak
et al., 2014) that show that R.rosea can be successfully
cultivated in cool and moist climates with precipitation
(Galambosi, 2006; Platikanov and Evstatieva, 2008;
Galambosi et al., 2009; Kylin, 2010; Adamczak et al.,
2014). However, it does not prefer shaded areas
(Kucinskaite et al., 2006). It is well grown in deep soil
in which it can easily penetrate (Galambosi, 2006).
Moreover, R.rosea prefers moderately rich and well-
drained slightly acidic soils (pH 6–7) (Galambosi, 2006;
Platikanov and Evstatieva, 2008). It can also grow in
sandy loam soils and even rocks (Alm, 2004; Galambosi,
2006). There are negligible reports regarding the benefi-
cial effects of fertilizers for the cultivation of Rhodiola
(Galambosi, 2006; Platikanov and Evstatieva, 2008;
Galambosi et al., 2009; Kylin, 2010; Adamczak et al.,
2014). However, it has been reported that the root size
of Rhodiola in weak soils is significantly lower than that
occurring in the cultivation that is because of insufficient
nutrients required for Rhodiola (Galambosi, 2006;
Platikanov and Evstatieva, 2008; Galambosi et al.,
2009; Kylin, 2010; Adamczak et al., 2014). It has also
been reported that R.rosea can be propagated by seed-
lings, root division as well as seed germination
(Furmanowa et al., 1995; Galambosi, 2006). The propa-
gation of seedlings is the most effective method for
larger scale cultivation of R.rosea (Galambosi, 2006;
Platikanov and Evstatieva, 2008).
PHYTOCHEMISTRY OF RHODIOLA ROSEA L.
Rhodiola rosea has a rich variety of phytochemical con-
tent including cinnamoyl glycosides (phenylethanoids),
flavonoids, phenylpropanoids, essential oil (monoter-
penes), phenolic acids, cyanogenic glucosides as well as
polysaccharides and oligomeric proanthocyanidins (Zhou
et al., 2014) (Fig. 1). Flavonoids appear to be the main con-
stituents in R.rosea asmainly,i.e.herbacetin,
gossypetin, and kaempferol derivatives. Early studies
originating from the 1980s indicated that the plant
contains a number of flavonoids such as tricin (4′,5,7-
trihydroxy-3′,5′-dimethoxyflavone) and its 7- and 5-O
glucosides, herbacetin (3,4′,5,7,8-pentahydroxyflavone),
and its derivatives; rhodionin (herbacetin 7-O-α-
rhamnopyranoside), rhodiosin (herbacetin 7-O-3″-O-β-
D-glucopyranosyl-α-L-rhamnopyranoside), rhodiolin (a
flavonolignan), rhodionidin (herbacetin-7-O-α-L-
rhamnopyranose-8-O-β-D-glucopyranoside), rhodiolgin
(gossypetin-7-O-α-L-rhamnopyranoside), rhodiolgidin (go
ssypetin-7-O-α-L-rhamnopyranose-8-O-β-D-glucopyrano-
side), rhodalin (herbacetin-8-O-β-D-xylopyranoside), rho
dalidin (herbacetin-8-O-β-D-xylopyranose-3-O-β-D-gluco
pyranoside), the flavonoid glycosides; gossypetin-7-O-L-
rhamnopyranoside and rhodioflavonoside, rhodioflavo
noside, kaempferol-3-O-β-d-glucopyranosyl-7-O-α-l-
rhamn-opyranoside, kaempferol 3-O-β-d-glucopyrano
side-(2 →1)-β-d-xylopyranoside 3, and herbacetin-8-O-
Figure 1. Main chemical classes present in Rhodiola rosea L.
534 S. F. NABAVI ET AL.
Copyright © 2016 John Wiley & Sons, Ltd. Phytother. Res. 30: 532–539 (2016)
β-d-glucopyranoside. In addition, Tolonen and Uusitalo
(Tolonen and Uusitalo, 2004) detected several flavonoid
derivatives in the flowers of R.rosea identified as
rhodiolgidin, rhodiolgin, rhodionin as well as some
unidentified flavonol-glucoside mixtures using a fast and
simple LC-MS method. Isolation of the common flavonoid
derivatives apigenin, luteolin, kaempferol, quercetin,
cosmosiin, astragalin, linocinamarin, rutin, and nicotiflorin
was reported by Jeong et al. (Jeong et al., 2009) as well as
kaempferol-7-O-alpha-L-rhamnopyranoside, herbacetin-
7-O-alpha-L-rhamnopyr-anoside, herbace-tin-7-0-(3″-O-
beta-D-glucopyran-oside)-alpha-L-rhamnopyranoside,
and 5,7,3′,5′-tetrahydroxy-flavanone.
Phenylpropanoids and cinnamyl alcohol glycosides
(or phenyl ethanoids) constitute a large quantity in R.
rosea. Thesalidroside (rhodioloside) [β-D-glucopyranoside
of β-(p-hydroxyphenyl)ethanol] (Fig. 2) is the first
cinnamyl glycoside reportedly isolated from this species
in 1967 (Troshchenko and Kutikova, 1967). Kurkin et al.
(Kurkin et al., 1991) successfully isolated 11
phenylpropanoid and cinnamyl glycosidic compounds
from the callus culture of the plant, some of which
were identified as p-coumaric acid 4′-glucoside and
1-glucoside, caffeic acid 3′-glucoside, triandrin,
lariciresinol 4-glucoside, vimalin, rosarin, and rosin
(Fig. 2). Later, cinnamyl-(6′-O-β-xylopyranosyl)-O-β-
glucopyranoside and 4-methoxy-cinnamyl-(6′-O-α-arabino
pyranosyl-O-β-glucopyranoside were obtained from R.
rosea as new phenylpropanoid derivatives, in addition to
picein and benzyl-O-beta-glucopyranoside (Tolonen et al.,
2003). Rosarin, rosin, and rosavin were also quantified in
the roots of the plant using high-performance thin layer
chromatography and reverse-phase HPLC methods
(Fig. 2). Among these derivatives, salidroside needs a spe-
cial mention as it possesses many potent biological activi-
ties. Although its presence was earlier reported from a
number of plant genera such as Salix species, Rhodo-
dendron ponticum,Comus sp., Forsythia sp., Strychnos
nux-vomica,Rehmannia glutinosa,Linaria japonica,
Penstemon acuminatus, etc., it is most common in
Rhodiola species and occasionally serves as a chemo-
taxonomic marker. Salidroside is the main substance
in R.rosea, which is responsible for many pharmaco-
logical activities reported by the plant as well as the
reference compound in quality assessment of
preparations containing roseroot extracts. R.rosea
roots also yielded rhodiolosides A–E, identified as five
new monoterpene glycosides. Their corresponding
chemical structures were elucidated as (2E,6E,4R)-
4,8-dihydroxy-3,7-dimethyl-2,6-octadienyl β-D-gluco
pyranoside (rhodioloside A), (2E,4R)-4-hydroxy-3,7-
dimethyl-2,6-octadienyl α-D-glucopyranosyl(1 →6)-β-
D-glucopyranoside (rhodioloside B), (2E,4R)-4-hy-
droxy-3,7-dimethyl-2,6-octadienyl β-D-glucopyranosyl
(1 →3)-b-D-glucopyranoside (rhodioloside C), (2E,4R)-
4,7-dihydroxy-3,7-dimethyl-2-octenyl β-D-glucopyranoside
(rhodioloside D), and (2E)-7-hydroxy-3,7-dimethyl-2-
octenyl α-L-arabinopyranosyl(1 →6)-β-D-glucopyranoside
(rhodioloside E) (Ma et al., 2006).
Moreover, a few studies have shown that the plant
contains essential oils. For instance, the sample of R.rosea
was found to contain myrtenol (36.9%), trans-pinocarveol
(16.1%), geraniol (12.7%), and dihydrocumin alcohol
(12.1%) as the major components. In another study, the
essential oils obtained from three samples of R.rosea
from Bulgaria, China, and India were analyzed, and
geraniol was determined as the chief compound in
Bulgarian and Chinese samples, whereas phenylethyl
alcohol was the major oil in the Indian sample. Other
chemicals found in R.rosea were reported as lotaustralin
(a cyanogenic glucoside) (Fig. 2), β-sitosterol, and
oligomeric proanthocyanidins composed of ()-epigallo-
catechin and its 3-O-gallate esters, polysaccharides, and
lignins. Rosiridol, the oxygenated derivative of geraniol,
was identified as the aglycon of rosiridin, suggested to be
an important bioactive compound for R.rosea (Fig. 2)
(Van Diermen et al., 2009).
RHODIOLA ROSEA L. IN TRADITIONAL
MEDICINE
Rhodiola rosea has been used in traditional medicine
from ancient times till current times for the treatment
of diarrhea, hysteria, hernias, headaches as well as cog-
nitive dysfunctions. Additionally, it has been widely
used as an astringent in traditional herbal medicine. It
has also been reported that Rhodiola infusion possesses
a beneficial effects on mouth pain and kidney stones,
swellings, back pain, as well as mood disorders
(Panossian et al., 2010; ; Cropley et al., 2015). In addition
to these beneficial effects, it has been reported that
Rhodiola infusion has significant effects on hair growth
(Panossian et al., 2010; Zhu et al., 2014). In traditional
medicine, its roots are also used for mitigation of differ-
ent skin diseases (Mamedov et al., 2005). According to
Grasnytjar, dried roots of Rhodiola have beneficial ef-
fects on freckles, scurvy, as well as physical and mental
weakness. It has also been reported that Rhodiola has
a stimulant effect as well as vasoconstrictive and hemo-
static activity on hemorrhoids (Sandberg and Bohlin,
1993; Linné, 2005). It has also been reported that R.
rosea can be used for the treatment of different mental
diseases such as schizophrenia. R.rosea is currently
Figure 2. Main compounds found in Rhodiola rosea L.
535RHODIOLA ROSEA L. AND ALZHEIMER’S DISEASE
Copyright © 2016 John Wiley & Sons, Ltd. Phytother. Res. 30: 532–539 (2016)
known as an adaptogen for treatment of fatigue and
weakness in the traditional herbal medicine (Panossian,
2003; Ishaque et al., 2012).
CLINICAL IMPACT OF RHODIOLA ROSEA L.
A search in http://clinicaltrial.gov/ with keywords
‘Rhodiola rosea’,‘Roseroot’and ‘Golden root’(6 October
2014) demonstrated that there are only three clinical
trials on the beneficial effects of R.rosea. The first clin-
ical trial is aimed at evaluating the beneficial role of R.
rosea in comparison with placebo on shift work nurses.
The second clinical trial evaluates the antidepressant
effect of R.rosea in comparison with the antidepres-
sant, sertraline, in patients who suffered from major
depressive disorder. The last clinical trial examines
the beneficial effects of R.rosea in comparison with
ginseng and placebo in patients who suffered from mild
depression. Details of clinical trials on R.rosea are pre-
sented in Table 1.
TOXICITY OF RHODIOLA ROSEA L.
At present, scientific reports regarding the adverse
effects of R.rosea are negligible (Adaptogen, 2001;
Ming et al., 2005). However, it has been reported
that the median lethal dose (LD
50
)forR.rosea ex-
tract is 3360 mg/kg body weight in rat (Khanum
et al., 2005). Therefore, it can be concluded that
equivalent dosage in a 70-kg man is about 235.2 g,
which represents a very high amount of extract.
The safety of daily consumption of R.rosea in
humans (at doses 200 to 600 mg per day) remains
negligible (Udintsev and Schakhov, 1991). It has
also been reported that the consumption of R.rosea
may be associated with hyperactivity, jittery, and/or
agitation (Uyeturk et al., 2013). Consumption of R.
rosea in the first weeks can interfere with sleep
and/or induce extra-vivid dreams in consumers
(Hartwich, 2010). Additionally, R.rosea should not
be consumed in patients who suffer from bipolar
disorder, because of its potent antidepressant activ-
ity that can trigger a manic episode (Gerbarg
et al., 2014).
NEUROPROTECTIVE EFFECTS OF RHODIOLA
ROSEA L.
Oxidative stress
Rhodiola rosea is composed of large tuberous roots
composed of several active compounds including pheno-
lics, flavonoids, and phenylpropanoids (Devasagayam
et al., 2004). The oligomeric proanthocyanidin
(OPCRR), a kind of phenolics, have demonstrated po-
tent antioxidant activity (Hernández-Santana et al.,
2014). One study evaluated the effects of OPCRR on
the antioxidant enzymes activity and lipid peroxide con-
tent in vivo. In particular, three biochemical biomarkers
were evaluated, including SOD, glutathione peroxidase
(GSH-Px), and malondialdehyde (MDA) in serum,
heart, liver, and brain tissues in mice. The data showed
that OPCRR significantly increased SOD and GSH-Px
activities,while reducing the MDA content inmice (Zhou
et al., 2014). The data suggests indicated that OPCRR is a
potent natural antioxidant because of its considerable an-
tioxidant activities both in vitro and in vivo.
Neuroinflammation
The activation of microglia is a major feature in the patho-
genesis of AD (McGeer and McGeer, 1999). Several stud-
ies have demonstrated that activated microglia can
produce significant quantities of inflammatory mediators
capable of releasing large amounts of ROS, nitric oxide
(NO), and proinflammatory cytokines such as TNF-α,
interleukin-1β(IL-1β), and interleukin-6 (IL-6), culminat-
ing in neuronal cell death (Gonzalez-Scarano and Baltuch,
1999). Therefore, drugs with antiinflammatory properties
represent a promising therapeutic strategy for the treat-
ment of AD. NO is the main mediator of neuroinflamma-
tion. Lee et al. (2013) investigated the neuroprotective
effect of R.rosea constituents on the NO production after
the activation of murine microglial BV2 cells by lipopoly-
saccharides. The study showed that the R.rosea constitu-
ents, rosarin, and salidroside suppressed the generation of
NO in activated microglia in a dose-dependent manner.
The expression of inducible nitric oxide synthase (iNOS)
was heavily increased by LPS leading to increased pro-
duction of TNF-α. The study also showed that rosarian
and salidroside can inhibit LPS-induced iNOS expression
and decreased the production of TNF-α,IL-1β, and IL-6
that are induced by LPS in BV2 microglia cells in a
Table 1. Details of our search in http://clinicaltrial.gov/ with keywords ‘Rhodiola rosea’,‘Roseroot’and ‘Golden root’
NCT number Study start Study type Condition Title
NCT01278992 January 2011 Interventional Fatigue Rhodiola rosea for Mental and Physical Fatigue
NCT01098318 June 2010 Interventional Depression Rhodiola rosea Therapy of Major Depressive Disorder
NCT01006460 November 2009 Interventional Depression, stress A Study With Arctic Root Compared With the Extract When
Combined With Schizandra and Russian Root (Adapt 232),
Standardized Ginseng Extract and Placebo Regarding Impact
on the Level of Energy, Ability to Work Under Stress, Quality
of Life and Wellbeing, in Middleaged Women Who Are Still
Employed
536 S. F. NABAVI ET AL.
Copyright © 2016 John Wiley & Sons, Ltd. Phytother. Res. 30: 532–539 (2016)
dose-dependent manner (Lee et al., 2013). TNF-α,which
potentiates damage to neuronal cell, is a costimulator that
is thought to be mediated in the regulation of iNOS gene,
via the mitogen-activated protein kinase (MAPK) and
NF-κB signaling pathway (Gautron et al., 2002). The
study further showed that oral administration of R.rosea
extract significantly decreased iNOS and proinflamma-
tory cytokine expression in the kidney and prefrontal cor-
tex of the brain (Lee et al., 2013). This suggests that R.
rosea constituents can cross the blood–brain barrier and
enter the brain to suppress inflammation in the CNS.
Excitotoxicity
R.rosea constituents have been shown to suppress L-Glu-
induced excitotoxicity in vitro in primary cortical neurons
in vitro. More specifically, rosin and salidroside prevented
neuronal toxicity following 18-h exposure with L-glu at
pathophysiological concentrations as evidenced by the
lactate dehydrogenase assay (Lee et al., 2013).
Effect on oncogenic kinase PAK1
Salidroside, one of the major ingredients in R.rosea,has
beenshowntoactivate5′AMP-activated protein
kinase (AMPK) (Li et al., 2008). Similarly, R.rosea
extract (10–25 μg/ml) has been shown to promote life
span in Caenorhabditis elegans by activating FOXO.
This longevity transcription factor can activate the heat
shock protein, HSP16. As AMPK is necessary for
activation of FOXO, the life extension properties of R.
rosea extract are most likely attributed to salidroside
(Wiegant et al., 2009). Moreover, salidroside has also been
shown to attenuate tumor-induced angiogenesis, which is
dependent on both PAK1 and AMPK. It is well
established that activation AMPK alone cannot amelio-
rate angiogenesis (Skopińska-Rózewska et al., 2008).
Taken together, these studies suggest that salidroside
can exert neuroprotection by inhibiting PAK1 and
activating AMPK.
Other effects against neurodegeneration
In AD brain, a strong correlation association between
neurotoxicity and MAPK activation, has been reported
in dystrophic neurons and astroglial cells (Webster
et al., 2006). MAPK cascades, which are involved in the
apoptotic signal transduction, are induced by neurotox-
icity. It is thought that activation of JNK and p38 MAPK
is closely associated with cytotoxic insult, whereas the
activation of extracellular signal-regulated kinase
(ERK) is associated with cell proliferation and acts as
an anti-apoptotic signal (Junttila et al., 2008). One study
showed that the R.rosea constituents, rosarin, and
salidroside can inhibit L-glu-induced JNK and p38
MAPK but not ERK phosphorylation (Lee et al., 2013).
CONCLUSION AND RECOMMENDATIONS
In this paper, we critically reviewed the available litera-
tures regarding the neuroprotective effects of the medic-
inal plant R.rosea L., against oxidative stress,
neuroinflammation, PAK1, and AD. Taken together,
current research using R.rosea has been shown to pos-
sess both preventive and/or protective effects in AD
Figure 3. Schematic representation of the neuroprotective effects of Rhodiola rosea L. Current research using R.rosea has been shown to
possess both preventive and/or protective effects in AD through the suppression of oxidative and nitrosative stress, reduction of
excitotoxicity, altered intracellular signaling, antiinflammatory effects, and upregulation of endogenous antioxidant enzymes in neuronal
tissue.
537RHODIOLA ROSEA L. AND ALZHEIMER’S DISEASE
Copyright © 2016 John Wiley & Sons, Ltd. Phytother. Res. 30: 532–539 (2016)
through the suppression of oxidative and nitrosative
stress in neuronal tissues (Fig. 3). In addition, we
showed that R.rosea is a non-toxic medicinal plant even
at high doses with limited interaction with other drugs.
Henceforth, R.rosea can be suggested as a potential
candidate for future clinical trials aimed at examining
the beneficial role of R.rosea in AD patients. R.rosea
can easily be cultivated in some European countries
and propagates by seedling propagation. However,
there are few clinical trials on the beneficial role of R.
rosea in humans, and therefore, it can be difficult to
make a clear decision about its most effective clinical
doses. Respect to negligible adverse effects of R.rosea,
it can be recommended that future studies should aim to
(1) ascertain the best method for large-scale cultivation
of R.rosea, (2) elucidate the exact molecular mechanisms
of neuroprotective effects of R.rosea, (3) identify the
neuroprotective constituents of R.rosea using new phyto-
chemical analysis techniques, (4) ascertain the most effec-
tive clinical doses of R.rosea, and (5) examine the
neuroprotective activities of R.rosea through clinical
studies.
Acknowledgements
None.
Conflict of Interest
The authors disclose no conflict of interest.
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539RHODIOLA ROSEA L. AND ALZHEIMER’S DISEASE
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