Available via license: CC BY 4.0
Content may be subject to copyright.
Journal of Food Studies
ISSN 2166-1073
2013, Vol. 2, No. 2
www.macrothink.org/jfs
31
In Vitro and in Silico Evaluation of the Potential for
Neuroprotection of Rhodiolife, A Rhodiola Rosea Roots
Extract
José M Zubeldia (Corresponding author)
Development, PoliNat SL
Taibique 4, Polígono Industrial Las Majoreras, 35240 Las Palmas, Spain
Tel: 34-92-873-4132 E-mail: jose@polinat.com
Aarón Hernández-Santana
Research, PoliNat SL
Taibique 4, Polígono Industrial Las Majoreras, 35240 Las Palmas, Spain
Tel: 34-92-873-4132 E-mail: aaron@polinat.com
Miguel Jiménez del Rio
Management & Production, PoliNat SL
Taibique 4, Polígono Industrial Las Majoreras, 35240 Las Palmas, Spain
Tel: 34-92-873-4132 E-mail: mjimenez@polinat.com
Verónica Pérez-López
Nutragenomics laboratory, PoliNat SL
Taibique 4, Polígono Industrial Las Majoreras, 35240 Las Palmas, Spain
Tel: 34-92-873-4132 E-mail: veronica@polinat.com
Received: Oct. 6, 2013 Accepted: November 28, 2013 Published: December 1, 2013
doi:10.5296/jfs.v2i2.4632 URL: http://dx.doi.org/10.5296/jfs.v2i2.4632
Journal of Food Studies
ISSN 2166-1073
2013, Vol. 2, No. 2
www.macrothink.org/jfs
32
Abstract
Rhodiola rosea, an adaptogen plant from cold regions, has been previously proposed for
alleviating dementia and other neurodegenerative diseases. The goal of our study was to
evaluate if our proprietary extract (RhodioLife) was able to elicit biological responses related
to neuroprotection in neuronal cultures. NS20Y cells were cultured according to procedures
and increasing concentrations of RhodioLife were added to the media. Viability at 24h using
Presto BlueTM showed no statistically significant differences at those concentrations (0-50
ppm). Quantitative real-time RT-PCR analysis (G-coupled protein receptor [GCPR] array)
showed statistically significant (p<0.05) upregulation of 3 genes: calcitonin receptor-like
(CALCRL), cyclin-dependent kinase inhibitor 1A (CDKN1A), and lysophosphatidic acid
receptor 2 (LPAR2) (4, 3 and 2-fold respectively). In silico evaluation of the bioactives
contained in RhodioLife (www.molinspiration.com) revealed that Salidroside, Rosarin,
Rosavin, Rosiridin, Cinnamyl alcohol and p-Tyrosol all had 1 or no violations of the
Lipinski´s rule of five, suggesting favorable pharmacokinetics. The predicted G-coupled
protein receptor bioactivity was greatest for Rosarin (0.39) and Salidroside (0.35). We
conclude that RhodioLife contained substances which had relevant biological activity and
molecular properties suggesting a role in neuroprotection. Studies in suitable animal
models are recommended.
Keywords: Neurodegenerative disease, Rhodiola rosea, G-coupled protein receptor,
Quantitative real-time RT-PCR analysis
Journal of Food Studies
ISSN 2166-1073
2013, Vol. 2, No. 2
www.macrothink.org/jfs
33
1. Introduction
As the world population grows older and lifespan increases the prevalence of dementia and
other neurodegenerative disorders increases. More than 24.2 million people worldwide were
estimated to have dementia by 2005 and 4.6 millions of new cases have been diagnosed every
year since. Although prevalence is highest in North America and Western Europe, developing
countries are not free of the disease either. The overall prevalence in Africa has been reported
to reach 2.4% of those older than 50. Both westernized societies and developing countries
share the common traits of increasing prevalence with increasing age (George et al, 2012;
Reitz et al 2011).
It is clear that cognitive decline is a mayor public health issue and its monetary costs cannot
be overlooked. In 2010 researchers calculated a cost per person between $41,689 and $56,290
per year which amounted to a total of $157 to $215 billion in the United States alone (Hurd et
al, 2013). Similar overall estimated costs have been also published in Europe
(Luengo-Fernández et al, 2011). Until new effective therapies are brought into the regular
clinical care preventive interventions, including nutrition are of the utmost importance.
Rhodiola rosea (RR), also known as Aaron´s rod, is a perennial plant typical of very cold,
harsh climatic conditions located in areas at altitudes 1,800 m above sea level in Europe and
Asia. Traditional uses include increasing resistance to stress, aiding in mental acuity or
ameliorating high altitude sickness amongst many others (Kelly, 2001). Biochemical
investigations have shown that an alcoholic extract of RR can cause inhibition of
acetylcholine esterase (AChE) explaining its mental and memory enhancing properties.
Specifically, hydroquinone, gossypetin-7-O-L-rhamnopyranoside and rhodioflavonoside have
been implicated in this inhibition and have been proposed as the basis for treating
Alzhemier´s dementia (Hillhouse et al, 2004,Wang et al, 2007). More recently Lee et al have
also reported that rosin was able to reduce the neurotoxicity induced by L-glutamine in
neuronal cells. Additionally, L-glutamine increased the level of phosphorylated MAPK,
pJNK and pp38, but treatment with Rosin and Salidroside resulted in a decrease indicating
the potential for RR for the treatment of inflammation and neurodegeneration (Lee et al,
2013).
Our aims were to explore if our proprietary RR extract (RhodioLife) showed in vitro
biological activity related to protection in dementia and neurodegeneration and investigate
the molecular plausibility of acting in the central nervous system.
2. Materials and methods
2.1 Rhodiola rosea extract preparation
Approximately 5 year old Rhodiola rosea roots were obtained from the Altai region in Siberia,
cleaned, cut, dried, and sieved. A water:ethanol extraction process under controlled
temperature was later applied followed by filtration, distillation, concentration and drying.
The chromatographic analysis of the final product showed a total Rosavins content of >3%
and salidroside >1%.
Journal of Food Studies
ISSN 2166-1073
2013, Vol. 2, No. 2
www.macrothink.org/jfs
34
2.2 Cell culture
A mouse neuroblastoma cell line, NS20Y (American Type Culture Collection, UK), was
cultured in Dulbecco´s Modified Eagle´s Medium ( HyClone DMEM/High Glucose)
supplemented with 5% fetal bovine serum (Lonza, Belgium), 5% calf serum, 1%
L-Glutamine 200mM and 1% penicillin/streptomycin (PAA, Austria). Cells were
maintained at 37°C in a humidified 5% CO2 incubator and medium was replaced every day.
2.3 Cell Viability
Cell viability was determined using the Presto Blue cell viability kit (Invitrogen, Spain)
following the manufacturer´s instructions. The cells were seeded into 96-well plates at a
density of 6x10⁴ cells/ml. The culture medium was replaced with DMEM containing various
concentrations of Rhodiolife® for 1, 24, 48 and 72 h. Control cells were cultured in DMEM
without extract. Before Presto Blue kit reagents were added, the medium was removed. The
cells were incubated with Presto Blue for 1h at 37°C. Fluorescence was measured on a
MX3005P Q-PCR System (Agilent Technologies, Spain) using a Cy3 filter set on plate read
mode.
2.4 RNA and Protein extraction and Quantitative real-time RT-PCR analysis
NS20Y cells were incubated with 50ppm Rhodiolife® for 24 h. RNA and protein were
extracted using All Prep RNA/Protein Kit (Qiagen, Spain). RNA was stored at -80°C and
protein at -20°C until further use.
Total RNA was quantified using a fluorometric method with Quant-iT kit (Invitrogen, Spain).
cDNA was reverse-transcribed from the RNA extract using RT² First Stand cDNA kit and a
RT² Profiler PCR Array was used to analyze a panel of 84 genes representative of and
involved in G-Protein Coupled Receptor-mediated signal transduction pathways (Qiagen,
Spain). Quantitative real-time RT-PCR was carried out using a SYBR-Green/ROX detection
in a MX3005P Q-PCR System. Samples were heated at 95°C for 10 min, followed by a
second stage composed of 15 sec at 95°C, 1 min at 60°C which was repeated 40 times and
third stage for dissociation curve composed of 1 min at 95°C, 30 sec at 55°C and 30 sec at
95°C.
To analyze the PCR-array data, an MS-Excel sheet with macros was downloaded from the
manufacturer’s website (http://www.sabiosciences.com). This program calculated relative
gene expression and statistical significance.
2.5 In silico evaluation
SMILES formulas of main bioactive compounds found in Rhodiola Rosea were uploaded into
Molinspiration engine (www.molinspiraiton.com) from where molecular characteristics and
predicted bioactive data were calculated and downloaded for tabulation.
3. Results and discussion
NS20Y is a cholinergic cell line derived from mouse neuroblastoma C1300. This cell line is a
well-established in vitro model to study neuronal functions. The cells multiply rapidly in vitro,
Journal of Food Studies
ISSN 2166-1073
2013, Vol. 2, No. 2
www.macrothink.org/jfs
35
yet exhibit many properties characteristic of differentiated neurons (Nelson et al, 1969). In
this context, NS20Y were used to study cell viability and changes in modulation of genes
involved in GPCR-mediated signal transduction pathways upon treatment with RhodioLife.
The normal biological processes regulated by GPCR include, but are not limited to,
behavioral and mood regulation, autonomic nervous system transmission, inflammation and
immune system regulation, vision and smell.
NS20Y were treated with Rhodiolife at concentrations ranging from 0.1 to 50 µg/mL for up
to 72 h, and cell viability was evaluated using PrestoBlue cell viability kit. This reagent is a
resazurin based, membrane permeable solution that is reduced to resofurin by metabolically
active cells. Resofurin is a fluorescent compound which can be quantitatively measured to
determine viability (Lall et al, 2013). We did not observe any significant loss of cell viability
for the range of concentrations and treatment periods in this study (p>0.05).
Gene modulation profiles showed statistically significant upregulation of 3 genes (Table 1).
These genes belong to the G-coupled protein receptors (GCPR). Studies have found
alterations in various GPCRs and their downstream signaling in Alzheimer´s disease (Suo &
Li, 2010). The calcitonin receptor-like (CALCRL; fold >4, p<0.05) binds in conjunction with
receptor activity modifying protein type 1 RAMP1 to form calcitonin gene related peptide
(CGRP) which is widely expressed in central and peripheral nervous system (Edvinsson et al,
2011). CGRP is suggested to be involved in an increasing number of biological activities
including regulation of the blood vessels tone (Brain & Cox, 2006). Interestingly it has been
postulated that deposition of beta-amyloid plaques (a hallmark of Alzheimer´s disease)
exhibits a potent vasoconstrictor effect in rat microvasculature but cannot prevent CGRP
from inducing vasodilatation (Khalil et al, 1996).
Table 1. Gene modulation pattern induced in N0Y2 cells treated with RhodioLife
Gene Name Fold P
Calcrl calcitonin receptor-like 4,2022 0,02002
Cdkn1a cyclin-dependent kinase inhibitor 1A (p21, Cip1) 2,992 0,034467
Lpar2 lysophosphatidic acid receptor 2 2,0722 0,012122
The cyclin-dependent kinase inhibitor 1A (CDKN1A) was also upregulated (fold>2.9;
p<0.05). The encoded protein functions as a regulator of cell cycle progression at G1 by
binging and inhibiting the activity of cyclin-CDK2 or -CDK4 complexes (Sherr & Roberts,
1995). Although brain cells have been traditionally considered terminal cells (that is, not
being able to enter the cell cycle), experimental data have shown that cell cycle mediators
such as cyclin dependent kinases (CDKs) remain in the neurons under some form of
inactivation (Tamaru et al, 1993). Further work on the role of these mediators indicates CDKs
modulate stress-induced apoptosis through initiation of a cell cycle and using CDK-inhibitors
led to suppression of cell death and protection of neurons in several models (Kranenburg et al,
1996).
Journal of Food Studies
ISSN 2166-1073
2013, Vol. 2, No. 2
www.macrothink.org/jfs
36
Finally, the lysophosphatidic acid receptor 2 gene (LPAR2) was also up-regulated
significantly. This protein is a lysophosphatidic acid (LPA) receptor and is tightly involved in
Calcium mobilization (An et al, 1998). Calcium has different but fundamental roles in
neuronal plasticity and as a second messenger has been shown to participate in regulation of
gene expression, energy production, membrane excitability, synaptogenesis and synaptic
transmission amongst many others (Kawamoto et al, 2012). Studies in brain cells and mice
have shown the expression of presenilin and amyloid precursor protein (typical pathology
features of the Alzheimer´s dementia) later calcium homeostasis causing synaptic dysfunction
(Woods & Padmanabhan, 2012). Senile plaques made of β-amyloid proteins accumulated
over course of de development of this neurodegenerative disease further disrupts calcium
homeostasis as well which later induce membrane disruption and formation of reactive
oxygen species (Kawahara et al, 2011).
The second part of our experiment was to assess the plausibility of any of the bioactives
actually reaching the central nervous system (CNS). Adaptogenic activity related to Rhodiola
rosea has been traditionally attributed to the presence of four principal active ingredients:
salidroside, rosin, rosavin and rosarin (Sokolov et al, 1985; Furmanova et al, 1998). These
compounds are found at relatively high concentrations in the roots of this plant (> 0.5% - 3 %;
w: w), and are frequently employed for the standardization of commercial products (Markus
et al, 2001). Extracts used in most clinical trials are standardized to minimum 3% total
rosavins and 0.8-1% salidroside, as the naturally occurring ratio of these compounds in the
plant rhizomes is approximately 3:1 (Brown et al, 2002). Other biologically active substances
found in Rhodiola rosea include fl avonoids (rhodiolin, rhodionin, rhodiosin, tricin, rhodalgin
and acetylrhodalgin), monoterpenes (rosiridol and rosiridin), phenylmethanoids (benzyl
alcohol O-α- L-arabinopyranosyl- (1→6)-β-D-glucopyranosyde and phenyl methyl
O-α-L-arabinofuranosyl-(1→6)- β-D-glucopyranosyde), phenolic acids (gallic acid,
chlorogenic acid, caffeic acid and hydroxycinnamic acid) and cyanogenic glycosides
(rhodiocyanoside A and lotaustralin) (Ma et al, 2011; Avula et al, 2009).
Table 2. Molecular properties and predicted bioactivity of key compounds
Bioactives LogP TPSA NV GCPR MV (Å3)
Catechin 1,369 110,374 0 0,41 244,141
Rosarin -0,216 158,304 1 0,39 375,677
Salidroside -0,701 119,608 0 0,35 265,804
Chlorogenic acid -0,435 164,744 1 0,29 296,267
Rosin 0,325 99,38 0 0,23 296,319
Mongrhoside -1,446 167,538 2 0,15 390,608
Rosavin -0,955 158,304 1 0,13 375,677
PAC 3,054 209,754 3 0,13 493,201
Rosiridin 0,098 90,322 0 -0,17 315,74
Caffeic acid 0,941 77,755 0 -0,48 154,497
Gallic acid 0,589 97,983 0 -0,77 135,098
p-Tyrosol 1,005 20,456 0 -0,8 133,683
Journal of Food Studies
ISSN 2166-1073
2013, Vol. 2, No. 2
www.macrothink.org/jfs
37
Log P: Octanol-water partition coefficient logP. TPSA: Topological Polar surface area. NV:
Number of violations of the Lipinski´s rule of 5. GCPR: G-couple protein receptor. MV:
Molecular volume.
Experimental approaches to improve detection of ideal candidate compounds for drug
development have gained great popularity. In his 2001 article, Lipinski described how in silico
estimation of solubility and permeability could help predict desirable pharmacokinetic (PK)
properties and how research substances could potentially be more bio-available (Lipinski et al,
2001). Evaluation of the bioactives of RhodioLife showed most compounds with 0 violations
of the Lipinski ´s rule of 5, with Chlorogenic acid, Rosarin and Rosavin having 1, Mongrhoside
2 and Polymeric anthocyanins 3. Studies with pharmacokinetic (PK) analysis on Rhodiola
rosea extracts are scarce in the literature, but Salidroside and Rosavin have been isolated in the
plasma of human volunteers after oral administration (Panossian et al, 2010).
However these properties do not imply diffusion across the blood brain barrier (BBB) which is
more difficult to predict. Topological Polar surface area has been proposed as one key
molecular factor in predicting passage through the BBB, with most CNS drugs having TPSA
lower than 80-90Å2. However even compounds with 120 Å2 can still have a chance of crossing
it (Ghose et al, 2012). One example is fistein, a flavonoid with proven neuroprotective effects
in animal models while having a TPSA of 111.123 Å2. In our case (Table 2) we observed that
Cinnamyl Alcohol, p-Tyrosol, Caffeic acid, Rosiridin, Gallic acid, Rosin, Catechin and
Salidroside all hade TPSA lower than 120 Å2, while having no violations of the Lipinski´s rule
of 5 and thus making then potential candidates.
4. Conclusions
We have shown that our proprietary Rhodiola rosea extract (RhodioLife) contains bioactives
that are capable of stimulating gene modulation in brain cell cultures. In our model, the
statistically significant expression of CALCRL, CDKN1A and LPAR2 suggests a potential
role in neuroprotection. In silico evaluation of the molecular properties of the bioactives
offers additional plausibility by showing a predicted favorable pharmacokinetic profile.
Acknowledgment and funding
This work was entirely funded by PoliNat S.L.
Conflict of interest statement
José M Zubeldia, Aarón Hernández-Santana, Verónica Pérez-López, and Miguel
Jiménez-del-Rio work for PoliNat SL which manufactures RhodioLife.
References
An S, Bleu T, Zheng Y, & Goetzl EJ. (1998). Recombinant human G protein-coupled
lysophosphatidic acid receptors mediate intracellular calcium mobilization. Molecular
Pharmacololgy, 54, 881-888.
Avula B, Wang YH, Ali Z, Smillie TJ, Filion V, Cuerrier A,Arnason JT, & Khan IA. (2009).
RP-HPLC determination of phenylalkanoids and monoterpenoids in Rhodiola rosea and
identification by LC-ESI-TOF. Biomed Chromatography, 23, 865-872.
http://dx.doi.org/10.1002/bmc.1198
Journal of Food Studies
ISSN 2166-1073
2013, Vol. 2, No. 2
www.macrothink.org/jfs
38
Brain SD, & Cox HM. (2006). Neuropeptides and their receptors: innovative science
providing novel therapeutic targets. British Journal of Pharmacology, 147. Suppl 1:S202-211.
http://dx.doi.org/10.1038/sj.bjp.0706461
Brown, RP, Gerbarg P, & Ramazanov Z. (2002). Rhodiola rosea: a phytomedicinal overview.
Herbal Gram, 56, 40-52.
Edvinsson L, Eftekhari S, Salvatore CA, & Warfvinge K. (2011). Cerebellar distribution of
calcitonin gene-related peptide. (CGRP). and its receptor components calcitonin receptor-like
receptor. (CLR). and receptor activity modifying protein 1. (RAMP1). in rat. Molecular and
Cellular Neuroscience, 46, 333-339. http://dx.doi.org/10.1016/j.mcn.2010.10.005
Furmanowa M, Skopinska RE, Rogala E, Hartwich M. (1998). Rhodiola rosea in vitro culture
– phytochemical analysis and antioxidant action. Acta Societatis Botanicorum Poloniae
67:69-73. http://dx.doi.org/10.5586/asbp.1998.009
George-Carey R, Adeloye D, Chan KY, Paul A, Kol?i? I, Campbell H, & Rudan I. (2012). An
estimate of the prevalence of dementia in Africa: A systematic analysis. Journal of Global
Health, 2,20401. http://dx.doi.org/10.7189/jogh.02.020401
Ghose AK, Herbertz T, Hudkins RL, Dorsey BD, & Mallamo JP. (2012). Knowledge-Based,
Central Nervous System. (CNS). Lead Selection and Lead Optimization for CNS Drug
Discovery. ACS Chemical Neuroscinece, 3, 50-68. http://dx.doi.org/10.1021/cn200100h
Hillhouse B, Ming DS, French CJ, & Towers GHN. (2004). Acetylcholine Esterase Inhibitors
in Rhodiola rosea. Pharmaceutical Biology, 42, 68–72.
http://dx.doi.org/10.1080/13880200490505636
Hurd MD, Martorell P, Delavande A, Mullen KJ, & Langa KM. (2013). Monetary costs of
dementia in the United States. New England Journal of Medicine, 368, 1326-1334.
http://dx.doi.org/10.1056/NEJMsa1204629
Kawahara M, Ohtsuka I, Yokoyama S, Kato-Negishi M, & Sadakane Y. (2011). Membrane
Incorporation, Channel Formation, and Disruption of Calcium Homeostasis by
Alzheimer's ?-Amyloid Protein. International Journal of Alzheimers Disease, 304583.
http://dx.doi.org/10.4061/2011/304583
Kawamoto EM, Vivar C, & Camandola S. (2012). Physiology and pathology of calcium
signaling in the brain. Frontiers in Pharmacology.
http://dx.doi.org/10.3389/fphar.2012.00061
Kelly GS. (2001). Rhodiola rosea: a possible plant adaptogen. Alternative Medicine Reviews,
6, 293-302.
Khalil Z, Chen H, & Helme RD. (1996). Mechanisms underlying the vascular activity of
beta-amyloid protein fragment. (beta A(4).25-35). at the level of skin microvasculature. Brain
Research, 736, 206-216. http://dx.doi.org/10.1016/0006-8993(96).00685-3
Kranenburg O, van der Eb AJ, & Zantema A. (1996). Cyclin D1 is an essential mediator of
apoptotic neuronal cell death. The EMBO Journal, 15, 46-54.
Journal of Food Studies
ISSN 2166-1073
2013, Vol. 2, No. 2
www.macrothink.org/jfs
39
Lall N, Henley-Smith CJ, De Canha MN, Oosthuizen CB, & Berrington D. (2013). Viability
Reagent, PrestoBlue, in Comparison with Other Available Reagents, Utilized in Cytotoxicity
and Antimicrobial Assays. International Journal of Microbiology, 420601.
http://dx.doi.org/10.1155/2013/420601
Lee Y, Jung JC, Jang S, Kim J, Ali Z, Khan IA, & Oh S. (2013). Anti-Inflammatory and
Neuroprotective Effects of Constituents Isolated from Rhodiola rosea. Evidence Based
Complementary and Alternative Medicine 2013, 514049.
http://dx.doi.org/10.1155/2013/514049
Lipinski CA, Lombardo F, Dominy BW, & Feeney PJ. (2001). Experimental and
computational approaches to estimate solubility and permeability in drug discovery and
development settings. Advanced Drug Delivery Reviews, 46, 3-26.
http://dx.doi.org/10.1016/S0169-409X(00).00129-0
Luengo-Fernandez R, Leal J, & Gray AM. (2011). Cost of dementia in the pre-enlargement
countries of the European Union. Journal of Alzheimers Disease, 27,187-196.
Ma YC, Wang XQ, Hou FF, Ma J, Luo M, Lu S, Jin P, Terevsky N, Chen A, Xu I, Pate AV, &
Gorecki D. (2011). Rapid resolution liquid chromatography. (RRLC). analysis for quality
control of Rhodiola rosea roots and commercial standardized products. Natural Products
Communications, 6,645-650.
Markus G, Yurdanur Y. & Khan IA. (2001). Analysis of the marker compounds of Rhodiola
rosea L.. (golden root). by reversed phase high performance liquid chromatography.
Chemical and Pharmaceutical Bulletin, 49,465-467. http://dx.doi.org/10.1248/cpb.49.465
Nelson P, Ruffner W, & Nirenberg M. (1969). Neuronal tumor cells with excitable
membranes grown in vitro. Proceedings of the National Academy of Sciences USA, 64,
1004-1010. http://dx.doi.org/10.1073/pnas.64.3.1004
Panossian A, Wikman G, & Sarris J. (2010). Rosenroot. (Rhodiola rosea).: traditional use,
chemical composition, pharmacology and clinical efficacy. Phytomedicine, 17, 481-493.
http://dx.doi.org/10.1016/j.phymed.2010.02.002
Reitz C, Brayne C, & Mayeux R. (2011). Epidemiology of Alzheimer disease. Nature
Reviews Neurology, 7, 137-152. Epub 2011 Feb 8. http://dx.doi.org/10.1038/nrneurol.2011.2
Sherr CJ, & Roberts JM. (1995). Inhibitors of mammalian G1 cyclin-dependent kinases.
Genes & Development, 9, 1149-1163. http://dx.doi.org/10.1101/gad.9.10.1149
Sokolov S, Ivashin VM, Zapesochnaya G, Kurkin VA. & Shchavlinskii AN. (1985). Studies
of neurotropic activity of new compounds isolated from Rhodiola rosea.
Khimiko-Farmatsevticheskii Zhurnal, 19, 1367-1371.
Suo WZ, & Li L. (2010). Dysfunction of G protein-coupled receptor kinases in Alzheimer's
disease. Scientific World Journal, 10, 1667-1678. http://dx.doi.org/10.1100/tsw.2010.154
Tamaru T, Trigun SK, Okada M, & Nakagawa H. (1993). Identification of cells expressing a
D type G1 cyclin in matured brain: implication for its role in neuronal function. Neuroscience
Letters, 153, 169-172. http://dx.doi.org/10.1016/0304-3940(93)90314-B
Journal of Food Studies
ISSN 2166-1073
2013, Vol. 2, No. 2
www.macrothink.org/jfs
40
Wang H, Zhou G, Gao X, Wang Y, & Yao W. (2007). Acetylcholinesterase inhibitory-active
components of Rhodiola rosea L. Food Chemistry, 105, 24–27.
http://dx.doi.org/10.1016/j.foodchem.2007.03.031
Woods NK, & Padmanabhan J. (2012). Neuronal calcium signaling and Alzheimer's disease.
Advances in Experimental Medicine and Biology, 740, 1193-1217.
http://dx.doi.org/10.1007/978-94-007-2888-2_54
Glossary
AChE: Acetylcholine esterase
BBB: Blood brain barrier
CALCRL: Calcitonin receptor-like
CDKN1A: Cyclin-dependent kinase inhibitor 1A
CNS: Central nervous system
GCPR: G-coupled protein receptor
JNK: c-Jun N-terminal kinase
LPA: Lysophosphatidic acid
LPAR2: Lysophosphatidic acid receptor 2
MAPK: Mitogen-activated protein kinases
MV: Molecular volume
NV: Number of violations
PK: Pharmacokinetic
RAMP1: Receptor activity modifying protein type 1
RNA: Ribonucleic acid
RR: Rhodiola rosea
RT-PCR: Real time polymerase chain reaction.
SMILES: Simplified Molecular-Input Line-Entry System
TPSA: Topological polar surface area
Copyright Disclaimer
Copyright reserved by the author(s).
This article is an open-access article distributed under the terms and conditions of the
Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
