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48
ACTA MICROBIOLOGICA BULGARICA
Investigation of Antioxidant and Antiviral Properties of Geraniol
Milka Mileva1*, Ivanka Nikolova1, Nadya Nikolova1, Luchia Mukova1, Almira Georgieva2,
Anna Dobreva3, and Angel S. Galabov1
1 Department of Virology, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences
2 Department of Biological Effects of Natural and Synthetic Substances, Institute of Neurobiology, Bulgarian
Academy of Sciences
3 Institute for Rose and Aromatic Plants, Kazanlak, Bulgaria
Abstract
Geraniol is an acyclic monoterpene alcohol with characteristic rose-like odour. It is an important
constituent of Bulgarian Rosa alba L. and Rosa damascena Mill. essential oils. The purpose of the present
study was to investigate antioxidant ability as well to reveal the potential for antiviral activity of geraniol
against the replication of viruses belonging to different taxonomic groups and representing important hu-
man pathogens. Geraniol signicantly depressed the effect of oxidation - it showed good ability to capture
2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and to inhibit lipid peroxidation in a egg liposomal suspen-
sion. Geraniol showed low cytotoxicity toward HEp-2 cells. It was tested in vitro for its activity against
viruses representing important human pathogens assigned to different taxonomic groups: coxsackievirus
B1 (CV-B1) from the Picornaviridae family, respiratory syncytial virus (RSV) from the Paramyxovir-
idae family, and inuenza virus A/Aichi/68/H3N2 from the Orthomyxoviridae family. In vitro antiviral
effect was examined by the virus cytopathic effect inhibition assay. Geraniol showed antiviral activity only
against CVB1 - the ratio of selective index is 3.9. The investigated biological properties of geraniol, includ-
ing good antioxidant and antiviral activities against some virus families, together with negligible toxicity,
warrant further studies to explore the feasibility of formulating geraniol-containing consumer products with
health promoting properties.
Key words: geraniol, antioxidant activity, antiviral properties
Резюме
Гераниол е ацикличен монотерпенов алкохол с характерен мирис на роза. Той е важна съставна
част от етеричните масла на българската Rosa alba L. и Rosa damascena Mill. Целта на настоящото
проучване е да се изследва антиоксидантната способност, както и да се разкрие потенциала за
антивирусна активност на гераниол срещу репликацията на вируси, принадлежащи към различни
таксономични групи, които са важни човешки патогени. Гераниол показа добра способност да улавя
2,2-дифенил-1-пикрилхидразил (DPPH) радикали и да инхибира липидната пероксидация в моделна
система от яйчени липозоми. Гераниол демонстрира ниска цитотоксичност към НЕр-2 клетки. In vitro
беше тестванa неговата активност срещу вируси, които са важни човешки патогени, принадлежащи
към различни таксономични групи: Коксаки В1 вирус (CV-В1) от семейство Picornaviridae,
респираторен синцитиален вирус (RSV) от семейство Paramyxoviridae и грипен вирус A/Aichi/68/
H3N2 от семейство Orthomyxoviridae. Антивирусният ефект беше изследван in vitro в постановка
на многоциклов ЦПЕ (цитопатичен ефект)-инхибиращ тест. Гераниол показа антивирусно действие
само срещу CVB1 - селективният индекс е 3.9. Изследваните биологични свойства на гераниол, сред
които са добрата антиоксидантна и антивирусна активност срещу някои вирусни семейства, заедно
с незначителната токсичност, налагат провеждането на допълнителни изследвания, за да се проучи
приложимостта на гераниол-съдържащите продукти с добри здравословни показатели.
*Correspondence to: Milka Mileva
E-mail: milkamileva@gmail.com
49
Introduction
Compounds from natural plants are important
sources of drugs against a wide variety of diseases.
Geraniol (3,7-dimethylocta-trans-2,6-dien-1-ol) is
an acyclic monoterpene alcohol with the chemical
formula C10H18O. The product referred to as “ge-
raniol” is a mixture of the two cis-trans isomers
(Fig. 1) properly named geraniol (trans) and nerol
(cis). Geraniol has characteristic rose-like odour
and the taste (at 10 parts per million) is described
as sweet oral rose-like, citrus, with fruity, waxy
nuances (Burdock, 2010). It is an important constit-
uent of essential oil of ginger, lemon, lime, laven-
der, nutmeg, orange, rose, etc., an acyclic monoter-
penoid, and the main component of oil of rose, e.g.
Bulgarian Rosa alba L. and Rosa damascena Mill.
(Mileva et al., 2014). Geraniol is a fragrance ingre-
dient used in decorative cosmetics, ne fragranc-
es, shampoos, toilet soaps, and other toiletries as
well as in non-cosmetic products such as household
cleaners and detergents. Its use worldwide is ap-
proximately greater than 1 000 metric tones per an-
num (Lapczynski et al., 2008). In addition, geraniol
exhibits various biochemical and pharmacological
properties. Researchers have shown geraniol to be
an effective plant-based insect repellent (Barnard
and Xue, 2004) and its potential as an antimicrobial
agent has been highlighted in several studies (Bard
et al., 1988). Geraniol exerts in vitro and in vivo an-
titumor activity against murine leukemia, hepatoma
and melanoma cells (Burke et al., 1997; Yu et al.,
1995 a, b). Geraniol is reported to prevent cancer
(Carnesecchi et al., 2004).
Fig. 1. Chemical structure of geraniol and nerol
The purpose of the present study was to in-
vestigate antioxidant activity as well to reveal the
potential for antiviral activity of geraniol, against
the replication of viruses, belonging to different
taxonomic groups and representing important hu-
man pathogens.
Materials and Methods
Chemicals Used
All chemicals, standards, solvents, and cul-
ture media of high purity (>99%) were purchased
from Sigma-Aldrich Chemie GmbH, Merck (Ger-
many), and Givaudan (Switzerland).
DPPH Test
Hydrogen atoms and electron-donating po-
tential of geraniol was measured from the bleach-
ing of the purple-colored ethanol solution of DPPH.
The compound was dissolved in ethanol to a con-
centration of 100 mg.mL-1 stock solutions for the
following dilutions. DPPH assay was measured,
as follows: freshly prepared ethanolic solution
of DPPH (100 mM) was incubated with tested
substance in the concentration of 1 to 0.1 × 10-5
mg.mL-1; after incubation for 30 min in the dark,
at room temperature, the optical density (OD) was
monitored spectrophotometrically at wavelength
(l) of 517 nm. Inhibition of DPPH in percentage (I,
%) was calculated as given below:
I (%) = [(OD control – OD sample)/
(OD control)] X 100
IC50 was dened as the quantity of substance nec-
essary to decrease the initial DPPH by 50%. All
activities were compared against 2,6-di-tert-bu-
tyl-4-methylphenol (BHT) and ascorbic acid, as
well popular antioxidants. Data were obtained from
the plotted graph scavenging activity of each sam-
ple. Lower IC50 value means higher antiradical ac-
tivity. Each experiment was performed in triplicate
and data were presented as a mean of the three val-
ues (Singh et al., 2008).
Extraction of Liposomal Suspension
We used a liposomal suspension obtained
from phospholipids of egg yolk as lipid rich media,
extracted according to Folch et al. (1957). After
evaporation under vacuum, the chloroform fraction
was dissolved in 50 mM potassium-sodium phos-
phate buffer pH 7.4 (Sigma Chemicals Company
Ltd) to a nal concentration of 2 mg lipid.mL-1, and
vortexed for 10 min. Ultrasonic sonication was per-
formed in Branson ultrasonic bath for 30 min.
Antioxidant Activities in Liposomal Suspension
Antioxidant activities in liposomal suspen-
sion were measured by formation of endogenous li-
pid peroxidation products, reacting with 2-thiobar-
bituric acid (TBARS), and detected spectrophoto-
metrically (λ = 532 nm) by the method of Bishayee
and Balasubramanian (1971), adapted by Mileva et
50
al. (2000). Briey, each sample in the test tube con-
tains 1.8 ml liposomal suspension with concentration
of 2 mg lipid.mL-1, and 100 µL methanol solutions
of compounds to achieve concentrations of 0.01,
0.1, and 1 mg.mL-1, prepared immediately before
use. The samples were vigorously stirred and, after
pre-incubation for 10 min at 37°C, the induction of
lipid peroxidation was initiated by adding of 50 µl
Fe2+ and 50 µl ascorbic acid to a nal concentra-
tion of 1 mmol.L-1. After incubation for 30 min at
37°C, the reaction was stopped with 0.5 ml of 15 %
trichloroacetic acid and 0.5 ml of 0.67 % thiobarbi-
turic acid. The samples were heated at 100°C for 20
min and cooled in ice. 5 ml of n-butanol was added to
each tube - it was vigorously stirred and centrifuged
at 1200 × g for 10 min. The amount of TBARS gen-
erated in the system was determined from the upper
organic layer. The ratio of the absorption at 560 nm
for the sample, containing tested substances in dif-
ferent concentration and the same absorption for the
controls (without tested substances) in percentage
was called antioxidant activity (AOA). The experi-
ments were performed in triplicate.
AOA (%) = Es/Ec × 100%
where Es were content of TBARS, formed in sam-
ples, containing tested substances, and Ec were
TBARS of the controls (without tested substances).
All experiments were performed in triplicate and
data were presented as a mean of the three values.
As positive control served BHT.
Cells and Viruses
Coxsackievirus B1 (CV–B1) (strain Con-
necticut) from the Enterovirus genus of the
Picornaviridae virus family, human respiratory
syncytial virus A2 (HRSV-A2) from the Para-
myxoviridae family, were grown in the Hep-2 cell
line. Cells and viruses were from the cell culture
collection of the Stephan Angeloff Institute of the
Bulgarian Academy of Sciences, Soa, Bulgaria.
Cell lines were grown in a humidied atmosphere
at 37°C and 5% carbon dioxide in Dulbecco’s
Modied Eagle’s Medium (DMEM) (Gibco BRL,
Grand Island, NY, USA), in a growth medium con-
taining 5% fetal bovine serum and supplemented
with antibiotics (100 IU/mL penicillin, 100 μg/
mL streptomycin, and 50 μg/mL gentamycin).
When harvesting viruses and performing antiviral
assays, maintenance medium was used, in which
serum was reduced to 0.5%. Viruses themselves
were grown in a humidied atmosphere at 37°C
and 5% carbon dioxide.
Cellular Toxicity
Monolayer cell cultures in 96-well plates
(Cellstar®, Greiner Bio-one, GmbH, Frickenhausen,
Germany) were inoculated with 0.1 mL/well main-
tenance medium containing different concentrations
of the samples in 0.5 lg intervals. On the 48th hour
after incubation, they were subjected to the neu-
tral red uptake procedure (Borenfreund E, and J.A.
Puerner, 1985), and the 50% cytotoxic concentration
(CC50) was calculated. Briey, after removal of the
maintenance medium, which contained the test com-
pound, cells were washed and 0.1 mL fresh mainte-
nance medium, supplemented with 0.005% neutral
red dye (Fluka Chemie AG, Buchs, Switzerland),
was added to each well and cells were incubated
at 37°C for 3 hours. Afterwards, cells were washed
once with PBS and 0.15 mL/well desorb solution
(1% glacial acetic acid, 49% ethanol, 50% distilled
water) was added. After 10 min of mild shaking, the
optical density (OD) of each well was read at 540
nm in a microplate reader (Organon Teknika reader
530, Oss, Netehrlands). The CC50 value was dened
as the concentration of each sample that reduced the
absorbance of the treated cells by 50% when com-
pared to the untreated control. The CC50 values were
determined by regression analysis.
Antiviral Activity
The virus cytopathic effect (CPE) inhibi-
tion assay was used for evaluating the antiviral
effects of the samples. Monolayer cells in 96-well
plates were inoculated with 0.1 mL virus suspen-
sion containing 100 CCID50 (CCID50 is the 50%
Cell Culture Infectious Dose which was previ-
ously determined by the standard virus titration
assay in the respective cell culture). After one
hour for virus adsorption (two hours in the case
of HRSV-A2), excessive virus was discarded, and
cells were inoculated with 0.1 mL of maintenance
medium containing different non-toxic concen-
trations (in 0.5 lg intervals) of the test samples.
Then cells were further incubated in a humidied
atmosphere at 37°C and 5% carbon dioxide. The
CPE was scored daily till the appearance of its
maximum in the virus control wells (with no com-
pound in the maintenance medium), that happened
usually in 48 hours. Then viable cells were stained
according to the neutral red uptake procedure and
the percentage of CPE inhibition for each concen-
tration of the test sample was calculated using the
following formula:
% CPE = [OD test sample – OD virus control]/
[OD toxicity control – OD virus control] × 100.
51
N Compounds
DPPH
IC50 [µg.L-1]
AOA (%)
1 mg.mL-1
AOA (%)
10 mg.mL-1
AOA (%)
100 mg.mL-1]
1Geraniol 9.45 ± 0.34 31.13 ± 1.34 24.51 ± 0.34 22.33 ± 0.34
2 BHT 4.03 ±0.24 34 ± 2.11 27.62 ± 3.11 21.30 ± 1.87
3Ascorbic acid 3.12 ± 0.37 NT* NT* NT*
*NT – non tested; Results are expressed as average ± SD (n=3).
Table 1. DPPH scavenging activities and AOA in egg liposomal suspension of geraniol and reference
standards ascorbic acid and butylated hydroxyl toluene (BHT).
The concentrations that inhibited 50% of the
virus-induced CPE, and the 50% inhibitory con-
centrations (IC50), were determined by regression
analysis. The selectivity index (SI) was calculated
as the ratio between CC50 and IC50 (SI = CC50/IC50).
Results and Discussion
Antioxidant Properties
Antioxidant defence system of cells com-
prises of endogenous antioxidants, such as super-
oxide dismutase, catalase, glutathione peroxidase,
glutathione reductase, glutathione, ascorbic acid,
uric acid, etc., which act either independently, or
cooperatively, (or even synergistically) against
free radicals (Vandana et al., 2006). These anti-
oxidants protect against the deleterious effects of
reactive oxygen species by scavenging them, con-
verting them to non-toxic compounds, or chelat-
ing the ions required for their activation. Cells
suffer because of deterioration at physiological
processes during oxidative stress, when the an-
tioxidant defence system becomes inadequate
to neutralize the excess reactive oxygen species
(ROS) produced. The supplementation of exoge-
nous antioxidants has been found to be effective
in restoring the homeostatic disturbances due to
oxidative stress. This supports the role of natural
antioxidants in achieving strong immune system
as well as healthy aging (Han et al., 2005). This
study has been held to explore the antioxidant ef-
fect of geraniol in pro-oxidant conditions, as com-
pared with the reference standards ascorbic acid
and butylated hydroxyl toluene.
The DPPH assay usually involves a hydrogen
atom transfer reaction (Li et al. 2009). DPPH radi-
cal scavenging test is a sensitive antioxidant assay
and depends on substrate polarity. The presence of
multiple hydroxyl functions could be considered as
an option for the hydrogen donation and/or radical
scavenging activity.
Antiradical activities of tested substanc-
es against stable DPPH radical expressed in IC50
[µg.L-1] showed notable values (Table 1). A lower
IC50 value indicates a greater antioxidant activity.
Most active was BHT, the same activity demon-
strated ascorbic acid, and least active was geran-
iol. As a rule, the antioxidant properties of the plant
extracts cannot be attributed to activities of single
constituents. Their scavenging activity could be
explained by the combination of effects with one
another. Ruberto and Baratta (1999) demonstrated
that the most radical scavenging activities of nat-
ural extracts are mainly due to the cumulative ef-
fect of ingredients as polyphenols, as well as ne-
rol, eugenol and geraniol; within their structure has
been observed polar-bonded hydrogen. Undoubted-
ly, DPPH radical has little relevance to present in
biological systems as well in living organisms, but
this study is indicative of the capacity of geraniol to
scavenge free radicals, and will refer to hydrogen
atom or electron donation ability, independently of
any enzymatic activity.
AOA of tested compounds in Fe2+/ascorbic
acid-induced oxidation of egg liposomes are ex-
pressed as percentage of inhibition of oxidation
process in comparison to control sample (without
tested substances). Geraniol signicantly depressed
the effect of oxidation. It exhibited a protective ca-
pacity against Fe2+/ascorbic acid-induced lipid per-
oxidation in liposomes in a concentration-depend-
ent manner.
The damaging reactions of free radicals are
widely implicated in the etiology of numerous ox-
idative stress-related diseases (Piaru et al., 2010).
These typically electrophilic reactive moieties in-
teract with lipids, proteins, and nucleic acids, and
cause oxidative damages (Deighton et al,. 2010).
Lipid peroxidation is one of the effects induced by
free radicals, and it can occur in lipid system due to
the presence of structures rich in highly peroxidiz-
able, polyunsaturated fatty acids. The presence of
antioxidants in the fraction will minimize the ox-
idation of these structures due to the inhibition of
the chain reaction of lipid peroxidation (Sherry et
al., 2013). Antioxidant power of natural products is
an expression of their capacity to defend from the
action of free radicals as well as to prevent degen-
52
Fig. 2. Antiviral activity of geraniol against CVB1 and RSV virus in HEp2 cells. Data are present as
CC50 – percentage viable HEp2 cells, and IC50 – percentage protection.
eration from oxidants (Deighton et al., 2000, Piaru
et al., 2010, Sherry et al., 2013).
Yu et al. (1995 a) reported that geraniol
suppressed lipopolysaccharide-induced nitric ox-
ide and prostaglandin E2 production at a system
of RAW 264.7 macrophages in a dose-dependent
manner. The inhibitory efcacy of geraniol was
concomitant with decreases in protein and mRNA
expression levels of inducible nitric oxide synthase
(iNOS)
Although peroxidation in model membranes
may be very different from peroxidation in cell
membranes, the results obtained in the former
membranes may be used to advance understanding
of peroxidation in biological membranes (Schnitzer
et al., 2007).
Antiviral Test
The in vitro antimicrobial activity of euge-
nol against various pathogens has been reported
earlier; very little is known about its activity and
mode of action against viruses, which are impor-
tant human pathogens assigned to different taxo-
nomic groups: coxsackievirus B1 (CV-B1) from
the Picornaviridae family, respiratory syncytial
virus (RSV) from the Paramyxoviridae family,
and influenza virus A/Aichi/68/H3N2 from the
Orthomyxoviridae family. Therefore, the mode
of antiviral action of eugenol against those vi-
ruses in vitro was evaluated in the present study.
The results obtained demonstrated that geran-
iol was showing low cytotoxicity in a Hep2 cell
system (Table 2). In the same model system,
CC50 of geraniol is lower than that of disoxaril,
used as reference substance for the study of an-
tiviral effect of CVB1. Our research on antiviral
screening of geraniol showed that there is no an-
tiviral effect against influenza virus A/Aichi/68/
H3N2, as well as against RSV. The scientific lit-
erature also lacks data published on this subject.
Pronounced antiviral effect was observed
against the representative of the Picornaviridae
family - coxsackievirus B1. IC50 of geraniol is
48 μg/mL, about 30% lower than oxoglaucine
and about three times lower than disoxaril.
The antiviral activities of monoterpene
alcohols (including linalool, nerol, citronellol,
and geraniol) probably are due to their solubili-
ty in the phospholipid bilayer of cell membranes
and increased permeability of cells (Knobloch
et al., 1989; Devi et al., 2010).
These results suggest that geraniol exhib-
its anti-coxsackievirus B1 activity, supporting
its therapeutic potential for virus-associated
disorders.
In conclusion, geraniol is abundant and
occurs in a large number of plants. This mole-
cule is widely used as a fragrance chemical in
both cosmetic and household products. Sever-
al studies have confirmed the pharmacological
properties of this acyclic monoterpene alcohol.
Geraniol - with its good chemopreventive activ-
ity - may present a new class of antiviral agent,
and this renders a great opportunity for further
investigation. The investigated biological prop-
erties of geraniol, including antiviral activities
against some virus families, together with negli-
gible toxicity, warrant further studies to explore
the feasibility of formulating geraniol-contain-
ing consumer products with health promoting
properties.
53
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