Access to this full-text is provided by De Gruyter.
Content available from Open Chemistry
This content is subject to copyright. Terms and conditions apply.
Open Chem., 2018; 16: 349–361
The First Decade (1964-1972)
What Is So Different About
Neuroenhancement?
Pharmacological and Mental Self-transformation in Ethic
Comparison
Abstract: In the concept of the aesthetic formation of knowledge and its as soon
as possible and success-oriented application, insights and profits without the
reference to the arguments developed around 1900. The main investigation also
includes the period between the entry into force and the presentation in its current
version. Their function as part of the literary portrayal and narrative technique.
Keywords: Function, transmission, investigation, principal, period
Dedicated to
1 Studies and Investigations
The main investigation also includes the period between the entry into force and
the presentation in its current version. Their function as part of the literary por-
trayal and narrative technique.
*Max Musterman:
Paul Placeholder:
Research Article Open Access
Christina Khaleel*, Nurhayat Tabanca, Gerhard Buchbauer
α-Terpineol, a natural monoterpene: A review of its
biological properties
https://doi.org/10.1515/chem-2018-0040
received December 28, 2017; accepted March 3, 2018.
Abstract: Terpineols are monocyclic monoterpene tertiary
alcohols which are naturally present in plant species.
There are ve common isomers of terpineols, alpha-, beta-,
gamma-, delta- and terpinen-4-ol, of which α-terpineol and
its isomer terpinen-4-ol are the most common terpineols
found in nature. α-Terpineol plays an important role in
the industrial eld. It has a pleasant odor similar to lilacs
and it is a common ingredient in perfumes, cosmetics, and
aromatic scents.
In addition, α-terpineol attracts a great interest as it has
a wide range of biological applications as an antioxidant,
anticancer, anticonvulsant, antiulcer, antihypertensive,
anti-nociceptive compound. It is also used to enhance
skin penetration, and also has insecticidal properties.
This study reviews the relevance of α-terpineol based on
scientific findings on Google Scholar, Pubmed, Web of
Science, Scopus and Chemical Abstracts.
Collectively, the use of α-terpineol in medicine and
in the pharmaceutical industry plays an important role
in therapeutic applications. This review will, therefore,
support future research in the utilization of α-terpineol.
Keywords: p-menth-1-en-8-ol; monoterpene utilization;
monoterpenoid alcohol; monocyclic monoterpenoids;
terpenic alcohols.
Introduction1
Terpineols are naturally occurring unsaturated monocyclic
mono-terpenoid alcohols and can be found in owers
such as narcissus and freesia, in herbs, such as marjoram,
oregano, rosemary and in lemon peel oil. Reports on the
level of terpenoids in oils occasionally vary considerably
and one wonders how much this is due to the variation in
the plants and to the variations in the isolation process
as terpineols could also be an artifact [1,2]. In addition,
terpineols are interesting because of their wide range of
biological properties [3].
There are ve common isomers of terpineols; alpha- (α-T),
beta- (β-T), gamma- (γ-T), delta- (δ-T) and terpinen-4-ol
(T-4-ol) (Figure 1).
α- and β-Terpineol occur in optically active forms and
as a racemate. Both α-T and T-4-ol are the most important
commercial products and they occur in a large number of
essential oils. On the other hand, β-, γ- and δ- terpineols do
not occur very often in nature [1]. Terpineols, especially the
most commonly used compounds as α-T and T-4-on, exert
a wide range of different biological actions on humans,
animals, and also plants. They are not only popular
fragrance ingredients used in perfumes, cosmetics, and
household cleaning products, but also used to flavor
foods and beverages. They also possess various important
biological and medicinal properties [1-3].
α-T, a volatile monoterpenoid alcohol, is the major
component of essential oils of several species of aromatic
plants such as Origanium vulgare L. and Ocimum canum
Sims which are widely used for medicinal purposes. α-T
can also be isolated from a variety of sources such as
*Corresponding author: Christina Khaleel, Department of
Pharmaceutical Chemistry, Division of Clinical Pharmacy and
Diagnostics, Center of Pharmacy, University of Vienna, Althanstrasse
14, A-1090 Vienna, Austria, E-mail: christina.khaleel@gmail.com
Nurhayat Tabanca: USDA-ARS, Subtropical Horticulture Research
Station, Miami, FL 33158, USA
Gerhard Buchbauer: Department of Pharmaceutical Chemistry,
Division of Clinical Pharmacy and Diagnostics, Center of Pharmacy,
University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria
The First Decade (1964-1972)
What Is So Different About
Neuroenhancement?
Pharmacological and Mental Self-transformation in Ethic
Comparison
Abstract: In the concept of the aesthetic formation of knowledge and its as soon
as possible and success-oriented application, insights and profits without the
reference to the arguments developed around 1900. The main investigation also
includes the period between the entry into force and the presentation in its current
version. Their function as part of the literary portrayal and narrative technique.
Keywords: Function, transmission, investigation, principal, period
Dedicated to
1 Studies and Investigations
The main investigation also includes the period between the entry into force and
the presentation in its current version. Their function as part of the literary por-
trayal and narrative technique.
*Max Musterman:
Paul Placeholder:
Open Access. © 2018 Christina Khaleel et al., published by De Gruyter.
The First Decade (1964-1972)
What Is So Different About
Neuroenhancement?
Pharmacological and Mental Self-transformation in Ethic
Comparison
Abstract: In the concept of the aesthetic formation of knowledge and its as soon
as possible and success-oriented application, insights and profits without the
reference to the arguments developed around 1900. The main investigation also
includes the period between the entry into force and the presentation in its current
version. Their function as part of the literary portrayal and narrative technique.
Keywords: Function, transmission, investigation, principal, period
Dedicated to
1 Studies and Investigations
The main investigation also includes the period between the entry into force and
the presentation in its current version. Their function as part of the literary por-
trayal and narrative technique.
*Max Musterman:
Paul Placeholder:
This work is licensed under the Creative Commons
Attribution-NonCommercial-NoDerivatives 4.0 License.
OH
OH OH
OH
α-terpineol β-terpineol γ-terpineol 4-terpineol
OH
δ-terpineol
Figure 1: Terpineol isomers.
350 Christina Khaleel et al.
cajeput oil, pine oil and petitgrain oil [1]. It is a colorless,
crystalline solid, smelling of lilac, and is an optically
active monoterpenoid that occurs naturally in the (+)-, (-)-
and (±) forms. The presence of natural racemic mixtures
of α-T was discovered in geranium oils and in Morio-
Muscat-wine aroma. α-T enantiomers which are found
in the Myrtaceae family, in citrus and lavender oil, were
separated by means of a two-columned coupled system
and a mixture of two chiral phases, respectively [1,3].
Because of its pleasant odor similar to lilac, α-T is widely
used in the manufacturing of cosmetics, soaps, perfumes,
antiseptic agents and is considered one of the most
frequently used fragrance compounds. Its acetate and
other simple esters of α-T are also used in perfumes and
aromatic scents. Therefore, the most important reaction
for the fragrance industry is its esterification particularly
the acetylation of terpinyl acetate [1,4]. In addition, α-T
possesses a wide range of biological applications as it
exhibits an antihypertensive and antiproliferative effect
on human erythroleukemic cells [5,6], as well as anti-
inflammatory properties [7], as it was found to be a potent
inhibitor of superoxide production [8]. And many studies
have reported that α-T has an obvious anticancer effect
[9].
This review explores some of the important α-T
biological activities from specific papers (Figure 2).
We accessed electronic sources from various scientific
databases such as Google Scholar, Pubmed, Web of
Science, Scopus and Chemical Abstracts and interpreted
existing literature on these activities.
Biological properties of α-terpineol2
Cardiovascular and antihypertensive effects2.1
Systemic arterial hypertension and cardiovascular
diseases increase the risk of mortality and morbidity
worldwide [10,11]. Arterial hypertension is considered to
be the major risk factor for both heart attack and stroke
[12]. Because “It has been shown that blood pressure
levels are strongly and directly related to the relative risks
of stroke and heart disease. Endothelial dysfunction in
hypertension triggers an imbalance between the production
and release of these factors, increasing the generation of
reactive oxygen species and diminishing (nitric oxide) NO
synthesis and bioavailability. L-arginine is the precursor
of NO synthesis by NO synthase (NOS), an enzyme that
exists in three isoforms: neuronal (nNOS), inducible (iNOS)
and endothelial (eNOS)” [5]. Furthermore, inhibition
of NOS activity and then NO biosynthesis by means of
5
Figure 2: Schematic representation of review section 2.
2. Biological properties of α-terpineol
2.1. Cardiovascular and antihypertensive effects
Systemic arterial hypertension and cardiovascular diseases increase the risk of mortality
and morbidity worldwide [10,11]. Arterial hypertension is considered to be the major risk
factor for both heart attack and stroke [12]. Because “It has been shown that blood pressure
levels are strongly and directly related to the relative risks of stroke and heart disease.
Endothelial dysfunction in hypertension triggers an imbalance between the production and
release of these factors, increasing the generation of reactive oxygen species and diminishing
(nitric oxide) NO synthesis and bioavailability. L-arginine is the precursor of NO synthesis
O
H
-
terpineol
Search
Google
Schol ar
Pubmed
Web of
Scien ce
Scopus
Chemical Abstracts
2
.
Various
biological
properties
of
α
-
terpineol
2
.
1
.
Cardiovascular
and
antihypertensive
effects
2
.
2
.
Antioxidant
activity
2
.
3
.
Antican cer
activity
2.4
.
Antinociceptive
activity
2.5.
Antiulcer
activity
2.6.
Anticonvulsant and sedative activity
2
.
8
.
Skin penetration enhancing activity
enhhh
enh
2
.
9
.
Insecticidal
activity
2
.
7
.
Antibronchitis
activity
Figure 2: Schematic representation of review section 2.
α-Terpineol, a natural monoterpene: A review of its biological properties 351
L-arginine analogs administration such as L-nitro arginine
methyl ester (L-NAME) leads to hypertension [13,14].
Accordingly, many reports were designed to investigate
the cardiovascular and antihypertensive eects of α-T in
rats with hypertension induced by L-NAME [5,15]. The NOS
inhibitor L-NAME has been used extensively as a mean of
inducing hypertension in animal models [5].
Sabino et al. examined the effect of α-T on
hemodynamic parameters which was evaluated by the
treatment of non-anesthetized rats once a day with
different doses of α-T (25, 50 or 100 mg/kg/day) for one
week. The results indicated that the induction of a marked
hypotensive effect in rats occurred by oral administration
of α-T. Hypotension may be exerted due to a decrease in
peripheral vascular resistance. The beneficial effects
of α-T on isolated mesenteric from L-NAME–induced
hypertensive rats were demonstrated, and as a result,
α-T in a concentration-dependent manner, relaxed the
endothelium-intact mesenteric rings pre-contracted with
phenylephrine and depolarization with KCl. Furthermore,
α-T-induced relaxation was not considerably reduced by the
mechanical removal of the endothelium in phenylephrine
pre-contracted mesenteric rings. According to these
results, it was proposed that the vasorelaxant activity of
α-T is endothelium-dependent and that α-T blocks Ca+2
entry through voltage-dependent Ca+2 channels, which is
involved in the mechanism by which relaxation can be
produced. Further results indicated that α-T was able to
inhibit contractions induced by the cumulative addition
of phenylephrine without endothelium preparations
suggesting that α-T could exert its activity on vascular
smooth muscle contractile machinery [5].
Several mechanisms for an endothelium-independent
vasodilation are in its relaxant activities of vascular smooth
muscles. Among these mechanisms are (a) inhibition of
agonist-mediated release of Ca+2 from intracellular stores,
(b) blockage of extracellular Ca+2 influx by transmembrane
Ca+2 channels, (c) inhibition of the contractile apparatus
and (d) opening of K+ channels. The influx of extracellular
Ca+2 occurs by means of two kinds of transmembrane Ca+2
channels: receptor-operated Ca+2 channels (ROCC) and
voltage-operated Ca+2 channels (VOCC) [16]. α-T attenuated
significantly the concentration induced by CaCl2 which
indicates that α-T can inhibit vasoconstriction induced by
extracellular Ca+2 influx through VOCC [5]. It is also known
that the Cav1.2 (voltage-gated calcium channel α1 subunit),
which is considered as a CavL (L-type calcium channel)
subtype present in various smooth muscle cells (VSMCs),
is the main voltage-operated calcium channel found in
VSMCs. The Cav 1.2 is a subtype of the L-type calcium channel,
which is found in different cell types such as myocytes,
smooth muscle myocytes and they are responsible for the
excitation-contraction coupling, hormone release, and
regulation of transcription as well as synaptic integration
[17]. In summary, the reduction of calcium influx occurring
through the voltage-sensitive CavL channels may result in
a decrease in vascular resistance which is attributed to α-T
leading to hypotension induction. [5].
In conclusion, α-T-induced hypertension
and vasorelaxation are mainly mediated by
releasing NO and activating the NO-cGMP (cyclic
guanosine 3’, 5’-monophosphate) pathway. In addition,
oral administration of α-T was able to reduce mean
arterial pressure, and in mesenteric artery rings it induced
a vascular endothelium-independent vasodilatation,
showing alternations in biochemical parameters which
indicate an antioxidant effect as well. These data indicate
that the ability of α-T to decrease the arterial pressure is
mainly depending on restoring the enzymatic antioxidants
in L-NAME-induced hypertensive rats and reducing the
vascular resistance [5,15].
Antioxidant activity2.2
“Antioxidants, such as vitamins, enzymes or Fe+2, etc.
are able to neutralize free radicals. They exert a health-
enhancing eect on the human organism because they
protect cells from oxidative damage” [18]. Oxidative stress
has an important inuence on the development and
progression of many diseases, such as cardiovascular
diseases, inammation, neurodegenerative diseases and
aging processes. In addition, oxidative stress is mainly
characterized by the presence of high bioavailability of
reactive oxygen species (ROS) [19]. α-T shows an antioxidant
activity, as it was previously mentioned that it is able to
suppress the superoxide production by agonist-stimulated
monocytes but not neutrophils [8]. “The antioxidant
action of α-T reects its capacity to act as a preservative in
food, cosmetics, and pharmaceutical products, preventing
oxidative degeneration of their components” [20].
Arterial hypertension can be developed from oxidative
stress and is believed to result from systemic damage
in different target tissues by oxygen free radicals. Non-
enzymatic antioxidants (e.g. reduced glutathione) and
antioxidant enzymes (catalase, superoxide dismutase,
and glutathione peroxidase) are the factors which are
used to help the performance of intracellular defense
against active oxygen species [21]. Reduction of catalase
and glutathione peroxidase in L-NAME-treated rats were
observed when compared with L-NAME control groups.
Based on these data, α-T proved to possess a potent
352 Christina Khaleel et al.
antioxidant activity against free radicals causing injury
[5].
α-T exerts an anti-proliferative effect, therefore, it
can be used in the prevention or even treatment of cancer.
The anti-proliferative capacity of α-T can be measured
using two methods: 2,2-Diphenyl-1-picrylhydrazyl
(DPPH), which is a simple and accurate indirect method
determining scavenging potential of free radical, and
Oxygen Radical Absorbance Capacity (ORAC). This is used
as a direct method to determine the ability of lipophilic
and hydrophilic substances, via hydrogen atoms transfer,
to resist the oxidation reactions with peroxyl radicals.
Results revealed that α-T showed very low antioxidant
activity in DPPH assays, but it could be compared to
commercial antioxidants in the ORAC assay. It was shown
that α-T demonstrated a potential antioxidant capacity
against peroxyl radicals. Moreover, α-T also exerted
cytostatic activities which were found to be very effective
against six human cancer cell lines, such as prostate,
breast, lung, leukemia and ovarian, especially against
breast adenocarcinoma (MCF-7) and chronic myeloid
leukemia (K-562). In a range of 181-588 μM the impressive
results also revealed that α-T with an antioxidant potential
similar to BHA (butylated hydroxyanisole), which is
considered to have a potential protective activity in
foodstuffs, acts as a natural preservative [20]. Thus, α-T
attracts the interest for further research that can culminate
in its use as a functional additive, as well as in its role in
cancer-prevention in vivo. Hereafter, in vivo assays must be
performed to confirm the antioxidant potential of α-T.
Anticancer activity2.3
“Cancer is characterized by uncontrolled growth of cells
disregarding the normal limits, by invasion and, in the worst
case, by metastasis, the expansion of the disease to another
non-nearby organ by lymph or blood” [13]. α-T is a bioactive
component of Salvia libanotica essential oil extract and
has shown antitumor activity [9]. S. libanotica (Lamiaceae)
is a species endemic to the Eastern Mediterranean which
induces cell cycle arrest and apoptosis in human colorectal
cancer cells, depending on the synergistic action of its
three bioactive components: α-T, camphor and linalyl
acetate, via caspase activation, mitochondrial damage
(cytochrome C release), and PARP cleavage [22].
The link between the development of cancers and
chronic inflammation is found to be related to the activation
of the transcription factor NF-κB. Since several types of
human tumors express mainly NF-κB, blocking this factor
was proposed to increase its sensitivity to the action of
anti-tumor agents or stopping the proliferation caused
by tumor cells [23]. Hassan et al. proved that α-T acts as a
potential anticancer agent by suppressing NF-κB signaling.
The cytotoxicity of α-T towards 14 different human tumor
cell lines representing different hematological and non-
hematological malignancies was evaluated in vitro where
α-T exerted a considerable cytotoxic effect on the cell line
of the small cell lung carcinoma, representing a tumor-
specific activity. Interestingly, the effective cytotoxic
activity of α-T shows a promising effect for treatment of
patients with drug-resistant tumors due to the limited
effects of resistance represented by α-T [9]. The risk of
toxicity against normal lymphocytes is reduced due to
tumor selectivity of α-T, helping as an important feature in
many of the cytotoxic drugs which are clinically used [24].
“Treatment with α-T induces cell cycle arrest and apoptosis
in the cell line tested in a dose- and time-dependent manner.
The results suggest that cell cycle phase arrest by α-T may
depend on drug concentration at the shorter exposure time.
This finding is consistent with α-T which showed that it is
active in including cell cycle changes if combined with
linalyl acetate rather than if used alone in colorectal tumor
cells” [9].
Hassan et al. also demonstrated that the inhibition
of the NF-κB translocation and activity in tumor cells
was exerted by the anticancer activity of α-T in a dose-
dependent manner, as indicated by means of the two NF-κB
assays. Moreover, the response of NF-κB expression to α-T
treatment and other related genes as IL-1R1, IL-1β, ITK,
AKT1S1, EGFR, IFNG, BAG1, and TNIK was indicated via
microassay analysis showing significant down-regulation.
Furthermore, the probable influence of α-T on kinases
was examined by using the cell-free assay representing
a modest inhibitory effect on AKT, JNK1, JNK2 and IKK
beta kinases. The supposed correlation of α-T with AKT
kinase and NF-κB inhibitors is attributed to this moderate
inhibition of AKT and IKK beta kinases. In addition,
the release of cytochrome C due to the disruption of the
mitochondrial membrane potential cannot be ignored
as an extra cytotoxic mechanism for α-T which helps in
the induction of apoptosis in colon cancer cell lines,
when linalyl acetate and camphor are combined with α-T
[9,22]. On the other hand, the antifungal activity exerted
by α-T is also represented by the uncommon structure
of mitochondria of the fungi and its cell membrane
disruption [25].
Based on the results of many experiments, α-T appears
to inhibit the growth and induces cell death in tumor cells
by a mechanism that involves inhibition of NF-κB activity
and translocation in a dose-dependent manner by means
of two NF-κB assays, and is also able to downregulate
α-Terpineol, a natural monoterpene: A review of its biological properties 353
many NF-κB related genes expressions such as IL-1β and
IL1R1. [9]. It was also indicated that linalyl acetate and α-T
exhibit synergistic anti-proliferative effects. The potential
combination of treatment showed significant suppression
of a basal and tumor necrosis factor (TNF)-α-induced NF-κB
activation using DNA binding assays. Moreover, IκB-α
degradation and inhibition of p65 nuclear translocation
are found to be in correspondence with this suppression.
As a result, it is shown that the anticancer activity of α-T
is partly mediated by the suppression of NF-κB activation,
suggesting its use in a combination with linalyl acetate
with chemotherapeutic agents to induce apoptosis [26].
Anti-nociceptive activity2.4
“Another important activity which is correlated to α-T is
the anti-nociceptive activity. A nociceptor is a sensory
receptor that responds to potentially damaging stimuli by
sending nerve signals to the spinal cord and brain. The
anti-nociceptive eect is a reduction in pain sensitivity
made within neurons when endorphins or a similar opium-
containing substance combines with a receptor” [18]. One of
the most important symptoms of an inammatory disease
is a pain. Sanitation of primary aerent nociceptors
can result in allodynia and/or hyperalgesia, known
as hypernociception in animal models [27]. The main
function of pain is to avoid the damage of tissue stimuli
via activating the spinal reex withdrawal mechanisms.
Thus, it helps in protecting the tissues of the organism
from damaging. In acute pain conditions, pain exists for a
while even aer healing the injury. Alternatively, chronic
pain conditions can be explained by the presence of typical
inammation and neuropathy [28]. Moreover, available
anti-nociceptive drugs show low ecacy to relieve
painful conditions in patients and possess numerous side
eects [29]. Therefore, natural products showing fewer
side eects, exert promising therapeutic activities in
developing new drugs which can manage certain chronic
pain conditions [30].
Golshani et al. reported that the essential oil of
Dracocephalum Kotschyi Boiss (Lamiaceae), containing
α-T as an active component, possesses anti-nociceptive
properties [31]. Therefore, many experiments based on
these results took place to investigate the anti-nociceptive
effect of α-T. The results of another study revealed that
α-T possesses both peripheral and central analgesic
properties. α-T produced significant (p<0.01 or p<0.001)
analgesic effects by reduction at the early and late phases
of paw licking and reduced the acetic acid-induced
writhing reflex in mice. Those effects are probably in
relation to the inhibition in the peritoneal fluid levels of
PGE2 and PGF2α with the release inhibition of substance
P and other inflammatory molecules, such as serotonin,
histamine, bradykinin, and prostaglandins [32].
It has been investigated that glutamate plays an
important role in transmitting the nociceptive signals
from the peripheral nervous system to the spinal cord,
mainly the dorsal horn. Moreover, glutamate injections
provoked nociceptive responses, which are mediated by
neuropeptides (Substance P) released from C fibers, due
to the activation of glutamate receptors [i.e., N-methyl-D-
aspartate acid (NMDA)] that can stimulate the production
of a variety of intracellular second messengers. These
are NO, then pro-inflammatory cytokines, such as
tumor necrosis factor alpha (TNF-α) and IL-1β, which act
synergistically in the excitation of the neurons [33]. Trink
et al. indicated that the intravaginal treatment with α-T,
one of the main components of Artemisia princeps Pamp
(Asteraceae) essential oil (APEO), significantly decreased
viable Gardnerella vaginalis and Candida albicans germs
in the vaginal cavity by inhibition of the expression of
pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), COX-2,
iNOS. Based on these results, α-T most potently inhibited
the expression of pro-inflammatory cytokines and NF-κB
activation [34]. Additionally, it was found that spinal,
supraspinal, and peripheral sites of action are involved in
the induced nociceptive response by glutamate which is
mainly mediated by both non-NMDA and NMDA receptors
[35]. Thus α-T produces an inhibition of the nociception
induced by glutamate [32]. The anti-inflammatory activity
of α-T was assessed in another study, where α-T showed
inhibition of bovine cyclooxygenase-1 and 2 (COX-1 and
COX-2). α-T exerted selective COX-2 inhibition, where its
IC50 values against COX-1 and COX-2 were 5.14 mM and 0.69
mM, respectively. This indicated that α-T showed higher
COX-2 activity inhibition than Aspirin®, which is the most
popular NSAID [36].
Sakurada et al. suggested that the capsaicin-
induced pain model examines substances which act
on pain of neurogenic origin. Furthermore, capsaicin
can be defined as an extracted neurotoxic substance
from red pepper, resulting in the irritation of the skin
when applied or injected into animals causing a painful
sensation and subsequent desensitization to chemically
induced pain. Many reports have revealed that capsaicin
provokes the release of neuropeptides, nitric oxide
(NO), excitatory amino acids (glutamate and aspartate),
and pro-inflammatory mediators and also helps in the
transmission of nociceptive information to the spinal
cord [37]. The analgesic action of α-T was presented by Le
Bars et al. involving the supraspinal as well as the spinal
354 Christina Khaleel et al.
components by the utilization of the hot plate test [38].
The results suggested that α-T (only at a higher dose) has
a central analgesic effect, due to the occurrence of time
response delay during a hot plate test, when mice were
exposed to a nociceptive stimulus [32].
According to Poole et al. releasing primary
hypernociceptive mediators are believed to be stimulated
by a cascade of cytokines and not directly by means of
inflammatory stimuli [39]. Mechanical hypernociception
is induced by carrageenan (CG) using this cascade of
cytokines. TNF-α is the first cytokine to be set free and
subsequently triggers the release of other cytokines such
as IL-1β [40]. This can lead to a neurogenic inflammation
which contributes to the inflammatory process resulting
in central and peripheral hyperalgesia. Moreover,
the α-T’s anti-nociceptive activity indicated that the
development of this mechanical hypernociception is
inhibited by pre-systemic treatment with α-T at doses
of 25, 50 or 100 mg/kg. i.p. A similar action was also
noticed upon prostaglandin E2 (PGE2) and dopamine
(DA) administration, where it was observed that α-T
was able to maintain the baseline nociceptive threshold
and significantly inhibited the neutrophil-influx in the
pleurisy model [28]. These results may conclude that the
synthesis of compounds, such as eicosanoids which are
correlated with the inflammatory process, is inhibited
by α-T possibly by means of suppressing NF-κB signaling
[5]. α-T (1, 10 and 100 μg/mL) also significantly reduced
(p<0.01) nitric oxide (NO) production in macrophages
stimulated by lipopolysaccharides (LPS) in vitro [28].
In summary, the data collected so far provide
information about the anti-nociceptive and anti-
inflammatory properties of α-T which attract great
pharmaceutical interest in developing new clinical drugs
which can be useful in managing and controlling painful
and/or inflammatory disease [28,32].
Antiulcer activity 2.5
“Peptic ulcer is one of the most common gastrointestinal
diseases. Gastric ulcers are generally caused by a disruption
in the balance between aggressive factors (pepsin and
hydrochloric acid) and mucosal defensive factors, such as
blood ow, mucus, and bicarbonate secretion. In recent
years, a widespread search has been launched to identify
new anti-ulcer drugs from natural sources” [41].
As α-T is an isomer of the monoterpene alcohol
terpinen-4-ol (T-4-ol) which possesses anti-ulcer activity
[42], it was also of interest to evaluate and present the
anti-ulcer activity of α-T- in the present review. The
gastroprotective activity of α-T was determined in the two
ethanol-and indomethacin-induced ulcer models in rats.
In the ethanol-induced ulcer model the oral administration
of α-T furnished a gastroprotective activity, by reduction
of the gastric lesions. Stimulation of defense mechanisms
(cytoprotective effect) is the suggested mechanism of drug
action showing gastroprotective activity against ethanol-
induced gastric lesions, rather than the inhibition of
aggressive ones (anti-secretory effect). The indomethacin-
induced gastric lesions were also decreased by means of
an oral treatment with α-T, but a considerable inhibition
(p<0.01) was noticed only at concentrations of 30 mg/
kg and 50 mg/kg. This result shows that α-T exerted its
gastroprotective action in a dose-dependent manner
[41]. Moreover, there is a relationship between gastric
acid and the gastric lesion formation which was induced
by indomethacin. Gerkens et al. proposed that the
indomethacin-induced lesion formation was attributed to
the decrease of gastric mucosal blood flow [43].
Pre-treatment with indomethacin (10 mg/kg) did
not inhibit the gastroprotective action of α-T on ethanol-
induced ulcers. Based on this result, an increase in
prostaglandin synthesis is not believed to be involved in
the gastroprotective action of α-T at a concentration 50
mg/kg. On the other hand, the secretion of gastric acid
can be inhibited by either proton pump inhibitors and/
or histamine H2 receptor antagonists, which represent the
currently used drugs in order to treat ulcers. However,
α-T has not changed proton concentration values, pH,
and the gastric volume after pylorus ligation, indicating
that its gastroprotective action is not suggested to be
due to gastric secretion inhibition. On this basis of such
evidence, α-T exerts its gastroprotective effect probably by
means of cytoprotective mechanisms which need further
investigations to be more explained [41].
Anticonvulsant and sedative activity2.6
Around 450 million people worldwide suer from many
problems during their lives, such as neurological, mental
or behavioral disturbance [44]. Epilepsy can be dened
as a disorder accompanied by recurrent spontaneous
seizures, caused by several complex mechanisms
including dierent neurotransmitter systems as GABA
(γ-aminobutyric acid) and cholinergic system. Despite
using more ecient and modern anticonvulsant drugs
to treat epilepsy patients worldwide, seizures are still
considered to be unmanageable in more than 20% of the
cases. Furthermore, most of the currently used antiepileptic
drugs are obtained by means of chemical syntheses, such
α-Terpineol, a natural monoterpene: A review of its biological properties 355
as benzodiazepines and succinimides [45]. Therefore,
recent studies on monoterpene compounds such as α-T
have been performed to examine their pharmacological
aspects to develop new anticonvulsant drugs with lower
side eects and more advantages than that of the currently
used pharmaceutical drugs [45].
De Sousa et al. investigated the anticonvulsant
activity of α-T. The results of this study indicated that
the latency to pentylenetetrazole-induced convulsions
is increased by treatment with α-T at concentrations
of 100 and 200 mg/kg and the incidence of hind-limb
extension produced by MES (maximal electroshock
seizure) is reduced at concentrations 200 and 400 mg/kg
in a dose-dependent manner in mice [46]. Another study
analyzed the therapeutic effect of α-T as a relaxing drug
and tranquilizer. The data showed that α-T increased the
sleep time of the mice indicating a sedative property, due
to the suggested action on central mechanisms affecting
the inhibition of the metabolism of pentobarbital or the
regulation of sleep in mice. In other words, α-T exhibited a
depressant effect on the pentobarbital-induced sleep test,
indicating a sedative property [47].
Anti-bronchitis activity2.7
“Chronic obstructive pulmonary disease (COPD) is a chronic
obstructive lung disease and is frequently found in well-
developed countries due to the issue of aging population.
COPD can lead to the restriction of lung function” [48,49].
The current treatment options for COPD are very limited
and their side eects of treatment frequently noted is
Cushing Syndrome caused by long-term steroid use [50].
At the nal state of severe COPD patients need lung
transplants but still the survival outcome is poor [51].
Despite improvement with regard to pharmacy and drug
invention the occurrence of COPD and mortality related to
COPD continues to rise [52]. Clearly, eorts to stop smoking
and to control pneumonia could be the appropriate
prevention methods to limit deterioration in cases of
COPD. However, there are no other useful ways to attempt
to cure the COPD; thus it remains the leading cause of
death throughout the world [53]. Therefore, prevention
of the occurrence of COPD is the most important issue to
address, but not only the above-mentioned methods but
also by the inhibition of IκB-kinase beta (IKK2) which is
linked to COPD occurrence [54,55].
Tsou et al. investigated the effect of α-T against
COPD. The top three traditional Chinese medicine (TCM)
compounds were found to be sinapic acid-4-O-sulphate,
kaempferol and α-T belonging to the TCM herbs Magnolia
officinalis (Magnoliaceae), Bupleurum chinese (Apiaceae),
respectively [56]. α-T exerts an antimicrobial effect and
in particular, prevents infections that originate from
periodontopathic and carcinogenic bacteria [57]. As a
result, it was indicated that the above mentioned TCM
compounds can have an effect on IKK2 inhibition and
prevent exacerbation and disease progression with
regards to COPD [56].
Skin penetration enhancing activity2.8
Over the last two to three decades, the skin has become
an important route for the administration of drugs for
topical, regional or systemic action. The skin has evolved
as a physical and biochemical protective barrier which
prevents the loss of water from the body, and guards
against entry into the body of external toxic chemicals and
infectious agents, thereby maintaining homeostasis. The
role of the skin as a barrier to the external environment
renders the absorption and transdermal delivery of most
drugs problematic. The stratum corneum (SC) which is
the outermost layer of the skin and comprised of keratin-
rich cells embedded in multiple lipid bilayers has been
considered the rate-determining structure governing
percutaneous absorption of permeants. Therefore, most of
the drugs are not able to penetrate the SC or to be delivered
through it [58]. “Many strategies have been employed to
enhance dermal and transdermal delivery. These include
the use of chemical penetration enhancers, preparation of
supersaturated drug delivery systems, electrically driving
molecules through the tissues by iontophoresis, and
physically disrupting the skin structure by electroporation
or sonophoresis” [59].
Delivery of drugs via the skin has numerous
advantages, like non-invasiveness, the potential for
continuous or controlled delivery, and potential for delivery
of certain classes of drugs that are not amenable for the
administration via other routes of drug delivery. Various
types of penetration enhancers with different modes of
action have therefore frequently been used in the field
of transdermal drug delivery research [58]. Transdermal
delivery of drugs promises many advantages over oral or
intravenous administration such as decreasing the side
effects, improving patients compliance, first-pass effect
elimination, sustained drug delivery and interruption of
the drug treatment if required [60], though human skin
provides an effective barrier to the permeation of most
drugs in the form of SC [61,62]. Many factors have a great
influence on the dermal absorption such as skin type,
the origin (human, animal), environmental factors, as
356 Christina Khaleel et al.
well as the physicochemical activities with the dermal/
transdermal absorption in humans. [63]. Transdermal
therapeutic systems offer a more reliable mean of
administering the drug through the skin by various
physical, chemical, biochemical, supersaturation and
bioconvertable prodrug enhancement strategies [64].
Out of these strategies, a popular technique is the use
of chemical permeation enhancers, which reversibly alters
the permeability barrier of the SC. α-T is considered one of
these chemical enhancers, which is currently believed to
improve solubility within the SC or increase lipid fluidity
of the intracellular bilayers [58,64]. Many studies have
reported that α-T appears to be acceptable as a promising
skin penetration enhancer as indicated by following
advantages [63]:
high percutaneous enhancement ability, –
less toxic with low irritancy potential, –
reversible effect on the lipids of SC –
Several studies suggest that the activity of α-T as an
enhancer is a result of disrupting the intracellular lipid
bilayers. Evidence from skin electrical conductivity
measurements suggests that α-T may create polar pathways
across the SC for ions and polar drug penetration. In
addition, results from electron paramagnetic resonance
have demonstrated that α-T can uidize the SC lipids
and weaken the hydrogen-bonded network of the polar
interface of the SC [60,65,66]. The mechanism of action
of α-T appears to be dicult, depending on the nature of
permeants (e.g. hydrophilic or lipophilic). Furthermore,
α-T is an alcoholic monoterpene with a high degree of
unsaturation and appears to be a better candidate for
enhancing the permeation of hydrophilic drugs such as
e.g. 5-uorouracil by increasing the diusion of the drug
in the SC [58,64]. “The interaction of α-T with SC lipids and
keratin can be elucidated with instrumental methods such
as Fourier transform infrared spectroscopy (FT-IR) and
dierential scanning colorimetry (DSC). The FT-IR provides
the information about the molecular and conformational
changes of lipids and proteins, whereas the DSC provides
information about their thermotropic behavior” [60].
As skin penetration enhancer, α-T has been employed
directly or in combination with co-solvents such as
propylene glycol or ethanol. Synergistic activity has been
reported between α-T and propylene glycol as well as
between α-T and ethanol [60,65]. It was reported that the
in vitro permeation of haloperidol (HP), an antipsychotic
drug, is increased through human skin by using α-T at
a concentration of 5% w/v in 100% propylene glycol
(PG). Haloperidol is a lipophilic drug and may play an
important role in developing the transdermal dosage form.
Since HP is clinically needed to be found in a long-acting
formulation to avoid psychosis relapse, it was required to
use as a skin penetration enhancer α-T and as co-solvent
PG to increase the permeation of HD [60].
Narishetty et al. investigated the effect of this
monoterpene alcohol and other various oxygen-containing
monoterpenes, such as 1,8-cineole, menthol, menthone,
pulegone and carvone for the ex vivo permeation of
zidovudine (AZT), the first approved and wide clinically
used anti-HIV substance, in a solution of 66.6 % ethanol
in water across rat skin. Based on the result of this study,
it was indicated that a hydrogen bonding interaction is
formed by α-T with the ceramide head group of SC lipids
and a subsequent reduction in the skin barrier property
occurred [65].
According to many skin penetration studies using the
skin of hairless mice and excised animal skin, it was found
that α-T was effective in enhancing the skin penetration of
model permeants, such as caffeine [67] and 5-Fluorouracil
[68], respectively. α-T exerted an effective penetration
enhancing activity for hydrocortisone percutaneously and
also increased the permeation between 3.9-fold and 5-fold,
and α-T was the most active compound among several
other compounds to increase the delivery of triamcinolone
acetonide [63,67].
The use of local anaesthetics in combination with
penetration enhancers could overcome the barrier
properties of the skin to epicutaneous penetration of local
anesthetic drugs. Lidocaine is a topical anaesthetic agent
with low skin permeability which cannot adequately
penetrate the intact skin. On the other hand, the ideal
topical anaesthetic agent is one that provides 100 %
anaesthesia in a short period of time, is further effective
on the intact skin without systemic side effects, and
invokes neither pain nor discomfort [69]. The authors of
that study investigated the effects of some permeability
enhancers such as polysorbate 80, polysorbate 20,
dimethylsulfoxide (DMSO), tert-butyl cyclohexanol
(TBCH), and α-T in different concentrations on the
percutaneous permeation of lidocaine. According to
that literature review, α-T showed the best permeability-
enhancing effects on the lidocaine penetration through
the skin. Since α-T is a relatively safe compound, it can
be recommended to incorporate it into local anaesthetic
cream formulations at low concentrations. α-T exerts the
best effect at a concentration of 2.5%, as it is believed
that it can produce eutectic mixtures with lidocaine and
increase the thermodynamic activity of lidocaine in the
relevant formulation [69].
Interestingly, Fang et al. found that the best method
to enhance the curcumin permeation is the pre-treatment
α-Terpineol, a natural monoterpene: A review of its biological properties 357
of rat skin with 5% α-T in an ethanolic solution for 1 h [70].
Curcumin exhibits various biological properties such as
anticancer and anti-inflammatory. Therefore, it can be
used in the treatment of several disorders, such as tumors
and pro-inflammatory chronic diseases [71-73]. Because
of the insufficient aqueous solubility and bioavailability
of curcumin, it is not widely used in the clinical field for
treatment of cancer and other diseases [74]. In another
study, three terpenes, α-T, 1,8-cineole, and limonene, were
used to compose an oil phase of the microemulsions. They
provide another promising alternative for the dermal and
transdermal delivery of both hydrophilic and lipophilic
drugs [59]. Their effects on curcumin skin delivery were
evaluated using neonatal pig skin mounted on a Franz
diffusion cell. The results indicated that curcumin retained
in the skin increased in the order limonene > α-T > 1,8-
cineole [59]. Additionally, it was reported that α-T was used
as a transdermal enhancer for buspirone hydrochloride,
an anxiolytic, in hairless mouse skin [75]. Moreover, Jain et
al. showed the effect of α-T on imipramine hydrochloride
(IMH) permeation in the ethanol (EtOH): W (2:1) system.
By means of unjacketed Franz diffusion cells, permeation
studies of IMH were performed through rat skin. Based on
the results of this literature [76], it was found that α-T is an
effective permeation enhancer for IMH.
Insecticidal activity2.9
“Some facts indicate that the use of synthetic chemicals to
control insects and arthropods raises several concerns as to
the environment and human health. So, there is a growing
demand for alternative repellents or natural products. These
products possess good ecacy and are environmentally
friendly. Essential oils from plants belonging to several
species have been extensively tested to assess their
repellent and even insecticidal properties as valuable
natural resources” [18]. Searching for novel and eective
natural products which are based on biopesticides,
terpenoids have shown promising insecticidal activities
[77-79]. Aedes aegypti L. is the principal vector of dengue,
Zika and chikungunya, and the use of repellents is one
of the approaches to prevent these diseases. Scientists
at the Center for Medical, Agricultural and Veterinary
Entomology (Gainesville, Florida, U.S.) evaluated several
natural terpenes for the discovery of safe and potential
repellents against the female Ae. aegypti. They found that
(-)-α-T was a repellent at a minimum eective dosage (MED)
of 0.039 ± 0.008 mg/cm2 compared to positive control (N,N-
diethyl-3-methylbenzamide, DEET) (MED= 0.014 ± 0.002
mg/cm2) [79]. Campbell et al. also found that α-T showed
prompt olfactory responses in Ae. aegypti antennae [80],
however, α-T had a moderate repellent eect based on EAG
responses against the stable y Stomoxys calcitrans L. [81].
Mosquito larvae are important and attractive targets for
pesticide management programs. Tabanca et al. reported
that (-)-α-T did not show any mortality in the pre-screening
bioassays at a concentration of 100 ppm against 1st instar
Ae. aegypti [82].
The maize weevil, Sitophilus zeamais Motschulsky,
causes yield losses in storage products like corn. Under
laboratory conditions, α-T showed 100% mortality against S.
zeamais adults after 96 h of exposure at the highest dose (30
µL/µg) [83].
Booklice, Liposcelis bostrychophila Badonnel, have
a widespread distribution infesting domestic premises,
manufacturing factories, raw material stores; they are also
found in historical documents [84]. Due to the presence
of more damaging post-harvest primary pests, they are
often disregarded and are generally considered to be
secondary pests. Liu et al. reported that α-T exhibited
strong contact toxicity and repellent properties against
booklice [85]. α-T was a major compound (37.2%) in
Artemisia rupestris L. (Asteraceae) essential oil and this
essential oil, can be a great potential for the development
into natural insecticides or fumigants as well as repellents
for the control of insects in stored grains [85]. α-T also
demonstrated high fumigant toxicity against two-spotted
spider mites Tetranychus urticae Koch [86].
Termites are the most damaging insect pests damaging
wooden structures worldwide. There is an increasing
interest in naturally occurring toxicants to Formosan
subterranean (Coptotermes formosanus), invasive species
of termites [87]. α-T was selected to test for its antitermitic
activity against C. formosanus and showed slight
toxicity at a dose of 2.5 mg g−1 after seven days. However,
α-T demonstrated 100% termite mortality against C.
formosanus at a dosage of 4 mg g−1 after 7 days [87].
Based on these above research results, we can
conclude that α-T had responded to selective insects
and dose-dependent activity. To discover, develop and
understand the naturally based bio-pesticides, we need
more scientific research on the insect diversity, and α-T is
one of the natural compounds to be widely investigated.
Conclusion3
α-T is a monocyclic monoterpene tertiary alcohol with
a pleasant scent similar to lilac. Therefore, it is widely
used in the manufacturing of perfumes, cosmetics, soaps,
antiseptic agents and is considered one of the most
358 Christina Khaleel et al.
frequently used fragrant compounds [1]. In addition, α-T
possesses a wide range of biological actions which attract
a great interest in the medicinal eld [4].
The cardiovascular and the antihypertensive effects
of α-terpineol were investigated in several studies.
These results indicated that the oral administration of
α-T was able to reduce the mean arterial pressure and
endothelium-independent vasodilatation. Moreover, α-T
was able to restore enzymatic antioxidant in L-NAME-
induced hypertensive [5,15].
Additionally, α-T showed an anti-proliferative
(antioxidant) activity, which could be used in the
prevention or even treatment of cancer, as it was found
that α-T demonstrated a potential antioxidant capacity
effect against different human cancer cell lines (breast,
lung, prostate, ovarian and leukemia). α-T inhibits the
growth and induction of cell death in tumor cells by means
of an inhibition of NF-κB activity [9,20].
The anti-nociceptive activity is one of the most
important biological actions correlated to α-T. It was
indicated that α-T produced significant analgesic effects by
reduction at the early and late phases of paw licking and
reduced the acetic acid-induced writhing reflexes in mice
(formalin and writhing tests, respectively). Those effects
are probably in relation to the inhibition in the peritoneal
fluid levels of PGE2 and PGF2α and to the release inhibition
of substance P and other inflammatory molecules [32].
However, α-T exerted also a selective COX-2 inhibition
(0.69mM), therefore, it is believed that α-T showed higher
COX-2 activity inhibition than Aspirin® [36]. α-T might be
potentially interesting in the development of new drugs
for the management of painful and/or inflammatory
diseases, as well as the development of novel therapies
for COPD [56].
Several studies have reported that α-T also possesses
antiulcer activity. The results suggested that it presented
a gastro-protective activity by reducing the gastric lesions
at the doses 10, 30 and 50 mg/kg without the involvement
of gastric acid secretion inhibition or increase in
prostaglandin synthesis [41,42]. Furthermore, α-T showed
anticonvulsant and sedative activities via a depressant
effect on the pentobarbital-induced sleep test [47]. In
addition, it increased the latency to convulsions induced
by pentylenetetrazole and decreased the incidence of
hind limb extension produced by MES in a dose-related
manner [46].
Another important biological activit of α-T was its
promising effect as a chemical skin penetration enhancer,
currently believed to improve the solubility within the
stratum corneum (SC) or to increase the lipid fluidity of the
intracellular bilayers [58,64]. In addition, the insecticidal
activity of α-T attracted the interest of many scientists.
Therefore, it is suggested that α-T may be a potential agent
for the development into natural insecticides or fumigants,
as well as repellents for control of insects [77-87].
Consequently, α-T has exhibited a potential satisfaction
in certain activities due to its usage in pharmaceutical and
agricultural industries. Encouraging results from these
wide range of biological activities show that α-T is very
promising candidate in pharmaceutical and agricultural
applications.
Disclaimer: No potential conict of interest was reported
by the authors.
References
Bauer K., Garbe D., Surburg H., Common Fragrance and Flavor [1]
materials: Preparations, properties, and uses, 4th ed., Wiley,
New York, 2001.
Sell C., A Fragrant Introduction to terpenoid chemistry, 1st ed., [2]
The Royal Society of Chemistry, Cambridge, UK, 2003.
Baser K.H.C., Buchbauer G.,[3] Handbook of essential oils:
Science, Technology, and Applications, 2nd ed., Taylor and
Francis group, New York, US, 2010.
Bhatia S.P., Letizia C.S., Api A.M.,[4] Fragrance material review on
alpha-terpineol, Food Chem. Toxicol., 2008, 46(11), 280-285.
Sabino C.K., Ferreria-Filho E.S., Mendes M.B., Da Silva-[5]
Filho J.C., Cardiovascular effects induced by α-terpineol in
hypertensive rats, Flavour Frag. J., 2013, 28(5), 333-339.
Lampronti I., Saab A.M., Gambari A., Antiproliferative [6]
activity of essential oils derived from plants belonging to the
Magnoliophyta division, Int. J. Oncol., 2006, 29(4), 989-995.
Held S., Schieberle P., Somoza V., Characterization of alpha-[7]
terpineol as an anti-inflammatory component of orange juice
by in vitro studies using oral buccal cells, J. Agric. Food Chem.,
2007, 55(20), 8040-8046.
Brand C., Ferrante A., Prager R.H., Riley T.V., Carson C.F., [8]
Finaly-Jones J.J., et al., The water-soluble components of the
essential oil of Melaleuca alternifolia (tea tree oil) suppress
the production of superoxide by human monocytes, but not
neutrophils, activated in vitro, Inflamm. Res., 2001, 50(4),
213-219.
Hassan S.B., Muhtasib H.G., Goeransson H., Larsson R., Alpha-[9]
terpineol: a potential anticancer agent which acts through
suppressing NF-κB signaling, Anticancer Res., 2010, 30(6),
1911-1920.
Mayet J., Hughes A., Cardiac and vascular pathophysiology in [10]
hypertension, Heart, 2003, 89, 1104-1109.
Wang G., Zhang Z., Ayala C., Hospitalization costs associated [11]
with hypertension as a secondary diagnosis among insured
patients aged 18-64 years, Am. J. Hypertens., 2010, 23(3),
275-281.
Nguelefack T.B., Mekhfi H., Dongmo A.B., Dimo T., Watcho P., [12]
Hypertensive effects of oral administration of the aqueous
extract of Solanum torvum fruits in L-NAME treated rats:
α-Terpineol, a natural monoterpene: A review of its biological properties 359
Evidence from in vivo and in vitro studies, J. Ethnopharmacol.,
2009, 124(3), 592-599.
Moncada S., Higgs E.A., The discovery of nitric oxide and its [13]
role in vascular biology, Br. J. Pharmacol., 2006, 147, 193-201.
Fernandes-Santos C., Mendonca L.D., Mandarim-de-Lacerda [14]
C.A., Beneficial effects of angiotensin II AT1 blocker on
cardiovascular adverse remodeling due to nitric oxide
synthesis blockade. Int. J. Morphol., 2006, 24(3), 309-318.
Ribeiro T.P., Porto D.L., Menezes C.P., Antunes A.A., Unravelling [15]
the cardiovascular effects induced by α-terpineol: A role for
the nitric oxide–cGMP pathway, Clin. Exp. Pharmacol. Physiol.,
2010, 37(8), 811-816.
Jones R.D., Pugh P.J., Jones T.H., Channer K.S.,[16] The vasodilatory
action of testosterone: a potassium-channel opening or a
calcium antagonistic action, Br. J. Pharmacol., 2003, 138(5),
733-744.
Catterall W.A., Perez-Reyes E., Snutch T.P., Striessnig J., [17]
International union of pharmacology. XLVIII. Nomenclature
and structure-function relationships of voltage-gated calcium
channels, Pharmacol. Rev., 2005, 57(4), 411-425.
Adorjan B., Buchbauer G.,[18] Biological properties of essential
oils: an update review, Flavour Frag. J., 2010, 25, 407-426.
Touyz R.M.,[19] Oxidative stress and vascular damage in
hypertension, Curr. Hypertens. Rep., 2000, 2(1), 98-105.
Bicas J.L., Neri-Numa I.A., Ruiz A.L., De Carvalho J.E., Pastore [20]
G.M., Evaluation of the antioxidant and antiproliferative
potential of bioflavors, Food Chem. Toxicol., 2011, 49(7), 1610-
1615.
Saravankumar M., Raja B.,[21] Veratric acid, a phenolic acid
attenuates blood pressure and oxidative stress in L-NAME
induced hypertensive rats, Eur. J. Pharmacol., 2011, 671(1-3),
87-94.
Itani W.S., El-Banna S.H., Hassan S.B., Larsson R.L., Bazarbachi [22]
A., Gali-Muhtasib H.U., Anti colon cancer components from
Lebanese sage (Salvia libanotica) essential oil: Mechanistic
basis, Cancer Biol. Ther., 2008, 7(11), 1765-1773.
Garg A., Aggarwal B.B., Nuclear transcription factor-kappaB as [23]
a target for cancer drug development, Leukemia, 2002, 16(6),
1053-1068.
Lindhagen E., Rickardson L., Elliott G., Leoni L., Nygren P., [24]
Larsson R., et al., Pharmacological profiling of novel non-COX-
inhibiting indole-pyran analogues of etodolac reveals high
solid tumour activity of SDX-308 in vitro, Invest. New Drugs,
2007, 25(4), 297-303.
Park M.J., Gwak K.S., Yang I., Kim K.W., Jeung E.B., Effect [25]
of citral, eugenol, nerolidol and alpha-terpineol on the
ultrastructural changes of Trichophyton mentagrophytes,
Fitoterapia, 2009, 80(5), 290-296.
Deeb S.J[26] ., El-Baba C.O., Hassan S.B., Larsson R.L., Gali-
Muhtasib H.U., Sage components enhance cell death through
nuclear factor kappa-B signalling, Front. Biosci, 2011, 3,
410-420.
Parada C.A., Vivancos G.G., Tambeli C.H., De Queirόz Cunha F., [27]
Ferreira S.H., Activation of presynaptic NMDA receptors coupled
to NaV1.8-resistant sodium channel C-fibers causes retrograde
mechanical nociceptor sensitization, Proc. Natl. Acad. Sci.
U.S.A., 2003, 100(5), 2923-2928.
De Oliveira M., Marques R., De Santana M., Santos A., [28]
α-Terpineol reduces mechanical hypernociception and
inflammatory response, Basic Clin. Pharmacol. Toxicol., 2012,
111, 120-125.
Mendell J.R., Sahenk Z., Painful sensory neuropathy, N. Engl. J. [29]
Med., 2003, 348, 1243-1255.
De Sousa D.P., Analgesic-like activity of essential oils [30]
constituents, Molecules, 2011, 16(3), 2233-2252.
Golshani S., Karamkhani F., Monsef-Esfehani H.R., [31]
Andollahi M., Antinociceptive effects of the essential oil of
Dracocephalum kotschyi in the mouse writhing test, J. Pharm.
Pharm. Sci., 2004, 7(1), 76-79.
Quintans-Júnior L.J., Oliveria M., Santana M.F., Santana M.T., [32]
Guimaraes A., Siqueria J., De Sousa D., Almeida R., α-Terpineol
reduces nociceptive behavior in mice, Pharm. Biol., 2011,
49(6), 583-586.
Ribas C.M., Meotti F.C., Nascimento F.P., Jacques A.V., [33]
Dafre A.L., Antinociceptive effect of the Polygala sabulosa
hydroalcoholic extract in mice: Evidence for the involvement
of glutamatergic receptors and cytokine pathways, Basic Clin.
Pharmacol. Toxicol., 2008, 103(1), 43-47.
Trink H.T., Lee I.A., Hyun Y.J., Kim D.H., Artemisia princeps [34]
Pamp. Essential oil and its constituents eucalyptol and
α-terpineol ameliorate bacterial vaginosis and vulvovaginal
candidiasis in mice by inhibiting bacterial growth and NF-κB
activation, Planta Med., 2011, 77(18), 1996-2002.
Beirith A., Santos A.R., Colixto J.B.,[35] Mechanisms underlying the
nociception and paw oedema caused by injection of glutamate
into the mouse paw, Brain Res., 2002, 924(2), 219-228.
Kawata J., Kameda M., Miyazawa M., Cyclooxygenase-2 [36]
inhibitory effects of monoterpenoids with a p-methane
skeleton, Int. J. Essent. Oil Ther., 2008, 2(4), 145-148.
Sakurada T., Matsumura T., Moriyama T., Sakurada C., Ueno S., [37]
Sakurada S., Differential effects of intraplantar capsazepine
and ruthenium red on capsaicin-induced desensitization in
mice, Pharmacol. Biochem. Behav.,2003, 75(1), 115-121.
Le Bars D., Gozariu M., Cadden S.W., Animal Models of [38]
Nociception, Pharmacol. Rev., 2001, 53(4), 597-652.
Poole S., De Queirόz Cunha F., Ferreira S.H., Hyperalgesia from [39]
subcutaneous cytokines, P. Inflamm. Res., 1999, 59-87.
Lorenzetti B.B., Veiga F.H., Canetti C.A., Poole S., Cytokine-[40]
induced neutrophil chemoattractant 1 (CINC-1) mediates
the sympathetic component of inflammatory mechanical
hypersensitivity in rats, Eur. Cytokine Netw., 2002, 13(4),
456-461.
Souza R.H., Cardoso M.S., Menezes C.T., Silva J.P., De Sousa [41]
D.P., Batista J.S., Gastroprotective activity of α-terpineol in two
experimental models of gastric ulcer in rats, DARU J. Pharm.
Sci., 2011, 19(4), 277-281.
Matsunaga T., Hasegawa C., Kawasuji T., Suzuki H., Saito H., [42]
Isolation of the antiulcer compound in essential oil from the
leaves of Cryptomeria japonica, Biol. Pharm. Bull, 2000, 23(5),
595-598.
Gerkens J.F., Shand D.G., Flexner C., Nies A.S., Oates J.A., Data [43]
J.L., Effect of indomethacin and aspirin on gastric blood flow
and acid secretion, J. Pharm. Exp. Ther., 1977, 203, 646-652.
WHO. The World Health Report. Mental Health: New [44]
Understanding New Hope; WHO: Geneva, Switzerland, 2001.
De Almeida R.N., Agra M.D., Maior F.N., De Sousa D.P., Essential [45]
oils and their constituents: Anticonvulsant activity, Molecules,
2011, 16(3), 2726-2742.
360 Christina Khaleel et al.
De Sousa D.P., Quintans-Júnior L., De Almeida R.N., Evolution of [46]
the anticonvulsant activity of α-terpineol, Pharm. Biol., 2007,
45(1), 69-70.
De Sousa D., Raphael E., Brocksom U., Brocksom T., Sedative [47]
effect of monoterpene alcohols in mice: a preliminary
screening, Z. Naturforsch. C, 2007, 62(7-8), 563-566.
Taffet G.E., Donohue J.F., Altman P.R., Considerations for [48]
managing chronic obstructive pulmonary disease in the
elderly. Clin. Interv. Aging., 2014, 9, 23-30.
Vestbo J., Hurd S.S., Agusti A.G.,[49] Global strategy for the
diagnosis, management, and prevention of chronic obstructive
pulmonary disease, Am. J. Respir. Crit. Care Med., 2013, 187(4),
347-365.
Martinez F.J., Danohue J.F., Rennard S.I., The future of chronic [50]
obstructive pulmonary disease treatment difficulties of and
barriers to drug development, Lancet, 2011, 378(9795), 1027-
1037.
Bustacchini S., Chiatti C., Furneri G., Lattanzio F., Mantovani [51]
I.G., The economic burden of chronic obstructive pulmonary
disease in the elderly: results from a systematic review of the
literature, Curr. Opin. Pulm. Med., 2011, 17(1), 35-41.
Najafzadeh M., Marra C.A., Lynd L.D., Sadatsafavi M., [52]
FitzGerald J.M., Future impact of various interventions on the
burden of COPD in Canada: A dynamic population model, PLoS
ONE, 2012, 7(10), e46746
Ozyilmaz E., Kokturk N., Teksut G., Tatlicioglu T., Unsuspected [53]
risk factors of frequent exacerbations requiring hospital
admission in chronic obstructive pulmonary disease, Int. J.
Clin. Pract., 2013, 67(7), 691-697.
Banerjee A., Koziol-White C., Panettieri R.Jr., p38 MAPK [54]
inhibitors, IKK2 inhibitors, and TNFα inhibitors in COPD, Curr.
Opin. Pharmacol., 2012, 12(3), 287-292.
Adcock I.M., Chung K.F., Caramori G., Ito K., Kinase inhibitors [55]
and airway inflammation, Eur. J. Pharmacol., 2006, 533(1-3),
118-132.
Tsou Y.A., Huang H.J., Lin W.W., Chen C.Y., Lead screening [56]
for chronic obstructive pulmonary disease of IKK2 inhibited
by traditional Chinese medicine, Evid. Based Complement.
Alternat. Med., 2014, Vol. 2014, 1-16.
Park S.N., Lim Y.K., Freire M.O.,[57] Antimicrobial effect of linalool
and α-terpineol against periodontopathic and cariogenic
bacteria, Anaerobe, 2012, 18(3), 369-372.
Songkro S., An overview of skin penetration enhancers: [58]
penetration enhancing activity, skin irritation potential and
mechanism of action, Songklanakarin J. Sci. Technol., 2009,
31(3), 299-321.
Liu C.H., Chang F.Y., Hung D.K., Terpene microemulsions [59]
for transdermal curcumin delivery: Effects of terpenes and
cosurfactants, Colloids Surf. B Biointerfaces, 2011, 82(1),
63-70.
Vaddi H.K., Ho P.C., Chan S.Y., Terpenes in propylene glycol [60]
as skin-penetration enhancers: Permeation and partition of
haloperidol, fourier transform infrared spectroscopy, and
differential scanning calorimetry, J. Pharm. Sci., 2002, 91(7),
1639-1651.
Ahad A., Aqil M., Kohli K., Role of novel terpenes in [61]
transcutaneous permeation of valsartan: effectiveness and
mechanism of action, Drug Dev. Ind. Pharm., 2011, 37(5),
583-596.
Ahad A., Aqil M., Kohli K., Interactions between novel terpenes [62]
and main components of rat and human skin: Mechanistic view
for transdermal delivery of propanol hydrochloride, Curr. Drug
Deliv., 2011, 8(2), 213-224.
Herman A., Herman A.P., Essential oils and their constituents [63]
as skin penetration enhancer for transdermal drug delivery: A
review, J. Pharm. Pharmacol., 2014, 67(4), 473-485.
Patil U.K., Saraogi R., Natural products as potential drug [64]
permeation enhancer in transdermal drug delivery system,
Arch. Dermatol. Res., 2014, 306(5), 419-426.
Narishetty S., Panchagnula R., Transdermal delivery of [65]
zidovudine: effect of terpenes and their mechanism of action, J.
Control. Release, 2003, 95(3), 367-379.
Dos Anjos J.L., Alonso A., Terpenes increase the partitioning [66]
and molecular dynamics of an amphipathic spin label in
stratum corneum membranes, Int. J. Pharm., 2008, 350(1-2),
103-112.
Godwin D.A., Michniak B.B., Influence of drug lipophilicity on [67]
terpenes as transdermal penetration enhancers, Drug Dev. Ind.
Pharm., 1999, 25(8), 905-915.
Williams A.C., Barry B.W., Terpenes and the Lipid–Protein–[68]
Partitioning Theory of Skin Penetration Enhancement, Pharm.
Res., 1991, 8(1), 17-24.
Mohammadi-Samani S[69] ., Jamshidzadeh A., Montaseri H.,
Rangbar-Zahedani M., Kianrad R., The effects of some
permeability enhancers on the percutaneous absorption of
lidocaine, Pak. J. Pharm. Sci., 2010, 23(1), 83-88.
Fang J.Y., Hung C.F., Chiu H.C., Wang J.J., Chan T.F., Efficacy and [70]
irritancy of enhancers on the in-vitro and in-vivo percutaneous
absorption of curcumin, J. Pharm. Pharmacol., 2003, 55(5),
593-601.
Maheshwari R.K., Singh A.K., Gaddipati J., Srimal R.C., Multiple [71]
biological activities of curcumin: A short review, Life Sci., 2006,
78(18), 2081-2087.
Kuttan G., Kumar K.B., Guruvayoorappon C., Kuttar R., [72]
Antitumor, anti-invasion, and antimetastatic effects of
curcumin, Adv. Exp. Med. Biol., 2007, 595, 173-184.
Menon V.P., Sudheer A.R., [73] Antioxidant and anti-inflammatory
properties of curcumin, Adv. Exp. Med. Biol., 2007, 595,
105-125.
Anand P., Kunnumakkara A.B., Newman R.A., Aggarwal B.B., [74]
Bioavailability of curcumin: Problems and promises, Mol.
Pharm., 2007, 4(6), 807-818.
Al-Khalili M., Meidan V., Michniak B., Iontophoretic [75]
transdermal delivery of buspirone hydrochloride in hairless
mouse skin, AAPS J., 2003, 5(2), 61-71.
Jain A.K., Thomas N.S., Panchagnula R., Transdermal drug [76]
delivery of imipramine hydrochloride: I. Effect of terpenes, J.
Control. Release, 2002, 79(1-3), 93-101.
Tong F., Coats J.R., Quantitative structure–activity relationships [77]
of monoterpenoid binding activities to the housefly GABA
receptor, Pest. Manag. Sci., 2012, 68, 1122-1129.
Pandey S.K[78] ., Tandon S., Ahmad A., Singh A.K., Tripathi A.K.,
Structure-activity relationships of monoterpenes and acetyl
derivatives against Aedes aegypti (Diptera: Culicidae) larvae.,
Pest. Manag. Sci., 2013, 69(11), 1235-1238.
Sakhanokho HF[79] , Sampson BJ, Tabanca N, Wedge DE, Demirci
B, Baser KH, Bernier UR, Tsikolia M, Agramonte NM, Becnel
JJ, Chen J, Rajasekaran K, Spiers JM. Chemical composition,
α-Terpineol, a natural monoterpene: A review of its biological properties 361
antifungal and insecticidal activities of Hedychium essential
oils, Molecules. 2013, 18, 4308-4327.
Campbell C., Gries R., Gries G., Forty-two compounds in eleven [80]
EOs elicit antennal responses from Aedes aegypti., Entomol.
Exp. Appl., 2011, 138, 21-32.
Hieu T.T[81] ., Jung J., Kim S.I., Ahn Y.J., Kwon H.W., Behavioural
and electroantennogram responses of the stable fly (Stomoxys
calcitrans L.) to plant essential oils and their mixtures with
attractants, Pest. Manag. Sci., 2014, 70(1), 163-172.
Tabanca N[82] , Avonto C, Wang M, Parcher JF, Ali A, Demirci B,
Raman V, Khan IA. Comparative investigation of Umbellularia
californica and Laurus nobilis leaf essential oils and
identification of constituents active against Aedes aegypti, J.
Agric. Food Chem., 2013, 18, 61, 12283-12891.
Yildirim E, Emsen B, Kordali S. Insecticidal effects of [83]
monoterpenes on Sitophilus zeamais Motschulsky (Coleoptera:
Curculionidae), J. Appl. Bot. Food Qual., 2013, 86, 198-204.
Liu Z.L., Zhao N.N., Liu C.M., Zhou L., Identification of [84]
insecticidal constituents of the essential oil of Curcuma
wenyujin rhizomes active against Liposcelis bostrychophila
Badonnel, Molecules, 2012, 17(10), 12049-12060.
Liu X.C., Li Y.P., Li H.Q., Deng Z.W., Identification of repellent [85]
and insecticidal constituents of the essential oil of Artemisia
rupestris L. aerial parts against Liposcelis bostrychophila
Badonnel, Molecules, 2013, 18, 10733-10746.
Han J[86] ., Kim S.I., Choi B.R., Lee S.G., Ahn Y.J., Fumigant toxicity
of lemon eucalyptus oil constituents to acaricide-susceptible
and acaricide-resistant Tetranychus urticae, Pest. Manag. Sci.,
2011, 67(12), 1583-1588.
Cheng S.S[87] ., Lin C.Y., Chen Y.J., Chung M.J., Chang S.T.,
Insecticidal activities of Cunninghamia konishii Hayata against
Formosan subterranean termite, Coptotermes formosanus
(Isoptera: Rhinotermitidae), Pest. Manag. Sci., 2014, 70(8),
1215-1219.
Available via license: CC BY-NC-ND 4.0
Content may be subject to copyright.
