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Evaluating the effect of α-pinene on motor activity, avoidance memory and lipid peroxidation in animal model of Parkinson disease in adult male rats

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*Corresponding author: rafieirad.m@gmail.com, Tel/Fax: +9861-43643374
Research Journal of Pharmacognosy (RJP) 4(2), 2017: 53-63
Received: Nov 2016
Accepted: Feb 2017
Original article
Evaluating the effect of α-pinene on motor activity, avoidance memory and
lipid peroxidation in animal model of Parkinson disease in adult male rats
S. Goudarzi, M. Rafieirad*
Department of Biology, Faculty of Sciences, Izeh Branch, Islamic Azad University, Izeh, Iran.
Abstract
Background and objectives: Parkinson's disease (PD) is a common neuropathologic disorder that is
caused by degeneration of dopaminergic neurons of dense part of nigra. Oxidative stress has been
found in the pathophysiology of PD. Since α-pinene has strong anti-oxidant effects, the purpose of this
research was to study its effects on movement disorders and memory and lipid peroxidation in PD.
Methods: Thirty five male rats were divided in 5 groups: control, vehicle, PD (received injection of 6-
hydroxydopamine (6-OHDA)) and Parkinson's groups receiving doses of 100 and 200 mg/kg via
gavage for two weeks. Generating animal models for Parkinson was done by intracerebral injection of
6-OHDA in the left side of the brain in medial forebrain bundle (MFB). After the injection, the
movement balance of the rats was measured by Rotarod. Memory test was done by shuttle box; their
brain was extracted to analyze malondialdehyde (MDA) in striatum, hippocampus and blood. Results:
The results showed that Parkinson caused, movement disorder (p<0.01), avoidance memory reduction
(p<0.001) and malondialdehyde accumulation in hippocampus (p<0.05) and striatum (p<0.001)
tissues and in blood (p<0.001). Administration of 200 and 100 mg/kg α-pinene improved the
movement disorder (p<0.05). Administration of both doses of 200 and 100mg/kg showed
improvement in avoidance memory (p<0.001) and (p<0.01), respectively. Malondialdehyde showed
reduction in striatum (p<0.001) and hippocampus (p<0.05, p<0.001), respectively in the treatment
groups after administration of both doses. In the blood, the dose of 200 α -pinene significantly reduced
MDA in the tretment groups. Conclosion: The results of this research show that α-pinene could
reduce the symptoms of PD in rats.
Keywords: lipid peroxidation, memory, movement, Parkinson`s disease, α-pinene
Introduction
Parkinson disease (PD) was first described by
James Parkinson in 1817. This disease
demonstrates a progressive neurodegeneration,
which has already affected almost 1% of the
population over 50 years old [1]. Disturbances in
consciousness, memory, perception ability, and
visual-spatial function decline are observed in
these patients [2]. Parkinson is a degenerative
disease of the central nervous system in which
the substantia nigra cells in the midbrain
gradually vanish and dopamine production
gradually reduces [3]. The middle brain damage
can cause disruptions in the dopamine content of
striated objects, decrease in the density of
Goudarzi S. and Rafieirad M.
54 RJP 4(2), 2017: 53-63
dopamine receptors, decrease in neuronal
activity, and increase in the activity of brain free
radicals [4]. Degeneration of dopaminergic
neurons in the midbrain and the sharp decline of
dopamine at the back-middle of the dense part of
the substantia nigra [3,5]cause debilitating and
motor disorders such as bradykinesia, resting
tremor, rigidity, and postural instability [6].
Several hypotheses have been suggested about
the pathology and the death cause of pars
compacta dopaminergic neurons in substantia
nigra including oxidative stress, lipid
peroxidation, reducing glutathione level,
destruction of DNA, iron accumulation and
increasing free radical formation [7]. Oxidative
stress not only destroys dopaminergic neurons
but also leads to cell death by impairing the
oxidative phosphorylation process and reducing
energy production [8]. Endogenous sources of
oxidative stress include free radicals resulting
from the metabolism of dopamine and melanin.
Reactive radicals of oxygen are produced
constantly in the midbrain dopaminergic neurons
by dopamine metabolism and monoamine
oxidase B auto-oxidation enzyme [9]. The
pharmacologic treatment of PD can be further
divided into neuroprotective and symptomatic
therapy. In practice, nearly all of the available
treatments are symptomatic in nature and do not
appear to slow or reverse the natural course of the
disease. However, several potential
neuroprotective agents for PD have shown some
promise in animals and/or humans and are
undergoing further investigations. Antioxidants
with low molecular weight such as vitamins and
protein molecules such as superoxide dismutase,
glutathione peroxidase and glutathione can
protect the body from creating oxidative stress
induced by free radicals in the central nervous
system dopaminergic neurons [10]. Studies have
shown that plant phenols, such as flavonoids,
phenolic acids and flavonolignan acids can act as
effective antioxidants [11]. Dopamine has been
introduced as a potential substrate in synaptic
plasticity and memory mechanisms [12]. There is
pharmacological evidence for the role of
dopamine in learning and memory [13]. Both
dopamine receptors (D1, D2) are involved in
learning and memory processes [14]. It has been
reported that dopamine receptors enhance the
passive recognition [15] and improve cognitive
performance in rats while they do not affect
learning [16]. In recent years, a number of studies
have described cognitive dysfunction in
Parkinson's disease, which is significantly
associated with their disability status. Cognitive
dysfunction may include memory loss, difficulty
in concentrating, slowed information processing,
and cognitive problems in different tasks [17,18].
Memory disorder is one of the most common
cognitive dysfunctions in Parkinson's disease. α-
Pinene is an organic compound of
the terpene class, one of two isomers of pinene. It
is an alkene and contains a reactive four-
membered ring. It is found in the oils of many
species of coniferous trees. α-Pinene is naturally
found in plants such as Prangos ferulacea [19],
Hypericum richeri [20], Ferula gummosa.[21],
Teucrium stocksianum [22] Salvia officinalis
[23], Ferulago angulata [24], Origanum
majorana [25], and Salvia lachnocalyx [26]. α-
Pinene is an isomer used in multiple reactions
such as isomerization, oxidation, hydration,
acetylation, etc. It is also used in the preparation
of many terpenoids such as ocimene, terpinolene,
terpinene hydrate, and camphor [26]. α-Pinene is
the most important ingredient of turpentine that is
used as a flavoring. It is an important interface of
the aromatic compounds which is used as
flavoring in salts, household sprays, disinfectants,
and pesticides [27]. α-Pinene is the main
ingredient of essential oils from various plants
and has shown inhibitory effect of
acetylcholinesterase activity [28]. It also has
shown anti-depressant [29], anticonvulsants [30],
antioxidant [31], antispasmodic [19],
antibacterial [32], anti-inflammatory [33], anti-
tumor properties [34]. In the present study, due to
the antioxidant effects of α-pinene, the effect of
its chronic administration on behavioral disorders
and malondialdehyde (MDA) caused by the toxin
6-hydroxydopamine (6-OHDA) has been
investigated for the first time.
Experimental
Animals
Thirty five adult male rats were used with the
weight range of 200-250g, which were randomly
Effect of α-pinene on Parkinson disease in rats
55
divided into five groups of seven rats. All rats
were maintained under the same conditions,
including 21±2 °C, 12 h of light and 12 h of
darkness. All tests were done based on the ethical
protocols and standards of laboratory animal
protection (No. 1394.2002).
Experimental Group
The control group: no surgery was performed
(intact); vehicle group: stereotoxic injection
surgery was performed on this group without
neurotoxin 6-hydroxy-dopamine and they
recieved 3% Tween 80 [35] for 14 days by
gavage; Parkinson Group (PD): this group
received 2 µL containing 8 micrograms of
neurotoxin 6-hydroxy dopamine at MFB area by
stereotoxic surgery; Parkinson group received a
daily dose of 100 µg/Kg of α-pinene for 14 days
by gavage (α-pinene 100 mg/kg + PD) [35];
Parkinson group received a daily dose of 200
µg/Kg of α-pinene for 14 days by gavage
administration. (α-pinene 200 mg/kg + PD) [35].
Stereotoxic injection surgery procedure
Initially, the rats were weighed and then
anesthetized by intraperitoneal injection of 90
mg/kg ketamine hydrochloride (Alusan Co.,
Netherlands) and 10 mg\kg xylazine (Alusan Co.,
Netherlands). The rats were placed in stereo tax
device and fixed by the mouthpiece and bars on
the device. The skull dorsal hair was shaved and
the animal’s scalp was disinfected by alcohol and
a longitudinal cutting was created through the
back of the head between the eyes to the dorsal
surface between the ears. The crossbred tissues
were removed from the external of the cranium in
a way that bregma part was visible. Lambda and
bregma points were placed equal on a level and
the device index was set on. Then, (MFB)
peculiarities were determined according to the
extracted coordinates from the Atlas of brain
surgery AP;-3/8 DV;-8/2, ML±1/6. In this study,
the unilateral injection of 6-hydroxy-dopamine
was used anterior-middle category (MFB) to
create Parkinson's disease [3].
6-Hydroxy-dopamine solution preparation
6-Hydroxy-dopamine (Sigma, USA) was
prepared at a concentration of 8 µg per 2 µl of
normal saline dissolved in 0.01% ascorbic acid.
α-Pinene: α-pinene (Betagen, Iran) was
administered by gavage method after dissolving
in 3% tween 80.
Behavioral tests
Apomorphine-induced rotational behavior
Contralateral rotations of each animal were
recorded after subcutaneous injection of
apomorphine (0.5 mg/kg in normal saline
containing 0.01% ascorbic acid) to confirm the
dopamine depletion. Full spin were measured in a
cylindrical proper place for 60 min in 10-min
intervals [36].
Rotarod (motor coordination test)
This test aims to measure the motor balance and
harmony in movement (motor efficiency and
coordination). It measures the time (latency) it
takes for the mouse to fall off the rod rotating at
different speeds or under continuous acceleration.
Briefly, the animals were placed on a rotarod
device bar whose speed varied. The primery
speed of the bar was 5 rpm. Then, the speed of
rotation bars gradually increased within 300
seconds. The main standard for balance in all
groups was 25 rpm. Rats became familiar with
this device. Then, each animal was assessed 3
times and 45 minutes intervals between the
sessions and the average time was calculated
[37].
Passive avoidance memory test
This test was conducted using a shuttle box
(5500-ST, Borj Sanaat Co., Iran), which
contained two compartments, one was dark and
the other light. Their bottom was covered by
stainless steel wires with a diameter of 1 to 2 mm
and at a distance of one centimeter. A slight
shock was applied to animals’ paw by an electric
current generator (75 volt, 0.3 mA for 3 seconds)
in the dark compartment only once. Initially, the
animals were placed in the shuttle box with
guillotine doors for 10 min in order to become
familiar with the device (training) to move freely
between the inside and outside of their enclosure.
Goudarzi S. and Rafieirad M.
56 RJP 4(2), 2017: 53-63
Then, the animals were placed in the light box
and their delay time to go to the dark box was
recorded (learning). The guillotine door was
closed as soon as the animal entered the dark
compartment and the electric shock was applied
to their feet. After 24 h, their delay time for
entering the dark compartment was measured in
seconds (no electric shock) as the passive
avoidance memory. This operation was
conducted for all rats in all groups [38].
Malondialdehyde (MDA) measurement
For (MDA) measurement striatum and
hippocampus tissues of the brain were removed
and blood samples were also taken from the tail.
The MDA level of tissues was measured by
spectrophotometric method, using the thio-
barbituric acid (TBA) reagent, based on the
response of a chromogenic reagent, (TBA) with
MDA at 100 °C. Molecules of MDA would react
with TBA to yield a complex dye. MDA
concentration was measured at 532 nm [39].
Standard curve
Three mL of the 1% phosphoric acid solution
was added to 0.5 mL of the standard solution
with concentrations of 8, 10, 6, 4, 2, 1, 5.0 mM
and the rest of the steps were performed as
beofore and the absorption was recorded at 532
nm [39].
Statistical analysis
Data have been reported as mean ± SEM. The
results were analyzed using SPSS software.
ANOVA analysis was used to check the results in
different groups and discrepancy between groups
were considered significant if p<0.05.
Results and Discussion
All animals tolerated the stereotaxic surgical
procedures and no deaths were observed during
the study.
The results showed that rotation test of the
Parkinson's groups significantly increased in
contrast to the control group after the creation of
MFB lesion due to infusion of 6-OHDA in the
rats (p<0.001). In the Parkinson's groups which
were treated with α-pinene 100, 200 mg/kg for 14
days, it was found that the treatment groups had
less rotation [100, 200 mg/kg (p<0.001)].
Motor coordination in Parkinson group showed a
significant decrease compared to the control
group (p<0.01) and treatment with doses of 100
and 200 mg/kg of α-pinene could increase the
motor coordination significantly compared with
the Parkinson group (p <0.05) (figure 1).
The passive avoidance memory significantly
decreased in the group with Parkinson compared
to the control group (p<0.001) )figure 2(
furthermore, no perceptible difference was
observed between the control group and the
vehicle group. In addition, in all Parkinson's
groups doses of 100 and 200 of α-pinene
increased memory compared to the Parkinson
group (p<0.01) and (p<0.001), respectively.
Lipid peroxidation levels of experimental groups
have been shown in figures 4 and 5 and 6. MDA
level of hippocampal tissue homogenates
increased significantly compared to the control
group (p<0.05). In addition, no significant
difference was observed between the control and
the vehicle group. The results of fourteen-day
prescribing α-pinene with two doses of 100 and
200 mg/kg redused MDA in the hippocampus
tissue compared to Parkinson group (p<0.05) and
(p <0.001), respectively. On the other hand,
MDA levels increased in Parkinson's group
compared to the control group in the striatum
tissue (p<0.001). Similarly, there was no
significant difference between the control group
and vehicle group. By comparing MDA
measurement among Parkinson group that
recieved α-pinene 100, 200mg/kg for 14 days, it
was found that MDA had a significant reduction
in the group receiving α-pinene in comparison
with Parkinson group (p<0.001). For MDA
measurement in the blood, only the dose of 200
mg/kgof α-pinene significantly decreased lipid
peroxidation (p<0.001)
In the present study, the minimum amount of 6-
OHDA was used to induce Parkinson's disease.
The advantage of this model is that it is very
similar to the early stages of Parkinson's disease
in humans as well as minimizing or eliminating
Effect of α-pinene on Parkinson disease in rats
57
Figure 1. Effect of 14-day gastric gavage of of 100 and 200 mg/kg α-pinene on circling behavior in Parkinson's disease (PD).
(mean ± SEM; One-way ANOVA and Tukey's test (n=7) ); * shows significance between the control group and PD . # shows
significant difference between PD and treated groups.
Figure 2. Effect of 14-day gastric gavage of of 100 and 200 mg/kg of α-pinene a on rotarod in Parkinson's disease (PD). (mean ±
SEM; One-way ANOVA and Tukey's test (n=7) ). * shows significance between the control group and PD. # shows significant
difference between PD and treated groups.
Figure 3. Effect of 14-day gastric gavage of of 100 and 200 mg/kg of α-pinene on memory in Parkinson's disease (PD). (mean ±
SEM; One-way ANOVA and Tukey's test (n=7) ). * shows significant between the control group and PD . # shows significant
difference between PD and treated groups.
Goudarzi S. and Rafieirad M.
58 RJP 4(2), 2017: 53-63
Figure 4. Effect of α-pinene on MDA levels in hippocampus tissue between control group, PD and PD groups orally receiving
100 and 200 mg/kg of α-pinene for 14 days. (mean ± SEM; One-way ANOVA and Tukey's test (n=7) ). * shows significant
between the control group and PD . # shows significant difference between PD and treated groups.
Figure 5. Effect of α-pinene on MDA levels in striatum tissue between control group, PD and PD groups orally receiving 100
and 200 mg/kg of α-pinene for 14 days. (mean ± SEM One-way ANOVA and Tukey's test (n=7) ). * shows significant
difference between the control group and PD . # shows significant difference between PD and treated groups).
Figure 6. Effect of α-pinene on MDA levels in blood between control group, PD and PD groups orally receiving 100 and 200
mg/kg of α-pinene for 14 days. (mean ± SEM; One-way ANOVA and Tukey's test (n=7) ). * shows significant difference
between the control group and PD . # shows significant difference between PD and treated groups
Effect of α-pinene on Parkinson disease in rats
59
non-specific effects of neurotoxin on other
systems. The antioxidative treatment in the early
stages of Parkinson's disease has been examined
in the clinic. One treatment is to use antioxidants
to reduce the oxidative stress and protect
dopaminergic neurons. Biological antioxidants
play a vital role in protecting cells against
oxidative stress caused by free radicalsThe
results of the present study showed that the
chronic consumption of α-pinene improved
movement disorders in rats with Parkinson's
disease. The results of rotation testing in
Parkinson's group compared with the control
group demonstrated stricture and devastation of
dopaminergic neurons, while rotation in the
groups receiving α-pinene were much lower than
that in the lesion group, which can display
prevention from the demolition of dopaminergic
cells and reduction of motor coordination
following this destruction with the gavage of α-
pinene. Learning and passive memory avoidance
tests were performed under the same conditions
in the shuttle box for all groups. Increasing the
delay time for the first entry to the dark room and
the total time for spending in the light room and
decreasing the total time for spending in the dark
room indicated the improvement of passive
avoidance memory by α-pinene. In addition, our
results showed that the level of malondialdehyde
(MDA) in the hippocampus and striatum of
Parkinson group receiving α-pinene significantly
reduced and it possibly prevented the progression
of the disease. Some previous researches have
also investigated the effects of plant extracts on
animal models of PD. For example, oral
prescribtion of ginseng extract has led to stopping
cell damage of the substantia nigra and
decreasing the dysfunction in Parkinson rats [40].
In another study which was carried out on
Ginkgo biloba, it was found that the leaf extract
of this plant reduced the behavioral disorders
resulting from injuries caused by 6-
hydroxydopamine [41]. Studies have shown that
the unilateral damage of nigrostriatum
dopaminergic system by injecting striatal 6-
hydroxydopamine decreases the level of
dopamine and up-regulation of postsynaptic
dopaminergic receptors located on the affected
side of striatal neurons [42]. Salar et al. have
reported that the aqueous extract of barberry
could reduce the behavioral symptoms of
Parkinson by inhibiting the acetylcholinesterase
enzyme in the brain. In previous studies, barberry
extract had an antioxidant property and prevented
the production of lipid peroxidation and MAO-A
activity. As a result, the amount of dopamine and
monoamines increased in brain. MAO inhibitors
increase the amount of dopamine and
norepinephrine in the nerve synapse and they
have antidepressant effects [43]. It has been
reported that oral administration of rosemary leaf
extract induced neuroprotective effects on the
hippocampus and prevented memory impairment
caused by neurotoxin 6-hydroxydopamine.
Therefore, it might be considered to be used in
improving memory disorders in Parkinson
patients [4]. There are several reports showing
that oxidative stress is involved in the
pathogenesis of Parkinson disease by producing
free radicals and weakening the brain antioxidant
system [10,44]. Oxidative stresses cause
apoptosis and loss of dopamine cells [44,45].
Findings show that the use of plant extracts with
antioxidant substances can improve the cognitive
and motor symptoms of Parkinson disease [46].
α-Pinene is a single ring monoterpenoid [47].
Some terpenoids act as serotonin reuptake
inhibitors and increase the norepinephrine and
dopamine activity (like monoamine oxidase
inhibitors) [48-50]. It was also reported that
taking α-pinene at a dose of 100 mg/kg prevents
damage to gastric mucosa walls and protects the
gastric mucosa against acidification,
accumulation of bacteria, and mechanical forces
resulting from proteolytic digestion [51]. Various
pharmacological effects have been reported for α-
pinene, including anti-microbial, anti-
inflammatory, analgesic, antioxidant, memory-
enhancing, anti-anxiety and neuronal protection
properties [52]. Previous studies have shown that
α-pinene and many monotrepenoids have anti
acetyl-cholinesterase activity [53,54]. In addition,
such plants contain monoterpenes that are useful
for the treatment of memory disorders, including
Alzheimer's disease [55]. Findings have shown
that some plants possess terpenoids such as
Goudarzi S. and Rafieirad M.
60 RJP 4(2), 2017: 53-63
carvacrol and pinene and it has also been
reported that carvacrol, α-pinene, β-pinene, and
β-caryophyllene are able to increase GABA
evoked current responses. [56]. It seems that the
antioxidant properties of α-pinene plays an
important role in its protective effects which
suggest it to be used as an adjuvant treatment in
patients with Parkinson's disease. Antioxidant
effect of α-pinene was confirmed in the present
study by measuring oxidative stress parameters
such as malondialdehyde (lipid peroxidation) in
brain tissues and blood. α-Pinene enhances the
memory probably due to its anti-
acetylcholinesterase activity. On the other hand,
monoterpenes increase dopamine by interfering
with monoamine systems and MAO inhibition.
Terpenoids might adjust GABAergic system
modulation, which cause extra movements in the
weakened Parkinson patients. In order to treat
Parkinson, dopamine must be increased and
acetylcholine must be decreased. The dual
function of α-pinene might improve Parkinson's
symptoms and impaired memory.
Based on the results of this study, consumption of
α-pinene might protect dopaminergic neurons
against 6-OHDA-induced lesions, and possibly
could have a protective effect against Parkinson's
disease.
Acknowledgements
The authors would like to thank the Research
Deputy of Islamic Azad University, Izeh Branch
for its support to carry out this study. This article
was extracted from Mrs. Samira Goudarzi MSc
thesis. The research protocol was adopted by
Islamic Azad University, Izeh Branch based on
research ethics charter laws. This project was
financially supported by the student herself.
Declaration of interest
The authors declare that there is no conflict of
interest. The authors alone are responsible for the
content of the paper.
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... It has been reported that chronic oral administration of α-pinene suppresses 6-hydroxydopamine-induced passive avoidance learning and memory impairment in rats. [17] In addition, central administration of α-pinene attenuates capsaicin-evoked dental pulp nociception and inflammation. [18] α-pinene also has an interface with neurotransmitter systems in the brain. ...
... [14,15,24] Inconsistent with the current study results, Goudarzi and Rafieirad, using the 6-hydroxydopamine model of Parkinson's disease, showed that chronic daily administration of oral α-pinene for 2 weeks increases passive avoidance performance in rats. [17] In addition, it has been reported that systemic administration of α-pinene significantly improves scopolamine-induced cognitive dysfunction in mice. The effect was associated with enhanced levels of hippocampal antioxidant enzymes and choline acetyltransferase mRNA expression in the cortex of mice. ...
... α-pinene can also improve memory performance in Parkinsonian rats by decreasing hippocampal and striatal levels of malondialdehyde as an oxidative stress marker. [17] Moreover, α-pinene at low concentrations can increase total antioxidant capacity in cultured primary neurons. [28] Similarly, intraperitoneal administration of α-pinene increased mRNA expression of choline acetyltransferase in the cortex and protein levels of antioxidant enzymes. ...
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Background: This study investigated the effect of central administration of α-pinene and the interaction of α-pinene with GABAA receptor on pulpal nociception-induced changes in learning and memory performances in rats. Materials and methods: Sixty-six adult male Wistar rats were used. Pulpal nociception was induced by intradental application of capsaicin (100 μg/rat). α-pinene (0.1, 0.2, and 0.4 μg/rat) was injected centrally 10 min before the administration of capsaicin. In addition, α-pinene (0.4 μg/rat) was co-injected with bicuculline (0.5 μg/rat). Spatial and passive avoidance learning and memory were assessed using Morris water maze (MWM) and shuttle box tasks, respectively. Results: Experimental results of the MWM test showed that capsaicin increases escape latency and distance traveled to the hidden platform (P < 0.01). The effect was prohibited by α-pinene at the dose of 0.4 μg/rat. Moreover, capsaicin-treated animals spent less time in the target zone than capsaicin + α-pinene (0.4 μg/rat)-treated rats (P < 0.05). In the shuttle box test, α-pinene (0.2 μg and 0.4 μg) prevented an increased number of acquisition trials and time spent in the dark chamber induced by capsaicin, whereas it increased step-through latency (P < 0.01). However, the effects of α-pinene (0.4 μg/rat) in both tests were prohibited by bicuculline (0.5 μg/rat). Conclusion: The data showed that central administration of α-pinene might reduce pulpalgia-induced learning and memory impairment, at least partially, via modulation of GABAA receptors.
... Firstly, it exhibited antimicrobial properties and increased the effectiveness of commercial antibiotics against methicillin resistant Staphylococcus aureus [7]. α-pinene also reversibly inhibited acetylcholinesterase, and therefore has potential to treat neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease [1,9]. Additionally, α-Pinene reduced the impact of scopolamine-induced cognitive impairment in mice and 6-hydroxydopamine-induced Parkinson's disease in rats [9,10]. ...
... α-pinene also reversibly inhibited acetylcholinesterase, and therefore has potential to treat neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease [1,9]. Additionally, α-Pinene reduced the impact of scopolamine-induced cognitive impairment in mice and 6-hydroxydopamine-induced Parkinson's disease in rats [9,10]. Pinene itself is used as flavoring agent and in cosmetics, but is also used to derive the additional aromatic compounds, verbenone and carvone, which are used in perfumery and as insect repellents [8,11,12]. ...
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Pinene is a secondary plant metabolite that has functional properties as a flavor additive as well as potential cognitive health benefits. Although pinene is present in low concentrations in several plants, it is possible to engineer microorganisms to produce pinene. However, feedstock cost is currently limiting the industrial scale-up of microbial pinene production. One potential solution is to leverage waste streams such as whey permeate as an alternative to expensive feedstocks. Whey permeate is a sterile-filtered dairy effluent that contains 4.5% weight/weight lactose, and it must be processed or disposed of due its high biochemical oxygen demand, often at significant cost to the producer. Approximately 180 million m 3 of whey is produced annually in the U.S., and only half of this quantity receives additional processing for the recovery of lactose. Given that organisms such as recombinant Escherichia coli grow on untreated whey permeate, there is an opportunity for dairy producers to microbially produce pinene and reduce the biological oxygen demand of whey permeate via microbial lactose consumption. The process would convert a waste stream into a valuable coproduct. This review examines the current approaches for microbial pinene production, and the suitability of whey permeate as a medium for microbial pinene production.
... Upon entrance of the animal into the dark chamber, the guillotine door was closed, and electrical shock was applied to its sole. After 24 h (one day), the latency time of the animal's entrance into the dark chamber (which had had a shock but this time did not have any shock) was measured in terms of second as passive avoidance memory (step-through latency) [22]. ...
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Background: Ischemia causes severe neuronal damage and induces oxidative stress, memory impairment, and reduces pain threshold. Herniarin is a powerful antioxidant. Objectives: This study aimed to evaluate the effect of herniarin on memory, pain, and oxidative stress in an ischemia model in male rats. Materials & Methods: In this study, 50 male rats were divided into 5 groups of control, sham, ischemic, and two other ischemic groups, which received herniarin at doses of 150 and 300 mg/kg by gavage for 14 days. Behavioral tests were performed by shuttle box, and Y-maze and pain tests were performed by Tail-Flick test. Then, the rats’ brains were extracted to evaluate lipid peroxidation and measure the levels of thiol and Glutathione Peroxidase (GPX) in the hippocampus and striatum tissues. The results were expressed as Mean±SEM and then analyzed using suitable statistical methods of ANOVA and least significant difference post-hoc test in SPSS V. 20. Results: Herniarin significantly increased the avoidance memory, spatial memory, and pain thresholds of ischemic rats at different concentrations (P
... Neuroprotective potential through the modulation of ER stress pathway by β-asarone was further supported by the reduced mRNA levels of C/EBP homologous binding protein and glucose regulated binding protein and the decreased levels of phosphorylated 1/X-Box Binding protein 1 involved in ER stress pathway (Ning et al. 2016). In a similar study, thymol, a monoterpene found in many edible plants like Thymus spp., has shown potent neuroprotective activity by significantly reducing oxidative stress, inflammation, and the loss of dopaminergic neurons in rotenone-induced Wistar rat model of PD (Javed et al. 2019), whereas α-pinene, a major component from EO of many coniferous tree and other plant species, significantly reduced the PD symptoms by drastically improving the avoidance memory, movement disorder, and reducing the malondialdehyde levels in the hippocampus and striatum of 6-hydroxydopamine-induced rat model of PD (Goudarzi and Rafieirad 2017). ...
Chapter
Essential oils (EO), produced from isoprenoid pathways are a blend of hydrocarbons and its oxygenated derivatives, which possess many biological properties. EO are conventionally used in medications, and also for sanitary, cosmetic, fragrance, essence, preservatives, and food additives. In pharmaceutical applications, they are used as antimicrobial (viricidal, fungicidal, bactericidal), antiseptic, anti-parasitical, insecticidal, pesticidal, and herbicidal agents. Owing to the complexity and stability (singly or combinations) exhibited by EO, they have crossed the conventional boundaries, and are now explored for their efficacy against neurological disorders. EO are reported to exhibit antioxidant, anti-inflammatory, neuroprotective, anxiolytic, anticonvulsant or antiepileptic, memory enhancing, anticholinesterase, cognitive and mood effects, antidepressant, neuropathic, antinociceptive, anti-psychosis, anti-Parkinson’s, antimigraine, anti-meningitis, anti-dementia, and anti-Alzheimer’s properties. This has favored the use of EO in the prevention and cure of neurological disorders. Moreover, the mode of action of EO for these arrays of biological properties is identified, and several unknowns are being investigated. With the advent of modern technologies and methodologies, EO from many aromatic and medicinal plants are now isolated, characterized, and explored against many neurological disorders, and some have succeeded to reach the phases of clinical trials. Furthermore, EO pose negligible side effects, and are permeable to blood–brain barrier. Efforts are in progress to further increase their stability, release, and potency against neurological disorders. Thus, in this chapter, an updated summary of EO explored against some common neurological disorders along with their possible mode of action has been presented.
... In addition, in mice with 6-OHDA-induced PD, administration of α-pinene im-proved the movement disorder and avoidance memory. It led to a reduction in the MDA level in the striatum and hippocampus [73]. This substance has been shown to exert anxiolytic effects as well. ...
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Neuroprotective agents are able to defend the central nervous system against acute or chronic neuronal injuries. Even with the progress made over the last decades, most of the medications prescribed for the management of neurodegenerative diseases can only reduce their symptoms and slow down their progression. Based on natural product research, there are potential effective medicinal plants and phytochemicals for modulating neuronal functions and protecting against neurodegeneration. Plants in the genus Pistacia are also among valuable natural resources for neuroprotection research based on experiences in traditional medicine. Studies have supported the value of bioactive compounds of the genus Pistacia for central nervous system disorders such as Alzheimerʼs, Parkinsonʼs, multiple sclerosis, cerebral ischemia, depression, and anxiety. Related literature has also revealed that most of the evidence on neuroprotection in the genus Pistacia is in the form of preliminary studies, mainly including models of behavior, motor function, and memory impairments in animals, neural toxicity, cerebral ischemia and seizure models, evaluation of their effects on antioxidant and inflammatory biomarkers, amyloid β aggregation, and acetylcholinesterase as well as investigations into some cellular pathways. Along with the phytonutrients in kernels such as pistachios, various phytochemicals, mostly terpenes, and phenolic compounds have also been identified in different plant parts, in particular their oleoresins, of species in the genus Pistacia. In this review, the pharmacology of neurological effects and related molecular mechanisms of the plants belonging to the genus Pistacia and its active constituents, as well as pharmacokinetics aspects, are discussed.
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α-pinene is a well-known compound representative of the monoterpenes group with a wide range of pharmacological activities. This article aims to determine effects of the prenatal exposure to α-pinene on reflexive motor behaviors in mice offspring. Forty pregnant female NMRI mice (8–10 weeks old) were allocated into 4 groups. Group 1 served as control and groups 2-4 were intraperitoneally (i.p) injected α-pinene (0.1, 0.5 and 1 mg/kg) on 5, 8, 11, 14 and 17 days of gestation (GD). The control group injected with saline at the same days. Following delivery, 20 pups from each litter were selected and reflexive motor behaviors determined using ambulation, hindlimb foot angle, surface righting, hindlimb strength, grip strength, front-limb suspension and negative geotaxis tests. Based on the findings of the present study, maternal exposure to α-pinene increased ambulation score, hind-limb suspension score, grip strength, front-limb suspension compared to the control group (P<0.05). Also, prenatal exposure to α-pinene decreased surface righting, hind-limb foot angle and negative geotaxis in mice offspring compared to the control group (P<0.05). α-pinene (0.1, 0.5 and 1 mg/kg) decreased blood MDA and increased SOD and GPx levels in mice offspring (P<0.05). These results suggested α-pinene exposure during pregnancy has positive effect on reflexive motor behaviors in mice offspring possibly due to its antioxidant properties.
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Among today's health problems, metabolic diseases are at the forefront. Hypothyroidism (HT) is a disease characterized by increased TSH, decreased T3&T4 concentrations in serum, with overall metabolic slowdown. Although there are many studies in the literature about oxidative status in HT, statements in these studies are contradictory. In our study, the effect of essential oils obtained from the leaves, flowers, and roots of Myrtus communis L. on oxidative metabolism in an HT model induced by propylthiouracil (PTU) in rats was investigated. A total of 36 Wistar albino rats were randomly divided into six groups as follows: (1) Control, (2) PTU, (3) M. communis L. oil 200 (MO 200), (4) M. communis L. oil 400 (MO 400), (5) PTU + MO 200, and (6) PTU + MO 400. In our study, while oxidative status deteriorates in groups given PTU, antioxidant activity increases in groups given M. communis L. oil. Practical applications Essential oils are aromatic oily liquids derived from different parts of plants. M. communis L. is one of the best‐known herbs in the class of aromatic and medicinal plants. This paper emphasizes the effect of M. communis L. oil on the negative oxidative state that occurs in HT conditions. The present study provides a positive effect of essential oils obtained from the M. communis L. on the oxidative state seen in HT. In light of this information, it may be beneficial to use M. communis L. oil due to its antioxidative effect in HT conditions.
Background Ischemic stroke is a severe neurological disorder that affected millions of people worldwide. Neuro-inflammation and apoptosis play an essential role in the pathogenesis of neuronal death during ischemic stroke. Alpha-pinene is a bicyclic terpenoid with anti-inflammatory and anti-apoptotic activities. Accordingly, the main purpose of this study was to assess the protective effect of α-pinene in ischemic stroke. Materials and Methods To induce ischemic stroke in male Wistar rats, the middle cerebral artery was occluded for 60 min followed by 24 h reperfusion. Alpha-pinene was injected intraperitoneally at the beginning of reperfusion. A day after reperfusion, the neurological deficits, volume of infarct area, and blood-brain barrier (BBB) permeability were evaluated. The mRNA expression of inflammatory cytokines as well as pro- and anti-apoptotic genes was assessed by using reverse transcription-polymerase chain reaction. The protein levels of inflammatory cytokines were also measured by ELISA method. Results The results showed that α-pinene (50 and 100 mg/kg) significantly improved sensorimotor function and decreased the volume of infarct area in the brain. The high permeability of BBB was also alleviated by α-pinene (50 and 100 mg/kg) in ischemic areas. Besides, α-pinene (100 mg/kg) attenuated neuro-inflammation through decreasing both the gene and protein expression of TNF-α and IL-1β in the hippocampus, cortex, and striatum. Besides, α-pinene (100 mg/kg) suppressed apoptosis via downregulation of the pro-apoptotic Bax mRNA expression with a concomitant upregulation of anti-apoptotic Bcl-2 gene expression. Conclusions Overall, it was concluded that α-pinene exerts neuroprotective effect during ischemic stroke through attenuating neuroinflammation and inhibition of apoptosis.
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Chemical composition of Rosmarinus officinalis L. and Ocimum basilicum L. ssp. basilicum essential oils as well as their phytotoxic effects against seed germination and seedling growth of Portulaca oleracea, Lolium multiflorum and Echinochloa crus-galli has been investigated. Seventy-eight compounds accounting between 98.10-99.15% of the total commercial oils were identified by GC/MS analysis. The oxygenated monoterpenes 1,8-cineole (24.95±0.11%) and camphor (20.45±0.05%) were the main compounds of rosemary essential oil, whereas large amounts of the aromatic compound methyl chavicol (79.09±0.29%) was found in basil essential oil. Rosemary essential oil significantly inhibited the seed germination of L. multiflorum and E. crus-galli and the seedling growth of the three weed, whereas basil essential oil only showed significant effects in hypocotyl and/or radicle length depending of the weed and dose.
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Background: Parkinson's disease is a neurodegenerative disease of dopaminergic neurons in substancia nigra. Superoxides formation is one of the main etiologies of the disease, and angiotensin converting enzyme inhibitors (ACEIs) are able to suppress superoxide formation. Objective: Berberis vulgaris is an ACE inhibitor and considered for this purpose. Methods: Male rats (n=32) were divided in 4 groups: Sham, Neurotoxin (injection of 6-hydroxydopamine into left hemisphere SNC), Berberis vulgaris aqueous extract (10 mg/kg) and Captopril. Berberis and Captopril were injected i.p. 7 days before and 3 days after 6-hydroxydopamine injection. Muscle rigidity, apomorphine test, brain protein oxidation and lipid peroxidation as well as serum and brain ACE activity were assayed in all 4 groups. Results: Rotation test with apomorphine in Captopril and Berberis groups were significantly lower than neurotoxin group (p=0.002). Lipid peroxidation in Captopril was significantly lower than neurotoxin (p=0.013). Captopril and Berberis both inhibited serum ACE activity respectively, but Berberis inhibited brain ACE too. Conclusion: Berberis vulgaris aqueous extract is an ACE inhibitor with anti-parkinsonism effect and should be studied more.
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Background: Parkinson's disease is one of the prevalent degenerative diseases of the neural system. Oxidative stress, which has been recognized as the most important factor of Parkinson's disease, plays a main role in the death of neurons in this disease. Antioxidants have a proved role in the prevention of oxidative stress. Objective: Considering the presence of evidence regarding antioxidant property of Ferulago angulata, effect of oral administration of hydroalcoholic extract of this plant was investigated on parameters of the oxidative damage caused by Parkinson's disease in adult rats. Methods: In this research, 40 Wistar rats with the average weight of 200 to 250 g were randomly assigned to 5 groups, each with 8 rats. Also, to develop Parkinson's disease animal model, 2 μl of 6-hydroxydopamine drug was injected into medial forebrain bundle on the left side of the animals and the treatment groups received Ferulago angulata extract with doses of 400, 200, and 100 mg/kg for 2 weeks as gavage. Then, the brain of the animals was isolated and parameters of Malondialdehyde and Thiol were measured. Results: Results showed that Parkinson's disease induced significantly increased brain peroxidation lipid, which is one of the factors of oxidative stress, and reduced Thiol level (p<0.001). Further, treatment of Parkinson's disease with Ferulago angulata extract significantly decreased peroxidation lipid in striatum and hippocampus and increased Thiol level (p<0.001). Conclusion: oral administration of hydroalcoholic extract of Ferulago angulata probably reduces oxidative damage and also reduces Malondialdehyde and increases Thiol in the treated groups due to its strong antioxidant property.
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Introduction: Neuroinflammation may play as an important risk factor in progressive degeneration of dopaminergic cells. Antioxidants have protective effects against free radicals induced neural damage in Parkinson’s disease (PD). In the present study, we examined the effects of ellagic acid (EA) on locomotion and neuroinflammatory biomarkers in a rat model of PD induced by 6-hydroxidopamine (6-OHDA). Methods: 6-OHDA (16 μg/2 μl) was injected into the right medial forebrain bundle (MFB) in MFB-lesioned rat’s brain. Sham group received vehicle instead of 6-OHDA. PD-model was confirmed by rotational test using apomorphine injection. EA (50 mg/kg/2 ml, by gavages) was administered in PD+EA group. One group of MFB-lesioned rats received pramipexole (PPX; 2 mg/kg/2 ml, by gavages) as positive control group (PD+PPX group). Motor activity was assessed by stride length and cylinder tests. The levels of TNF-α and IL-1β were measured in both striatum and hippocampus tissues. Results: MFB lesion caused significant reduction of stride-length (P<0.001) and also increased the contralateral rotations (P<0.001) and score of the cylinder test (P<0.001). Use of 6-OHDA to induce the PD significantly increased the levels of TNF-α (P<0.001) and IL-1β (P<0.001) in MFB-lesioned rats. EA significantly restored all of the above parameters. Discussion: EA can improve the motor impairments in the MFB-lesioned rats via reducing the neuroinflammatory biomarkers and protect the brain against free radicals-induced neural damage. The results suggest that EA can be helpful in management of PD treatment.
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Pine needle oil from crude extract of pine needles has been used as an anti-cancer agent in Traditional Chinese Medicine. The α-pinene is a natural compound isolated from pine needle oil which has been shown anti-cancer activity. In previous study, we found that pine needle oil exhibited significant inhibitory effect on hepatoma carcinoma BEL-7402 cells. In this study, we investigate the inhibition of α-pinene on hepatoma carcinoma BEL-7402 cells in vitro and in vivo and further explore the mechanism. The results show that liver cancer cell growth was inhibited obviously with inhibitory rate of 79.3% in vitro and 69.1% in vivo, Chk1 and Chk2 levels were upregulated, CyclinB, CDC25 and CDK1 levels were downregulated. Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.
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Cerebral ischemia causes some disorders in behavioral patterns, including memory disorders and pain, which is due to the production of free radicals. Ferulago angulata, known in Iran as chavir, contains some bioactive compounds having antioxidant and free radical-scavenging properties. This study aimed to evaluate the effect of two weeks oral administration of hydroalcoholic extract of F. angulate (100, 200 and 400 mg/kg) on pain as well as active and passive avoidance memories after permanent, bilateral common carotid artery occlusion or cerebral ischemia/hypoperfusion in male adult rats. In this study, 35 male rats were randomly allocated to test and control groups. To make animal model of permanent cerebral hypoperfusion/ischemia, carotid arteries were ligatured as upper and lower and cut bilaterally. It was found that the administration of 400 mg/kg hydroalcoholic extract of F. angulate for two weeks after brain hypoperfusion ischemia increased the passive avoidance memory (P < 0.001) and latency time of painful tail reflex significantly (P < 0.05). Ferulago angulata extract, because of its antioxidant activities, is probably capable of removing free radicals and oxidant substances from brain and thus it can improve behavioral disorders in brain hypoperfusion ischemia model.
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Tarchonanthus camphoratus (camphor bush) has been widely used for numerous medicinal purposes. The aim of the present study was to evaluate the antioxidant properties, cytotoxicity and monoamine oxidase inhibition activities of the crude dichloromethane leaf extract of T. camphoratus. The antioxidant activities were assessed using the thiobarbituric acid-reactive substances (TBARS) assay and the nitroblue tetrazolium (NBT) assay. The cytotoxicity assays were performed according to the microculture MTT method. From the MTT assay, it was determined that at a concentration of 10 mg/ml of crude extract, 95% of the neuroblastoma cells were killed. Almost 99% of the cells were viable at a concentration of 0.08 mg/ml extract. The extract also showed the ability to inhibit monoamine oxidase (MAO-A and MAO-B) with the corresponding inhibitory concentration, IC 50 values of 1.371 and 0.2737 mg/ml, respectively. The antioxidant activity and cytotoxic effect of the extracts increased with increase in concentration. This study suggests that the dichloromethane leave extract of T. camphoratus can potentially be used as a readily accessible source of natural antioxidants.
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The aerial parts of Hypericum richeri Vill. subsp. grisebachii (Boiss.) Nyman were collected from two different locations in Croatia and subjected to hydrodistillation. GC/FID and GC/MS analysis of the isolated essential oils revealed 64 compounds representing 94.7% and 98.2% of the total oils. Predominant constituents in both samples were: germacrene D (10.90%; 6.0%), bicyclogermacrene (4.7%; 3.5%), alpha-pinene (6.8%; 6.9%), beta-pinene (8.1%; 5.1%), decanoic acid (4.5%; 6.8%), beta-caryophyllene (3.3%; 7.5%), delta-cadinene (7.0%; 4.4%), spathulenol (6.0%; 9.5%) and tetracosane (3.1%; 5.8%). Comparison of both samples revealed similarity in the chemical composition with minor fluctuations of constituent percentages. The chemical profile of Croatian oils was in general similar to those reported for other geographic areas regarding major mono- and sesquiterpene constituents. However, spathulenol, delta-cadinene and bicyclogermacrene were more abundant in Croatian oils. The presence of decanoic acid (4.5%; 6.8%) in Croatian oils was the major difference between acids and fatty acids derivatives. Higher abundance of alkanes (particularly tetracosane and docosane) was also noticed.
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Ferulago angulata Boiss. known in Iran as Chavir, has some bioactive compounds having antioxidant activity. Because of its antioxidant activities, it sounded Chavir extract can be a good candidate for finding chemopreventive agents having inductive apoptosis properties on cancer cells. In this study, the cytotoxic effects and proapoptotic activities of Chavir’s leaf and flower extracts were investigated on human adenocarcinoma gastric cell line (AGS). The ferric reducing antioxidant power (FRAP) assay was used to determine antioxidant activity of the extract. Cytotoxic effects of the extract were performed by trypan blue and neutral red assays. For apoptosis detection, we used Annexin V staining, flow cytometry and DNA fragmentation assays. The FRAP assay results showed that antioxidant activity of leaf extract was higher than flower extract. Cytotoxicity and apoptosis–inducing activity of flower and leaf extracts changed coordinately, indicating the cytotoxicity of chavir extracts is due probably to induce apoptosis. Our results revealed that the cytotoxic effects of F. angulate Boiss. extracts on AGS cell line is close to some other plant extracts such as Rhus verniciflua Stokes (RVS) and Scutellaria litwinowii. This is the first study on cytotoxic and apoptosis–inducing effects of chavir leaf and flower extracts against AGS cell line. The Further investigation can be identification of the agent(s) by which these effects is observed.
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Objective:Screening of alpha-pinene on L-arginine induced acute pancreatitis model. Material and Methods:In this model the acute pancreatitis was determined at 24h by determination of pancreatic wet weight/body weight ratio, nitrate/nitrite levels, lipid peroxidation (thiobarbituric acid reactive substances (TBARS)], proinflammatory cytokines [tumor necrosis factor (TNF)-α, C-reactive proteins (CRP) and interleukin (IL)], pancreatic myeloperoxidase (MPO) activity and serum levels of amylase and lipase. Results:Administration of L-arginine had induced pancreatitis and this was characterized by pulmonary complication including altered pancreatic wet weight/body weight ratio, nitrate/nitrite levels, proinflammatory cytokines, TBARS, MPO and serum levels of amylase and lipase. Treatment with alpha-pinene (100 and 200mg/kg) dose significantly attenuated the L-arginine-induced pancreatitis and related complication. Conclusion:The histological findings proved the amelioration of pancreatic injury by alphapinene and biochemical parameters proved anti-inflammatory and antioxidant property of alpha-pinene.
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