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Evaluation of the Anxiolytic Activity of NR-ANX-C (a Polyherbal Formulation) in Ethanol Withdrawal-Induced Anxiety Behavior in Rats

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The present study investigates the anxiolytic activity of NR-ANX-C, a standardized polyherbal formulation containing the extracts of Withania somnifera, Ocimum sanctum, Camellia sinensis, Triphala, and Shilajit in ethanol withdrawal- (EW-) induced anxiety behavior in rats. Ethanol dependence in rats was produced by substitution of drinking water with 7.5% v/v alcohol for 10 days. Then, ethanol withdrawal was induced by replacing alcohol with drinking water, 12 hours prior to experimentation. After confirming induction of withdrawal symptoms in the alcohol deprived animals, the anxiolytic activity of the test compound in graded doses (10, 20, and 40 mg/kg) was compared to the standard drug alprazolam (0.08 mg/kg) in the elevated plus maze and bright and dark arena paradigms. In our study, single and repeated dose administration of NR-ANX-C reduced EW-induced anxiety in a dose-dependent manner. Even though the anxiolytic activity was not significant at lower doses, NR-ANX-C at the highest dose tested (40 mg/kg) produced significant anxiolytic activity that was comparable to the standard drug alprazolam. Based on our findings we believe that NR-ANX-C has the potential to be used as an alternative to benzodiazepines in the treatment of EW-induced anxiety.
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Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine
Volume 2011, Article ID 327160, 7pages
doi:10.1155/2011/327160
Research Article
Evaluation of the Anxiolytic Activity of NR-ANX-C
(a Polyherbal Formulation) in Ethanol Withdrawal-Induced
Anxiety Behavior in Rats
L. Mohan,1U. S. C. Rao,1H. N. Gopalakrishna,1and V. Nair1, 2
1Department of Pharmacology, Kasturba Medical College, Mangalore, Karnataka 575001, India
2Department of Pharmacology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
Correspondence should be addressed to V. Nair, vinodnair1979@hotmail.com
Received 18 May 2010; Accepted 10 July 2010
Copyright © 2011 L. Mohan et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The present study investigates the anxiolytic activity of NR-ANX-C, a standardized polyherbal formulation containing the extracts
of Withania somnifera, Ocimum sanctum, Camellia sinensis, Triphala, and Shilajit in ethanol withdrawal- (EW-) induced anxiety
behavior in rats. Ethanol dependence in rats was produced by substitution of drinking water with 7.5% v/v alcohol for 10
days. Then, ethanol withdrawal was induced by replacing alcohol with drinking water, 12 hours prior to experimentation. After
confirming induction of withdrawal symptoms in the alcohol deprived animals, the anxiolytic activity of the test compound in
graded doses (10, 20, and 40 mg/kg) was compared to the standard drug alprazolam (0.08mg/kg) in the elevated plus maze and
bright and dark arena paradigms. In our study, single and repeated dose administration of NR-ANX-C reduced EW-induced
anxiety in a dose-dependent manner. Even though the anxiolytic activity was not significant at lower doses, NR-ANX-C at the
highest dose tested (40 mg/kg) produced significant anxiolytic activity that was comparable to the standard drug alprazolam. Based
on our findings we believe that NR-ANX-C has the potential to be used as an alternative to benzodiazepines in the treatment of
EW-induced anxiety.
1. Introduction
Ethanol has always occupied an important place in the
history of Human civilization as a social recreational agent
and is the most widely used intoxicating substance in the
world [13]. When used in low to moderate quantities,
it relieves anxiety and fosters a feeling of well being and
euphoria. However, excessive alcohol consumption over a
prolonged period of time results in the development of
alcohol dependence [4]. Subsequently, a decline in the
concentration of ethanol in the brain, either due to total
cessation of alcohol consumption or a reduction in intake,
leads to the emergence of abstinence syndrome [5]. Ethanol
withdrawal (EW)/abstinence syndrome is characterized by a
constellation of signs and symptoms, with anxiety being a
hallmark symptom in humans. Along with this, anxiety is
also thought to be the most important negative motivation
to revert to alcohol use [6].
Although agents like benzodiazepines are the mainstay
for management of anxiety in EW, their use is associated with
side eects like development of sedation, drug dependence,
and so forth, which limits their usefulness in the clinical
setting [7]. Therefore, of late there have been attempts to
develop newer agents from Complimentary and Alternative
systems of Medicine, as these agents are claimed to be
as ecacious as the standard drugs while having minimal
side aects [8]. A number of plants like Ocimum sanctum,
Withania somnifera, and Camellia sinensis have been used
as components of polyherbal formulations in the Ayurvedic
system of medicine for treatment of anxiety disorders. Prac-
titioners of Ayurvedic system of medicine prefer polyherbal
formulations over individual agents as the Ayurvedic treaties
state that a combination of drugs ensures the potentiation of
the therapeutic ecacy of the main drug [9].
The test drug NR-ANX-C is a standardized polyherbal
formulation developed by Natural Remedies Pvt. Ltd,
2 Evidence-Based Complementary and Alternative Medicine
Bangalore, India. It is made up of the standardized extracts
of Withania somnifera (Ashwagandha),Ocimumsanctum
(Tulsi),Camelliasinensis(Green Tea),Triphala (made up
of fruits of Emblica ocinalis, Terminalia chebula, and
Terminalia bellericans), and Shilajit. There are a large number
of experimental studies that have evaluated the central
activity of these individual plant extracts. Withania somnifera
[10],Ocimumsanctum[11], and Camellia sinensis [12]have
been demonstrated to be eective as antistress agents, and
Withania somnifera [13] and Shilajit have been reported
to possess significant anxiolytic activity [14]. Previously,
experimental studies carried out in our laboratory have also
shown significant anticataleptic [15] and antianxiety [16]
activity in NR-ANX-C. Based on this evidence of central
activity, we hypothesized that NR-ANX-C could also possess
beneficial eects in EW-induced anxiety. In the present
study, we have evaluated the anxiolytic eects of NR-ANX-
C in EW-induced anxiety. Since anxiety in animals is a
subjective state and dicult to quantify [17,18]wehave
relied on objective animal models for characterization of this
behavioral state.
2. Methods
2.1. Animals. Male Wistar albino rats weighing 180–200 g
from our breeding stock were used in the study. They
were housed in groups of three animals per cage and
maintained on a 12:12 hour light/dark cycle at an ambient
temperature of 25 ±2C. The study protocol was approved
by Institutional Animal Ethics Committee, Kasturba Medical
College, Mangalore, and all experiments were carried out in
accordance with “Guidelines for care and use of animals in
scientific research (Indian National Science Academy 1998,
Revised 2000).
After acclimatization for seven days, the animals were
housed singly in metabolic cages. They were divided into two
sets, set one containing six groups and set two containing
five groups (n=6). Set one was used for acute study and
set two was used for chronic study. One group from set
one received water and food ad libitum for 10 days and
served as the normal control. This group was tested under the
same conditions and was used to demonstrate the increase in
anxiety behavior after EW in the alcohol-fed animals. The
other five groups from set one and all groups from set two
received alcohol (7.5% v/v) in drinking water and food ad
libitum for 10 days [19].
2.2. Test Drug. The test drug NR-ANX-C is a standardized
polyherbal formulation (supplied by Natural Remedies Pvt.
Ltd, Bangalore) containing extracts of Withania somnifera
17 percent (aqueous extract of root: total withanolides 2.1%
w/w), Ocimum sanctum 17 percent (70% alcohol extract of
leaves: ursolic acid 2.9% w/w), Camellia sinensis 33 percent
(70% alcohol extract of leaves: total polyphenols 60.1%
w/w),triphala 25 percent (aqueous extract of fruits: total
tannin 33.5% w/w), and shilajit 8 percent (aqueous extract:
fulvic acid 52.6% w/w; humic acid 16.7% w/w).
2.3. Experimental Protocol. The standard drug alprazolam
and test drug NR-ANX-C were freshly prepared in 1%
gum acacia (vehicle) before administration. Five groups of
animals were used from each set. Group I received the vehicle
and served as the EW control, Group II received alprazolam
(0.08 mg/kg body weight), and Groups III, IV, and V
received NR-ANX-C in doses of 10, 20, and 40 mg/kg body
weight, respectively. For acute study, after alcohol exposure
for 10 days, alcohol was withdrawn and substituted with
drinking water 12 hours before starting the experiments.
DevelopmentofEWsymptomsinratswasconrmedby
using the scoring system defined by Gatch and Selvig [20].
After confirmation of EW symptoms, drugs/vehicle was
administered to the respective animals. For chronic study,
drugs/vehicle administration was maintained along with
alcohol exposure for 10 days. As in acute study, alcohol was
withdrawn and substituted with drinking water 12 hours
before starting the experiments.
2.4. Evaluation of Antianxiety Activity. Sixty minutes after
administration of drug/vehicle the animals were sequentially
exposed to the following experimental models of anxiety,
namely, elevated plus maze and the bright and dark arena. All
apparatus were cleaned thoroughly with alcohol after testing
each animal in order to mask the odour left by the animal.
2.5. Elevated Plus Maze. Theelevatedplusmazeismade
of two open arms (50 ×10 cms) and two enclosed arms
(50 ×10 ×40 cms) with an open roof, arranged around a
central square, such that arms of same type are opposite to
each other. The entire maze is raised 50 cm above the ground.
In this test, the animal was gently placed in the central square
of the maze facing one of the open arms. The number of
entries, time spent, and the number of rears in each type of
arm (open/closed) was recorded for the duration of 5 min
[21].
2.6. Bright and Dark Arena. The apparatus consists of an
open-top wooden box with two distinct chambers, namely,
a dark chamber (20 ×30 ×35 cms) painted black and
illuminated with a dim red light, and a bright chamber
(30 ×30 ×35 cms) painted white and brightly illuminated
with a 100 W white light source placed 17cms above the box.
The two chambers are connected by a small open doorway
(7.5 cms) located at floor level in the center of the partition.
In this test, the animal was placed in the center of the brightly
lit arena. The total number of entries into bright arena, time
spent in bright arena, number of rears in bright and dark
arena, and the duration of immobility in dark arena were
recorded for a period of 5 minutes [22].
2.7. Statistical Analysis. Statistical analysis was done by using
GraphPad Instat version 3.06 (San Diego, USA). Dierence
between groups was compared by One-way ANOVA followed
by Dunnett’s Multiple Comparison test. P<.05 was consid-
ered significant.
Evidence-Based Complementary and Alternative Medicine 3
Tab le 1: EW increases anxiety behavior in elevated plus maze.
Treatment group No. of entries into To t a l ar m
entries
%ofopen/total
arm entries Time spent in (s) No. of rears in
Open arms Closed arms Open arms Closed arms Open arms Closed arms
Normal control 2.8±0.45.3±0.78.0±1.033.9±1.932.6±5.4 207.6±21.82.6±0.48.1±0.9
EW control 2.3±0.45.1±0.97.1±1.127.9±5.418.6±5.0270.0±5.51.1±0.510.1±1.4
Values are mean ±SEM; Statistical analysis by One-way ANOVA followed by Dunnett’s Multiple Comparison test. P<.05.
Tab le 2: Acute NR-ANX-C pretreatment reduced EW-induced anxiety behavior in elevated plus maze.
Treatment
group Number of entries into To t a l ar m
entries
%ofopen/total
arm entries Time spent in (s) Number of rears in
Open arms Closed arms Open arms Closed arms Open arms Closed arms
EW control 2.3±0.45.1±0.97.1±1.127.9±5.418.6±5.0270.0±5.51.4±0.510.1±1.4
Alprazolam
(0.08 mg/kg) 6.2±0.6∗∗ 7.3±0.213.3±0.7∗∗ 45.2±2.381.8±12.5∗∗ 207.0±18.55.7±0.8∗∗ 14.3±1.0
NR-ANX-C
(10 mg/kg) 1.8±0.54.3±0.96.2±1.327.2±5.629.0±10.7254.0±12.91.7±0.57.5±0.7
NR-ANX-C
(20 mg/kg) 2.7±0.53.7±0.86.3±1.342.8±4.256.0±17.9235.0±18.52.3±0.811.5±1.7
NR-ANX-C
(40 mg/kg) 7.0±0.6∗∗ 8.0±0.615.0±1.1∗∗ 48.2±2.3∗∗ 73.8±13.2215.0±11.18.7±1.2∗∗ 13.0±0.8
Values are mean ±SEM; Statistical analysis by One-way ANOVA followed by Dunnett’s Multiple Comparison test. P<.05; ∗∗ P<.01.
Tab le 3: EW increases anxiety behavior in bright and dark arena.
Treatment group No. of entries into
bright arena
Time spent in bright
arena (s)
Rears in bright
arena
Rears in dark
arena
Duration of
immobility (s)
Normal control 2.2 ±0.6 16.6 ±1.5 2.5 ±0.4 9.6 ±0.7 14.1 ±1.2
EW control 1.9 ±0.2 12.4 ±1.11.0 ±0.314.5 ±0.919.8 ±1.1
Values are mean ±SEM; Statistical analysis by One-way ANOVA followed by Dunnett’s Multiple Comparison test. P<.05.
3. Results
3.1. Acute Study
3.1.1. Elevated Plus Maze. EW produced an increase in
anxiety behavior as demonstrated by a decrease in the
time spent and number of rears in the open arms and an
increase in the time spent and rears in the closed arms by
the EW control animals (Tab le 1). Acute administration of
alprazolam reversed this behavior and significantly increased
the open arm entries, closed arm entries, total arm entries,
percentage of open/total arm entries ratio, time spent in
open arms, and rears in open arms as compared to the
control (Ta ble 2). Even though NR-ANX-C produced a
dose-dependent increase in the anxiolytic behavior, it was
significant and comparable to alprazolam only in the highest
dose- (40 mg/kg) treated group.
3.1.2. Bright and Dark Arena. EW produced an increase in
behavioral anxiety, as seen by a decrease in the time spent
in the bright arena and an increase in the number of rears
in dark arena and duration of immobility by EW con-
trol animals (Tabl e 3 ). Acute administration of alprazolam
decreased the anxiety in the treated animals as is evident
by the significant reduction in duration of immobility and
increase in time spent in bright arena (Tab l e 4 ). The test
drug NR-ANX-C also produced a dose-dependent reduction
in anxiety as demonstrated by increase in entries into the
bright arena, time spent in the bright arena, rears, and a
decrease in the duration of immobility. However, change
in these behavioral parameters was significant only at the
highest dose (40 mg/kg) as compared to the control. At the
highest dose tested (40 mg/kg), NR-ANX-C was superior to
alprazolam in ameliorating EW-induced anxiety behavior in
rats.
3.2. Chronic Study
3.2.1. Elevated Plus Maze. Chronic administration of alpra-
zolam was eective in reducing EW-induced anxiety behav-
ior in animals as it significantly increased the number of
open arm entries, percentage of open arm/total arm entries,
4 Evidence-Based Complementary and Alternative Medicine
Tab le 4: Acute NR-ANX-C pretreatment reduced EW-induced anxiety behavior in bright and dark arena.
Treatment group Number of entries
into bright arena
Time spent in bright
arena (s)
Rears in bright
arena
Rears in dark
arena
Duration of
immobility (s)
EW control 1.9 ±0.2 12.4 ±1.1 1.0 ±0.3 14.5 ±0.9 19.8 ±1.1
Alprazolam (0.08 mg/kg) 3.3 ±0.4 28.6 ±3.1∗∗ 2.8 ±0.5 17.0 ±2.1 3.5 ±1.3∗∗
NR-ANX-C (10 mg/kg) 2.3 ±0.4 17.0 ±2.8 1.3 ±0.4 13.3 ±1.5 3.2 ±2.1∗∗
NR-ANX-C (20 mg/kg) 2.5 ±0.3 18.8 ±4.1 2.7 ±0.7 17.0 ±1.9 2.8 ±1.3∗∗
NR-ANX-C (40 mg/kg) 3.8 ±0.6∗∗ 30.7 ±3.5∗∗ 3.2 ±0.519.5 ±2.5 2.7 ±1.3∗∗
Values are mean ±SEM; Statistical analysis by One-way ANOVA followed by Dunnett’s Multiple Comparison test. P<.05; ∗∗ P<.01.
Tab le 5: Chronic NR-ANX-C pretreatment reduced EW-induced anxiety behavior in elevated plus maze.
Treatment group Number of entries into To t a l Ar m
entries
%ofopen/total
arm entries Time spent in (s) Number of rears in
Open arms Closed arms Open arms Closed arms Open arms Closed arms
EW control 1.6 ±0.4 5.7 ±0.8 7.4 ±1.1 19.8 ±5.1 15.1 ±5.7 277.0 ±5.0 1.1 ±0.4 10.6 ±1.3
Alprazolam
(0.08 mg/kg) 3.8 ±0.54.8 ±0.9 8.7 ±1.1 45.7 ±4.254.7 ±15.1234.0 ±15.13.7 ±0.616.2 ±1.5
NR-ANX-C
(10 mg/kg) 3.8 ±0.74.8 ±0.8 8.7 ±1.3 44.8 ±4.232.2 ±3.4 262.0 ±3.8 3.0 ±0.7 10.8 ±1.7
NR-ANX-C
(20 mg/kg) 4.5 ±0.64.2 ±0.8 8.7 ±0.3 53.1 ±7.945.0 ±10.0245.0 ±5.73.8 ±0.811.2 ±0.9
NR-ANX-C
(40 mg/kg) 4.8 ±0.34.3 ±0.7 9.1 ±0.9 52.74 ±5.649.7 ±11.1242.0 ±16.24.8 ±1.119.5 ±0.6
Values are mean ±SEM; Statistical analysis by One-way ANOVA followed by Dunnett’s Multiple Comparison test. P<.05; ∗∗ P<.01.
time spent in open arms, and number of rears, while
reducing the time spent in closed arms, as compared to the
control (Ta ble 5). As in acute study, NR-ANX-C produced
a dose-dependent anxiolytic eect, which was significant in
the higher two doses (20 and 40 mg/kg) as compared to
control. At the highest dose tested (40mg/kg), NR-ANX-C
was superior to the standard drug alprazolam in ameliorating
EW-induced anxiety behavior in rats.
3.2.2. Bright and Dark Arena. Similar to the results observed
in acute study, chronic administration of alprazolam amelio-
rated EW-induced anxiety behavior in animals as observed
by the significant increase in number of entries into the
bright arena, time spent in bright arena, rears, and reduction
in duration of immobility (Ta b l e 6). Chronic administration
of NR-ANX-C also produced a dose-dependent inhibition of
anxiety behavior. However, as compared to the EW control,
the anxiolytic activity was significant only at the higher
two doses tested (20 and 40 mg/kg). At the highest dose
(40 mg/kg), NR-ANX-C was comparable to the standard
drug alprazolam in reversing EW-induced anxiety.
4. Discussion
Chronic and excessive ethanol consumption followed by
withdrawal results in the development of abstinence syn-
drome [4,5]. The most common and prominent feature
of alcohol withdrawal is anxiety, which is also considered
to be the most important negative motivation to revert
to alcohol use [6]. These signs and symptoms of EW
have been attributed to the perturbation of central neu-
rotransmitters and ion channel activity. Evidence indicates
that during ethanol withdrawal there is an upregulation of
excitatory NMDA receptors [23] and a downregulation of
inhibitory GABA-A receptors [24]. Therefore, a drug that
either facilitates the action of GABA or decreases glutamate
activity may be eective in EW-induced anxiety behavior.
Since the extent of anxiety is subjective and often dicult
to quantify, objective animal models have been used to
study the behavioral measures of anxiety during alcohol
withdrawal [18]. The elevated plus maze and bright and dark
arena are the most commonly employed tests for assessing
anxiety like behavior after alcohol withdrawal [25].
In the elevated plus maze, open arms are more fear
provoking than the closed arms and the ratio of entries,
time spent, and rearing behavior in open arms/closed arms
reflects the animal’s perception of safety towards closed arms
andfearfulnesstowardsopenarms[20]. Typical anxiolytic
drugs increase the proportion of entries, time spent, rearing
in the open arms, and the ratio of open arm to closed arm
entries. In the present study, EW control animals showed
a reduction in the time spent and rears in the open arms,
but increased the time spent in closed arms as compared
to normal control (nonalcohol-fed) animals in the elevated
plus maze. In the bright and dark arena test, the brightly
Evidence-Based Complementary and Alternative Medicine 5
Tab le 6: Chronic NR-ANX-C pretreatment reduced EW-induced anxiety behavior in bright and dark arena.
Treatment group Number of entries
into bright arena
Time spent in bright
arena (s)
Rears in bright
arena
Rears in dark
arena
Duration of
immobility (s)
EW control 1.7 ±0.2 13.9 ±2.1 1.0 ±0.3 11.6 ±1.8 19.6±4.9
Alprazolam (0.08 mg/kg) 3.0 ±0.2∗∗ 25.7 ±1.53.0 ±0.220.7 ±1.6∗∗ 0.9 ±0.4∗∗
NR-ANX-C (10 mg/kg) 2.3 ±0.2 22.0 ±3.2 3.0 ±0.412.8 ±1.4 4.2 ±2.9∗∗
NR-ANX-C (20 mg/kg) 2.7 ±0.327.2 ±3.33.2 ±0.313.2 ±1.3 2.8 ±0.7∗∗
NR-ANX-C (40 mg/kg) 2.8 ±0.330.7 ±3.6∗∗ 7.0 ±0.9∗∗ 18.8 ±2.51.2 ±4.1∗∗
Values are mean ±SEM; Statistical analysis by One-way ANOVA followed by Dunnett’s Multiple Comparison test. P<.05; ∗∗ P<.01.
Ethanol withdrawal
Anxiety
GABA
activity
NMDA
Adenosine
Tribulin
Serotonin
Cortisol
Oxidative
stress
Ethanol
Consumption
W. somnifera
Shilajit
C. sinensis
O. sanctum
Triphala
Increase
Decrease
Relapse
Figure 1: EW decreases GABAergic activity and induces anxiogenic mediators in the brain, thus leading to withdrawal anxiety and a relapse
to ethanol consumption. The individual components of NR-ANX-C contribute towards correcting this altered homeostasis, thus alleviating
withdrawal anxiety.
lit area represents a noxious environmental stressor that
inhibits the normal exploratory behavior of rodents and
reduction in the number of entries, time spent, and rearing
in the bright chamber are considered to be a markers
of anxiety [22,26]. In this model also, the EW control
animals demonstrated a marked reduction in the time spent
and rearing behavior in the bright chamber as compared
to normal control (nonalcohol-fed) animals. Behavioral
changes in both these models suggest that EW augmented
the behavioral inhibition or anxiety like state in the animals.
Both single- and repeated-dose administration of NR-ANX-
C produced a dose-dependent anxiolytic eect in these
experimental models. At the highest dose tested (40 mg/kg),
the anxiolytic activity of NR-ANX-C was comparable to the
standard drug alprazolam.
The test drug NR-ANX-C is a standardized polyherbal
formulation containing the extracts of Withania somnifera,
Ocimum sanctum, Camellia sinensis, triphala, and shilajit.
Withania somnifera and its bioactive components have been
shown to have GABA mimetic activity [27,28]andwe
believe that this property might be primarily contributing
towards the anxolytic activity of NR-ANX-C. Additionally,
Withania somnifera has previously been shown to reduce the
levels of tribulin [10], serotonin, and corticotrophin in the
brain [29]. Similarly, shilajit has also been shown to reduce
the brain levels of serotonin [14]. As an increase in the
brain levels of these mediators has been associated with the
development of anxiety, a reduction in their levels by these
two components could have contributed towards ameliora-
tion of the anxiety state. A large number of experimental
studies have reported Ocimum sanctum to possess anxiolytic
activity which has been attributed to it antistressor, cortisol
sparing [30,31], and antioxidant properties [32]. Along with
neurotransmitters like GABA and serotonin, adenosine has
also been implicated in the development of EW syndrome
and adenosine antagonists have been shown to ameliorate
this state [33]. Camellia sinensis contains methylxanthines
which are central nervous system stimulants and adenosine
antagonists [34]. We believe that these properties could
also have contributed towards the anxiolytic activity of the
polyherbal formulation.
As all the individual constituents of NR-ANX-C have
been shown to possess antianxiety activity, a question arises
as to why a combination has to be used when a higher
dose of any single agent can be used to produce a similar
eect? The answer to this question lies in Ayurvedic treaties,
6 Evidence-Based Complementary and Alternative Medicine
which state that drugs when used in combination rather
than individually ensure potentiation of beneficial eects and
amelioration of side eect of the principal drug [9]. This
may be true in this case also, as Withania somnifera, due to
its GABA mimetic activity [27,28], has sedative properties,
and Camellia sinensis, due to its methyl xanthine content,
has a stimulating eects in brain [35], thus antagonizing the
sedative eect. Additionally, Ocimum sanctum, shilajit, and
Camellia sinensis themselves decrease levels of anxiogenic
mediators in the brain by dierent mechanisms, thus
potentiating the anxiolytic activity of Withania somnifera
(Figure 1).In our study, the anxiolytic activity of NR-ANX-
C (40 mg/kg) was comparable to that of the standard drug
alprazolam in both, elevated plus maze and bright and
dark arena paradigms. NR-ANX-C did not produce any
significant eect on normal locomotor activity as it did
not increase the duration of immobility in the bright and
dark arena paradigm. Based on the results of our study, we
believe that the polyherbal formulation NR-ANX-C has the
potential to be used as an alternative to benzodiazepines in
the treatment of ethanol withdrawal.
Acknowledgments
The authors thank Natural Remedies Pvt. Ltd., Bangalore,
India, for providing the test drug NR-ANX-C. The company
did not have any role in collection of data, analysis of results,
or the decision to publish the findings.
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... Plant extracts contain the phytochemical compounds that employ the therapeutic effects on health and pose antimicrobial activity (Heinonen 2007). Herbal remedies have started gaining greater attention in this modern era than ever before, just because of their easy availability, least side effects, efficacy, and low cost when compared with the market available drugs (Mohan et al. 2011). Respiratory tract infection was selected in this study because it is a common disease, especially among children, and is directly correlated with air pollution and industrialization. ...
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In the present study, the antibacterial activity and in vivo acute toxicity of five different extracts was analyzed. The Minimum Inhibitory Concentration and antibacterial activity of five different extracts, including Terminalia chebula, Camellia sinensis, Glycyrrhiza glabra, Vitis vinifera, and Terminalia arjuna, against three different bacterial species, namely, Streptococcus pyogenes, Haemophilus influenza, and Staphylococcus aureus was analyzed by broth dilution method and agar well diffusion method, respectively. The in vivo acute oral toxicity was analyzed by using Wistar rats. The antibacterial activity of different extracts was calculated by analyzing the zone of inhibition, and the maximum zone of 22 mm and minimum zone of 10 mm were observed against the different upper respiratory infections causing bacteria. The lowest MIC (0.8 mg/ml) found was of Camellia sinensis against the Streptococcus pyogenes and Staphylococcus aureus. No sign of toxicity and mortality was observed during the 14 days of study. The in vitro results of the tested extracts indicate that they possessed antibacterial activity and were found non-toxic. So, it can be used as an alternative for the treatment of upper respiratory infection-causing bacteria.
... The individual constituents present in the POL-6 have been reported previously for their antianxiety activity at high doses, and then the need for the development of polyherbal preparation lies in Ayurveda which states that when the drugs are combined they show the potentiation of response even at low doses [42]. POL-6 might have potentiated the anxiolytic action as Withania somnifera is proven to have GABA mimetic activity, moreover; Withania somnifera has evidence to reduce the levels of mediators that cause anxiety [43]. Camellia sinensis has a stimulating effect on the brain due to its methylxanthine content that antagonizes adenosine thus ameliorating the ethanol withdrawal state [44]. ...
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... It's classified as an "adaptogen," meaning that it can help the body manage stress and hence it is popularly known as Ashwagandha [33] . W. somnifera also provides all sorts of other benefits for the body and brain [34,35] . Most of the therapeutic properties of W. somnifera are ascribed to bioactive steroidal lactones called withanolides. ...
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Alcohol dependency is one major problem all over the world that have caused increased mortality rate associated with the health risks, psychological, financial, social and economic deterioration. Most synthetic drugs used as treatment for alcohol dependency are reported to have numerous side effects. The development of low-toxicity and high efficiency medicines remains a challenging task for researchers. This current study aims to explore the effects of alcohol dependency and discovering newer plant based compounds to combat the ill effects of alcohol abuse.
... Roxb., and Phyllanthus emblica L. (syn. Emblica officinalis), and shilajit withdrawals ethanol induced anxiety behavior in rats (Nair et al., 2011), heightened ethanolinduced anxiolysis (Gupta and Rana, 2008), and weaken acquisition of oral ethanol administration under fixed and systemic increase in ratios ( Peana et al., 2014). In addition to this, it decreased the deprivation effects and did promote the reinstatement state in ethanol-seeking behaviors in experimental rat model (de Wit and Stewart, 1981;Spina et al., 2015). ...
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... Indeed, the animals treated with alcohol showed a marked reduction in the time spent in the light chamber compared to non-alcohol treated controls. These changes suggest that weaning increased anxiety in animals [39]. Excessive consumption of ethanol followed by withdrawal leads to withdrawal syndrome [40,41]. ...
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Terminalia chebula (T.chebula) fruit is referred as “King of Medicines” in Tibet and is listed as a key plant in “Ayurvedic Materia Medica” due to its diverse pharmacological activity. The present study was aimed to investigate the comorbid antidepressant-like and anxiolytic-like effects of ethanol extract from T.chebula fruit using experimental behavioral tests in mice. In addition, the study explored the effects of extract on monoamine oxidase –A (MAO-A) levels in mouse brain. Two doses of the T.chebula extract (100 or 200 mg/kg, p.o.) were treated continuously for fifteen days to mice. Regarding antidepressant-like effects, the treatment of T.chebula extract at both dose (100 or 200 mg/kg, p.o.) levels resulted with significant (p < 0.001) reduction in duration of immobility time and increase in swimming time as compared to control group in forced swimming test. Moreover, both doses declined the duration of immobility time in the tail suspension test and increased the number of crossing in the center area using open-field test. Additionally, the dose 200 mg/kg treatment showed a significant reduction (p < 0.05) in MAO-A activity in mouse brain. For anxiolytic activity, both doses significantly (p < 0.001) improved the time spent in open arm and the number of head dips in elevated plus maze test. The higher duration of time spent in light chamber and higher number of crossing between the light and dark chambers by extract treatment in light-dark box test also supported the anxiolytic behavior. The obtained results supported the antidepressant-like and anxiolytic-like effects of ethanol extract of T.chebula in mice.
Chapter
Anxiety is a very prevalent mental disorder. γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian brain and many anxiolytic drugs exert their action through interactions with the GABA receptors. In addition to the GABAergic system, serotonergic, dopaminergic, and noradrenergic systems are also implicated in the development of anxiety and stress in various animal models and humans. Furthermore, involvement of the hypothalamic–pituitary–adrenal axis and dysregulation of the immune system may also mediate stress and anxiety in humans and animals. While a number of anxiolytic drugs are available on the market, dietary supplements and herbal extracts are shown to exert equivalent calming effects with minimal to no addictive or adverse side effects. This chapter describes the pharmacological targets involved in the development of stress and anxiety and the role of various nutraceuticals and dietary supplements that have the potential to reduce anxiety and stress.
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Chapter
Stress in animals is evident through the disruptive behaviors exhibited, including excessive barking, restlessness, repetitive behavior, extreme vigilance, etc. Sociability is a key factor in determining the successful adaptation of pets to their environment. Sociable dogs are more comfortable with strangers and unfamiliar situations. Thus, reducing stress and anxiety in pets is essential in providing positive social interactions and to improve the quality of their life and that of the owners. γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian brain, and many anxiolytic drugs exert their action through interactions with the GABA receptors. In addition to the GABAergic system, serotonergic, dopaminergic, and noradrenergic systems are also implicated in the development of anxiety and stress in various animal models and in humans. Furthermore, the involvement of the hypothalamic-pituitary-adrenal (HPA) axis and dysregulation of the immune system may also mediate social stress in animals that produces aggression and/or depression. While a number of anxiolytic drugs are available on the market, dietary supplements and herbal extracts are shown to exert equivalent calming effects with no or minimal addictive or aversive side effects. This chapter describes the underlying mechanisms involved in the development of stress and anxiety and various nutraceuticals and substances that have potential to reduce the stress behavior and improve social interactions in canines.
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Ayurvedic literature describes psychotropic properties of many herbs. In recent years they have been evaluated for efficacy and safety by using modem methods of human pharmacological investigations. The article describes the observations of the authors while conducting clinical trials of some of the compounds claimed to have psychotropic properties.
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Ayurveda has quite a sophisticated classification of medicinal plants, as per the dominant pharmacological/therapeutic activity on mental functions etc. These need to be systematically evaluated by a multidisciplinary effort. The most interesting leads of CNS-active medicinal plants, which have emerged, besides Rauwolfia serpentina are (1) Mucuna pruriens for Parkinson's disease (2) Withania somnifera as anxiolytic (3) Centella asiatica and Bacopa monniera for learning and memory disorders (4) Acorus calamus as anxiolytic and (5) Oclmum sanctum as an antistress agent. The interface of molecular psychiatry and the active principles of some of these plants will be a major field for new developments in neuropharmacology and CNS-active drugs.
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A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated + -maze consisting of two open arms and two enclosed arms. The use of this test for detecting such drug effects was validated behaviourally, physiologically, and pharmacologically. Rats made significantly fewer entries into the open arms than into the closed arms, and spent significantly less time in open arms. Confinement to the open arms was associated with the observation of significantly more anxiety-related behaviours, and of significantly greater plasma corticosterone concentrations, than confinement to the closed arms. Neither novelty nor illumination was a significant contributor to the behaviour of the rats on the + -maze. A significant increase in the percentage of time spent on the open arms and the number of entries into the open arms was observed only within clinically effective anxiolytics (chlordiazepoxide, diazepam and, less effectively, phenobarbitone). Compounds that cause anxiety in man significantly reduced the percentage of entries into, and time spent on, the open arms (yohimbine, pentylenetetrazole, caffeine, amphetamine). Neither antidepressants nor major tranquilisers had a specific effect. Exposure to a holeboard immediately before placement on the + -maze showed that behaviour on the maze was not clearly correlated either with exploratory head-dipping or spontaneous locomotor activity.
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The behaviour of rats in a passive-avoidance test is described. Following the administration of painful electric footshocks the animals avoid the grid box by displaying overt flight behaviour (walking backwards and walking away) and stretched attention. The latter behaviour is followed either by approach or retreat. During stretched attention auditory stimulation is especially effective in producing flight behaviour. It is concluded that stretched attention is an ambivalent behaviour, indicating a behavioural conflict between exploratory (approach) and flight (avoidance) tendencies. The tension of the body and the absence of locomotion in high intensity stretched attention are taken as indications that, during the conflict, competition for the effectors takes place. The reversal of the orientation of flight evoked by auditory stimuli during stretched attention is best explained by assuming that a competition for the mechanisms of selective attention is also involved.
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Objective: To study the anxiolytic-like activity of NR-ANX-C, a polyherbal product, in rats Materials and Methods : Inbred, male, Wistar albino rats weighing between 150 and 180 g were used. The standard anxiolytic, diazepam (0.5 mg and 1 mg/kg), and the test drug, NR-ANX-C powder (5, 10 and 20 mg/kg), were dissolved/suspended in 1% gum acacia solution and administered orally. In acute study the vehicle and the drugs were given sixty minutes prior to the experiment, while in the chronic study they were given twice daily for 10 days with the last dose one hour prior to the experiments (elevated plus maze and light and dark box). Results: Acute (10 and 20 mg/kg) as well as chronic administration (5,10 and 20 mg/kg) of NR-ANX-C increased the number of entries, the time spent, and the rears in open arms of elevated plus maze model. Similarly, in light/dark box paradigm, at higher doses the test drug increased the time spent (10 and 20 mg/kg) and the number of rears (20 mg/kg) and decreased the duration of immobility (20 mg/kg). On the other hand, chronic administration of all the doses (5, 10 and 20 mg/kg), of the test compound increased the time spent and the number of rears in bright chamber and decreased the duration of immobility. At lower doses (5 and 10 mg/kg), the test compound increased the number of entries into bright chamber. Locomotor activity in the open field test was not affected at all by the doses tested in acute study. On repeated administration, however, the test drug increased the locomotor activity. These changes are similar to those induced by the standard anxiolytic diazepam. Conclusion: NR-ANX-C exhibited anxiolytic-like activity comparable to that of diazepam.