Heliyon 6 (2020) e04482

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Heliyon
journal homepage: www.cell.com/heliyon

Research article

Self-microemulsifying drug delivery system (SMEDDS) of curcumin

attenuates depression in olfactory bulbectomized rats
Manoj Aswar a, *, Mangesh Bhalekar b, Akshata Trimukhe a, Urmila Aswar c
a
Department of Pharmacology, Sinhgad Institute of Pharmacy, Narhe, Pune, Maharashtra, India
b
Department of Pharmaceutics, AISSMS College of Pharmacy, Pune, Maharashtra, India
c
Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune, Maharashtra, India

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Current therapies for depression remain limited and plagued by various side effects. Problems
Pharmaceutical science associated with curcumin administration include poor aqueous solubility and bioavailability issues. Hence to
Pharmacology overcome these, curcumin self micro emulsifying drug delivery system (SMEDDS) which will result in a nanosize
Toxicology
emulsion droplets when administered in vivo were formulated in the present study.
Depression
Curcumin
Methods: Depression was induced by bilateral olfactory bulbectomy and the animals were randomized into 8
Olfactory bulbectomy groups as normal, control [(vehicle 10 ml/kg, p.o., (per oral)], pure curcumin (10, 20, 40 mg/kg, p.o.), and
SMEDDS curcumin SMEDDS (10, 20, 40 mg/kg, p.o). After 14 days of respective treatment, behavioral parameters such as
open field test (OFT), ambulation counts and passive avoidance response (PAR) were evaluated. At the end of
experiments, blood was withdrawn from r.o.p (retro orbital plexus) for serum cortisol estimation.
Results: In OFT, increased central area frequency, peripheral area frequency, central area duration and decreased
rearing and grooming were recorded with an increased ambulation counts. In PAR, significant reduction in
number of trials and step down from platform was observed in the animals treated with test drug. Serum cortisol
level was also found to be decreased in the test groups.
Conclusion: Behavioral and biochemical estimations in the present study revealed the improved brain permeability
and further increase in biological activity of curcumin SMEDDS.

1. Introduction Inhibitors (SSRIs') are the mainstay for the management of depression [6,
7]. But existing drug therapies are linked with adverse effects like
The term psychiatric illness (or mental illness) encompasses a broad anorexia, decreased libido, activation and aggravation of psychosis, se-
range of medical conditions affecting thinking, feeling, mood, ability to rotonin syndrome, cheese reaction etc. [8]. Hence, plant derived prod-
relate to others and daily functioning within society. Such conditions ucts are increasingly being sought out as an option to avert the adverse
include schizophrenia, psychosis, depression, bipolar affective disorder, effects with an existing therapy. St John's Wort (Hypericum perforatum L.)
anxiety disorders (e.g. panic disorder, obsessive-compulsive disorder and is a drug from natural origin which is now accepted as the classified
post-traumatic stress disorder) and disorders relating to substance abuse antidepressant drug [9, 10].
[1]. As per WHO, major depression represents the most common mental Turmeric is most widely used as flavoring and coloring agent in
health problem worldwide with an estimated 322 million people, various Indian dishes. It has a wide biological and pharmacological
equivalent to 4.4% of the world's population [2]. Most common clinical profile as it is reported to possess anti-oxidant, anti-inflammatory and
manifestation includes feeling of intense sadness, worthlessness or anti-carcinogenic properties [11, 12]. It also possess hypocholester-
excessive guilt. Symptomatically, a significant increase or decrease in olemic, antibacterial, wound healing, antispasmodic, anticoagulant,
appetite, loss of interest or pleasure and in worsening conditions, suicidal antitumor and hepatoprotective activities [13]. Curcumin from Curcuma
ideation or suicidal attempts [3]. The clinical manifestation of different longa L. has also been reported for its potent antidepressant activity [14,
types of depression may be diverse but all these types of depression ul- 15, 16]. Curcumin is an inhibitor of monoamine oxidase (MAO) enzyme
timately affect mood or thoughts [4, 5]. Selective Serotonin Reuptake and also modulates the levels of norepinephrine, dopamine, and

* Corresponding author.
E-mail address: [email protected] (M. Aswar).

https://doi.org/10.1016/j.heliyon.2020.e04482
Received 8 April 2019; Received in revised form 16 October 2019; Accepted 14 July 2020
2405-8440/© 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
M. Aswar et al. Heliyon 6 (2020) e04482

serotonin in the brain [15, 16]. Curcumin being poorly water soluble for sonicated for 15 min for solubilization of drug. The formulation was
about 0.011 mg/ml, when administered orally, major portion is excreted stored at room temperature until further use.
through faeces and only small portion is absorbed within the intestine
[17]. The absorbed curcumin undergoes rapid metabolism in the liver 2.5. Characterization of curumin SMEDDS
and plasma and is extensively converted to its water soluble metabolites
(glucuronides and sulphates) and excreted through urine [18] which 2.5.1. Zeta potential
results in poor bioavailability [18]. The ability of curcumin and its The zeta potential of 1% dispersion of formulation in water was
nano-formulation to cross the Blood Brain Barrier (BBB) are closely measured using Malvern Zetasizer ZS 90 UK.
correlated with its hydrophobic property. Nanoparticle formulation has
significantly increased the retention time of curcumin in the cerebral 2.5.2. Particle size analysis
cortex (increased by 96%) and hippocampus (increased by 83%) as The particle size analysis was performed on Nanophox (Sympatec,
compared to pure curcumin [19]. Hence, self-micro emulsifying drug Germany).
delivery system (SMEDDS) of curcumin nanoparticles was formulated to
overcome the problems associated with oral absorption and poor 2.5.3. Ex-vivo study
bioavailability. Rat intestinal membrane was used to determine the drug release
Olfactory bulbs transmit the sense of smell to the frontal cortex of the study. Intestine (length postion s/a proximal) was washed with saline to
brain by transduction pathway where the physical stimulus (smell) is remove excretory product present in the intestine by flushing. Two in-
converted into action potential. Bilateral removal of the olfactory bulbs testines of equal size around 8 cm were taken and one was filled with
(OBX) elicits a variety of behavioral, neurochemical, neuroendocrine, curcumin SMEDDS and the other with pure curcumin in phosphate buffer
and neuroimmune alterations, many of which mimic the symptoms of (pH 6.8). These two intestinal segments were separately tied using nylon
depression [20]. Several authors have used this model in rats primarily thread and assembled into two different organ bath with aeration. The
for the detection of antidepressive properties [16, 21, 22, 23]. Even release study was performed in 50 ml of phosphate buffer at 37
0.5  C.
before its suggestion as a model for depression, the OBX model has been 2 ml sample was withdrawn at regular intervals i.e. 10, 20, 30, 40, 50 and
studied for changes in sexual behavior [24], food intake and preference 60 min and aliquot amount of phosphate buffer was replaced in order to
[25], as well as effects of handling [26], maternal behavior [27] and maintain sink condition. The withdrawn samples were analyzed for drug
nursing behavior [28]. Consequently in the present study, bilateral ol- content using UV-visible spectrophotometer at 400 nm [30].
factory bulbectomy model was used for the induction of depression in
rats.
2.6. Experimental animals

2. Materials and methods

Adult Wistar rats of either sex (250–350 g) were housed at Institute
Animal House in groups of six animals per cage at standard laboratory
2.1. Preformulation studies
condition with a temperature of 25
1 c, relative humidity of 45–55%.
All rats were allowed to access to food and water ad libitum. The 12hrs
Curcumin was dissolved in ethanol to produce (100 μg/ml) stock
light/dark cycle was maintained.
solution which was suitably diluted to produce final concentrations of 2,
4, 6, 8, 10 μg/ml. The UV absorbance was noted at λ max of 400 nm to
plot the calibration curve. 2.7. Approval of experimental protocol

The experimental protocol was approved by Institutional Animal

2.2. Determination of solubility of curcumin
Ethical Committee (IAEC) of Sinhgad institute of pharmacy, Narhe, Pune,
constituted as per the committee for purpose of supervision and control
The solubility of curcumin in oil, surfactant and co-surfactant was
on the experimental animal CPCSEA reg. no 1139/PO/a/07/CPCSEA.
determined by adding an excess amount of curcumin to 5 ml of excipient
The approved protocol number is SIOP/IAEC/2017/02/06.
separately. The mixtures were then shaken for 48 h at 25
0.5  C in an
orbital shaker. The equilibrated samples were centrifuged at 3500 rpm
for 15 min. The supernatant was diluted with ethanol analyzed for cur- 2.8. Induction of depression by olfactory bulbectomy
cumin content using validated UV- visible spectrophotometer. All mea-
surements were done in triplicate. For bilateral olfactory bulbectomy, rats were anaesthetized with ke-
tamine (80 mg/kg) and Xylazine (5 mg/kg) through intra-peritoneal
2.3. Pseudoternary phase diagram route. The animal was placed in streotaxic frame, head was shaven and
midline scalp sagittal incision (1 cm) was made. Bilateral burr holes were
Pseudoternary phase diagram was prepared by titrating oleic acid as drilled (2 mm diameter), 8 mm anterior to bregma and 2 mm lateral from
oil phase with tween 80 and propylene glycol as surfactant/co-surfactant midline. The olfactory bulbs from both the burr were aspirated using a
at ratio 1:1, 1:2 and 2:1 (v/v), The pseudoternary phase diagram were blunt hypodermic needle without damaging frontal cortex. The burr
constructed by titrating above mixture with double distilled water and holes were then filled with haemostatic sponge to prevent bleeding. The
visually observed for phase clarity. Nine different combinations of oil and incision was sutured and topical soframycin gel was applied to that re-
Smix, 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, 9:1 were made so that maximum gion. Intramuscularly, diclofenac sodium (2 mg/kg) was administered as
ratios were covered for the study to demarcate the boundaries of phases analgesic [22]. The animals were housed in an individual cage and
precisely formed in the phase diagrams. Pseudo-ternary plots were con- observed for 15 days and further on 16th day, the animals were grouped
structed using CHEMIX school trial version software 3.5 [29]. as per the protocol.

2.4. Formulation of curcumin SMEDDS 2.9. Experimental design

Comparison of phase diagrams with emulsion forming maximum area The animals were randomly divided into eight groups consisting of six
and uniform size distribution of the globules was selected. Accurately animals in each group. The animals received drug treatment once a day
weighed curcumin was placed in a glass vial and oleic acid, tween 80 and through oral administration for 14 consecutive days. The control group
propylene glycol in desired ratio were added to the vial and was received vehicle (10 ml/kg). The standard group received pure curcumin

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M. Aswar et al. Heliyon 6 (2020) e04482

(PC, 10, 20, 40 mg/kg) while the test group received curcumin SMEDDS
(CS, 10, 20, 40 mg/kg).

2.10. Behavioral parameters

After 14 days of treatment with respective drugs various behavioral

parameters such as passive avoidance test, open field test and ambulation
counts were evaluated.

2.10.1. Passive avoidance test

The passive avoidance apparatus consists of open box (50  50  50
cm3) with stainless steel grid floor. The electrified rods were connected to
the terminals of a shock generator that delivered a constant voltage. The
intensity of delivered shock was 0.75 mA which lasted for 1 s. Rats were
subjected to step-down passive avoidance training and testing on the
14th day of chronic curcumin administration. A platform (12  12  4
cm3) can be inserted through one side wall to allow a jump-up escape
response. Each rat was placed on this platform and when it stepped off
the platform with all four paws it received an electric shock. The animal
was immediately removed from the experimental apparatus and placed
in its home cage. After 30 s, the next trial was initiated. Each rat was
Figure 2. Solubility of curcumin in excipient.
trained until it learned to remain on the platform for 1 min [16].

2.10.2. Open field test (30  30  30 cm). When the rat breaks the beam of light, it activates the
Open field test apparatus consists of a square arena (60  60 cm) with digital counter where locomotion was expressed in terms of total number
white floor divided into 36 squares (10  10 cm). In this test, the 20 of ambulations [14].
squares adjacent to the wall represented the protected field named ‘arena
periphery’ while the other 16 squares represented an exposed field
named ‘arena centre’. The test was initiated by placing a single rat in the 2.11. Serum cortisol estimation
middle of the arena and letting it move freely for 5 min and the behavior
continuously video-graphed (V J instruments, India) [31]. The following At the end of experiments, blood sample was collected through r.o.p
parameters were evaluated during this 5 min session: for serum cortisol estimation. Rats were sacrificed on 16th day, brains
were excised on 16th day with high dose of anesthesia and brains were
a) Central area frequency excised quickly and stored at -25  C. Serum cortisol was assayed by chemi
b) Peripheral area frequency luminescent immuno assay (C.L.I.A) using Cortisol kit (Cusabio, USA,
c) Central area duration Catalog No. CSB-E05112r).
d) Rearing
e) Grooming
2.12. Statistical analysis
2.10.3. Ambulation counts by actophotometer
Locomotor activity (ambulations) was determined by using acto- Data for each parameter was analyzed by one-way ANOVA followed
photometer. The apparatus is equipped with 6 photocells at the bottom. by Dunnet's post hoc test using a graph pad, prism software, version 5.0,
Each animal was observed for a period of 5 min in a square closed field USA.

3. Results

3.1. Preformulation studies

3.1.1. Calibration curve of curcumin in ethanol

The curcumin obeyed Beers law in the concentration range 2–10 μg/
ml with high correlation coefficient R2 ¼ 0.9853. The regression equa-
tion was found to be y ¼ 0.07x þ 0.0838 (Figure 1).

3.1.2. Solubility of curcumin

The solubility of curcumin in oleic acid (oil) was found to be 6.43 mg/
ml whereas in tween 80 (surfactant) and propylene glycol (co-surfactant)
it was found to be 8.46 mg/ml and 14.46 mg/ml respectively (Figure 2).

3.2. Pseudoternary phase diagram of SMEDDS

The titration values obtained from the three ratios of oleic acid þ
Smix (tween 80: propylene glycol) i.e. 1:1, 1:2 and 2:1 were analyzed in
the CHEMIX school trial version software 3.5 for maximum area. The
maximum area was obtained in the ratio 1:1 as compared to the other
Figure 1. Calibration curve of curcumin in ethanol. ratios (Figure 3).

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M. Aswar et al. Heliyon 6 (2020) e04482

Figure 3. Pseudoternary phase diagrams.

Figure 4. Zeta potential of curcumin SMEDDS. Figure 5. Particle size analysis of curcumin SMEDDS.

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M. Aswar et al. Heliyon 6 (2020) e04482

and curcumin SMEDDS (10, 20, 40 mg/kg) groups when compared to

control group. Similarly step down from platform in control group was
significantly increased as compared to normal group. Non-significant
reduction was observed in pure curcumin (10 and 40 mg/kg) groups
while significant reduction was observed in curcumin SMEDDS (10, 20,
40 mg/kg) groups as compared to control group (Figure 7).

3.4.2. Open field test

Movement of animals in the central area frequency and the time spent
in the central area was reduced in control group as compared to normal
group. Treatment with pure curcumin (10 and 20 mg/kg) non-
significantly increased the same; whereas significant increase in fre-
quency and duration was noted in curcumin SMEDDS (20 and 40 mg/kg)
groups. Similarly significant reduction in peripheral area frequency was
observed in control group as compared with normal group which was
again non-significantly increased in pure curcumin (10, 20 mg/kg)
groups and significantly increased in curcumin SMEDDS (10, 20, 40 mg/
kg) groups. Rearing and grooming was significantly increased in control
group as compared to normal group which was further non-significantly
reduced in pure curcumin (10, 20 mg/kg) and significantly reduced in
curcumin SMEDDS (10, 20, 40 mg/kg) groups (Figure 8).
Figure 6. Percent cumulative drug release graph.
3.4.3. Ambulation counts by actophotometer
3.3. Characterization of curcumin SMEDDS [32] The movement of animals in the control group was significantly
reduced whereas treatment either with pure curcumin (20, 40 mg/kg)
3.3.1. Zeta potential and curcumin SMEDDS (10, 20 mg/kg) groups significantly increased the
Using oleic acid as oil and tween 80 as surfactant with co-surfactant count when compared with control group (Figure 9).
propylene glycol, the emulsion obtained was negatively charged with
zeta potential – 25.43
0.937 mV (Figure 4).
3.5. Estimation of serum cortisol
3.3.2. Particle size analysis
Serum cortisol was significantly increased in the animals of control
The globule size obtained was 44.13
0.695 nm. The polydispersity
group as compared to normal group. Significant reduction in cortisol
index (PDI) was found to be 0.446 (Figure 5).
level was observed in both the treatment groups (Figure 10).
3.3.3. Ex-vivo study
The samples of pure curcumin and curcumin SMEDDS withdrawn at 4. Discussion
regular intervals i.e. 10, 20, 30, 40, 50 and 60 min were analysed for drug
content using UV-visible spectrophotometer at 400 nm. The drug release Pharmacological management of depression is a major challenge
of pure curcumin was found to be less as compared to the curcumin because the cause and pathology of depression are still unknown. The
SMEDDS after 10 min and was observed maximum at 60 m (Figure 6). rate and extent of oral drug absorption of available drugs for depression
are often limited by their poor dissolution and solubilization within the
gastrointestinal tract [33]. Multiple studies have reported that, even with
3.4. Behavioral parameters high doses of curcumin, the levels of curcumin as well as its in vivo me-
tabolites are extremely low in serum and tissues after a short period of
3.4.1. Passive avoidance time [34, 35, 36]. The application of nanoformulation approaches to
A significant increase in number of trials was observed in control currently available drugs is a viable option for optimizing oral drug de-
group, which was reduced in pure curcumin (10, 20, 40 mg/kg) groups livery and maximizing treatment efficacy. SMEDDS are homogenous and

Figure 7. Effect of PC and CS passive avoidance response. A. No. of Trials, B. Step down from platform. Data was expressed as mean
SEM (n ¼ 6) and was analyzed
by one way ANOVA followed by Dunnett's test. Values in parenthesis indicates dose in mg/kg, ###p < 0.001 as compared with normal, ***p < 0.001 and *p < 0.05 as
compared with control, ns: non-significant.

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M. Aswar et al. Heliyon 6 (2020) e04482

Figure 8. Effect of PC and CS on locomotion in open field test. A. Central Area Frequency, B. Peripheral area frequency, C. Central area duration, D. Rearing, E.
Grooming. Data was expressed as mean
SEM (n ¼ 6) and was analyzed by one way ANOVA followed by Dunnett's test. Values in parenthesis indicates dose in mg/kg,
#
p < 0.05 as compared with normal and **p < 0.01, ***p < 0.001 as compared with control.

isotropic mixture of drug, oil, surfactant and co-surfactant with particle pharmacological activity [18, 19]. The small particle size, presence of
size 10–100 nm. They are used to overcome problems such as low surfactants and the anionic zeta potential must have increased the ab-
aqueous solubility, low permeability, high molecular weight, sorption of curcumin and may have also contributed to improved trans-
pre-systemic first pass-effect, enzymatic degradation, gastric irritation, port across blood brain barrier. For the induction of depression in rats,
enhanced bioavailability and stability of drugs [33]. Curcumin being a there are various animal models such as tail suspension test, forced swim
poor water soluble drug, at about 0.011 mg/ml it shows poor oral ab- test, olfactory bulbectomy and stress induced model. But the bilateral
sorption and decreased oral bioavailability [37]. Hence, the problems olfactory bulbectomy has garnered attention as a most efficient animal
associated with oral administration of pure curcumin can be overcome model of depression [20, 38, 39], as this model is based on the hypothesis
with formulation of nanoparticles in the form of SMEDDS. These that removal of the olfactory bulbs affects extensive efferent neuronal
SMEDDS also increases the brain permeability and improved networks and disturbs the connection and function of the whole limbic

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M. Aswar et al. Heliyon 6 (2020) e04482

represents fear and anxiety like behavior in animals which are the
mainstay symptoms of depression. High cortisol levels as observed in
current study has been accounted for generalized anxiety. In the standard
and test groups, the number of entries and time spent in central area was
significantly increased and it was more significant in test group indi-
cating anti-anxiety effects by curcumin SMEDDS which are in agreement
with the previous reports [15, 16, 31].
Ambulation count in the animals of control group was found to reduce
as compared to normal group which was significantly increased after
treating animals with curcumin. This indicates that the depressed ani-
mals show less exposure and locomotion due to fear and anxiety where
the animal prefers to stay immobile and steady by isolating into one place
giving least number of ambulation counts [14, 15].
OBX induced depression is reported to be associated with over ac-
tivity of Hypothalamus-Pituitary-Adrenal (HPA) axis as evident by over
expression of CRF neurons. The activation of HPA axis leads to the release
of CRH and ACTH to compensate stress which ultimately causes the
excessive release of cortisol. In the present study, the serum cortisol level
in OBX control group was found to be increased and was significantly
attenuated in standard and test groups which is in-line with the previous
Figure 9. Effect of PC and CS on ambulation counts. Data was expressed as
findings [40, 41]. As previously reported the anti-anxiety effects as well
mean
SEM (n ¼ 6) and was analyzed by one way ANOVA followed by Dun-
as serum cortisol lowering by curcumin SMEDDS can be corroborated to
nett's test. Values in parenthesis indicates dose in mg/kg, ###p < 0.001 as
compared with normal, *p < 0.05, **p < 0.01 as compared with control. its HPA axis amelioration effects. Curcumin have already proposed as
anti-depressant by Kulkarni et al. [14] and Chang et al. [13], probably by
inhibiting monoamine oxidase enzyme and modulating the release of
serotonin and dopamine. In the present study, the behavioral parameters
showed improve in memory, cognition and locomotion in curcumin
(SMEDDS) groups, also the serum cortisol level was decreased as
compared to test groups (pure curcumin) which are supporting to the
findings made by Kulkarni et al. [14]. On the basis, data in hand and with
support from literature therefore, it may be proposed that curcumin
SMEDDS increased the brain permeability and biological activity as
compared to the pure curcumin. Findings in the present study support the
contention of various authors indicating the efficacy of nanoformulation
over conventional drug delivery system for improved oral absorption and
poor bioavailability of curcumin.

5. Conclusion

Conventional dose of curcumin SMEDDS significantly increased the

locomotion in open field test and actophotometer, Improved memory and
cognition in passive avoidance test as well as reduced serum cortisol
level. These effects were considerably better than pure curcumin. Thus, it
can be concluded that the nanoformulation of curcumin in the form of
SMEDDS might be responsible for improved brain permeability and
Figure 10. Effect of PC and CS on serum cortisol level. Data was expressed as
thereby enhancing its biological activity.
mean
SEM (n ¼ 3) and was analyzed by one way ANOVA followed by Dun-
nett's test. Values in parenthesis indicates dose in mg/kg, ###p < 0.001 as
compared with normal, **p < 0.01, ***p < 0.001 as compared with control. Declarations

system [38]. The limbic circuit is essential for the maintenance of mood, Author contribution statement
emotional and memory components of behaviour and hence OBX model
was selected in the present study. Manoj Aswar, Mangesh Bhalekar: Conceived and designed the ex-
Passive avoidance test, Open field test and Ambulation counts plays periments; Analyzed and interpreted the data; Wrote the paper.
pivotal role to study memory, cognition and locomotion in animals. In Akshata Trimukhe: Performed the experiments.
passive avoidance test, training was given to the animals to remain on the Urmila Aswar: Contributed reagents, materials, analysis tools or data.
platform which indicates the determination of memory and cognition in
animals. In the present study, it was observed that the control group
Funding statement
required more number of trials as compared to the standard (pure cur-
cumin) and test (curcumin SMEDDS) groups acquiring less number of
This research did not receive any specific grant from funding agencies
trials which indicates increased memory and cognition which are in
in the public, commercial, or not-for-profit sectors.
accordance with the previous findings [15, 16].
In open field test, parameters such as central area frequency, pe-
ripheral area frequency, central area duration, rearing and grooming Competing interest statement
were evaluated. Animals in control group showed decreased total num-
ber of entries and also the duration of time spent in central area, this The authors declare no conflict of interest.

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M. Aswar et al. Heliyon 6 (2020) e04482

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depression: an update, Pharmacol. Ther. 74 (1997) 299–316.
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P.A. Thakurdesai, Antidepressant effects of standardized extract of Centella asiatica
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