Trends Nat. Prod. Res.

1(2): 70-77, 2020

Mechanism of the Anxiolytic Activity of Residual Aqueous Fraction of Solanum

aethiopicum (Linn.) Fruits in Mice

Abdullahi Rabiu Abubakar 1*, Ibrahim Haruna Sani2, Sani Malami1, Abdullahi Hamza Yaro 1
1
Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Bayero
University, Kano. Nigeria.
2
Unit of Pharmacology, College of Health Sciences, Yusuf Maitama Sule University, Kano,
Nigeria.

Key words: Solanum aethipicum, anxiolytic,
central nervous system, GABAA-receptor
*Corresponding author: unisza7@gmail.com /
raabdullahi.pha@buk.edu.ng,
09028774761 / 08099592480
DOI: 10. 48245/tnpr-2734391.2021.1.201
Page No.: 70-77
Volume: 1, Issue 2, 2020
Trends in Natural Products Research
Copy Right: NAPREG
Abstract: Solanum aethiopicum (L), family
Solanaceae is used in boosting memory, and also as
a sedative in the traditional management of
insomnia. The aim of this study was to evaluate the
mechanisms of the anxiolytic activity of residual
aqueous fraction of Solanum aethiopicum. The
anxiolytic activity of the residual aqueous fraction
(RAF) was investigated using elevated plus maze
test. The effect of some drug-receptor antagonists
such as bicuculine (BIC), naloxone (NAL),
chlorpromazine (CPZ), atropine (ATR), ketamine
(KT), picrotoxin (PIC), and flumazenil (FLU) on the
activity of RAF was tested. RAF and diazepam
(DZP) produced statistically significant increase in
open arm entry and duration of stay (p < 0.05)
compared to distilled water (DW) control group.
Simultaneous administration of NAL or PIC and
RAF caused significant increase in open arm entry
and duration of stay (p < 0.05), as well as decrease
in the duration of stay in the closed arm (p < 0.05).
There was no significant changes (p > 0.05) in the
number of entry and duration of stay in open and
closed arms when BIC, CPZ, ATR, KT, or FLU
were administered with RAF. The anxiolytic activity
of the residual aquoeus fraction of Solanum
aethipicum was antagonized by bicuculine,
chlorpromazine, atropine, ketamine and flumazenil
sugessting the participation of GABAergic,
dopaminergic, cholinergic, and glutaminergic
pathway in the mechanism of its anxiolytic activity.

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 Trends Nat. Prod. Res. 1(2): 70-77, 2020
INTRODUCTION
Anxiety is caused by abnormal firing of alarm circuit
in the amygdala controlling fear leading to changes
in the brain. Obsessive compulsive disorder is
believed to occur due to distortion of circuit in the
basal ganglia that control belief and information
processing. Anxiety could also result from
abnormality in cerebral cortex which is responsible
for maintaining stress coping strategy (Bystristsky et
al., 2013). Anxiety disorder has genetic origin
because it can be transferred from parents to their
children (Milton et al., 1999; APA, 2000; Bandelow
et al., 2012). Gamma-aminobutyric acid (GABA) is
the major inhibitory neurotransmitters in the brain.
The GABA is known for induction of sleep,
relaxation and prevention of excitation, therefore
depletion of GABA in occipital cortex is implicated
in pathophysiology of anxiety (Shiri et al., 2012;
Wiedermann, 2015). Serotonin originates from
raphe nucleus, and it modulates adrenergic and
dopaminergic pathways and also mediates anxiety.
Consequently, decrease in serotonergic activity
causes anxiety via unknown mechanism, and
selective serotonin reuptake inhibitors possessed
anxiolytic effect (Bystristsky et al., 2013;
Wiedermann, 2015). Dopamine participation in
anxiety disorder is complex, and its signals originate
from midbrain and substantia nigra and spreads to
limbic, cortex and infundibulum. Increase in
dopaminergic signals as well as blockage of D2-
dopaminergic receptors decrease anxiety (Brunton
et al., 2010). Bupropion, a dopaminergic agonist
reduces anxiety in some patients (by increasing
dopaminergic signals) but worsen in others
(activating D2-receptors) (Bystristsky et al., 2013;
Wiedermann, 2015). Noradrenaline originates from
pons and spreads throughout CNS and causes
anxiety (Bystristsky et al., 2013; Wiedermann,
2015). Propranolol a non-selective beta antagonist
reduces physical symptoms of anxiety by decreasing
heart rate, tremors, and voice shaking (Bystristsky et
al., 2013; Wiedermann, 2015). In addition, prazosin
an alpha antagonist reduces nightmare in post-
traumatic stress disorder (PTSD) (Bystristsky et al.,
2013; Wiedermann, 2015). Glutamate is an
excitatory neurotransmitter which activates N-
methyl-D-aspartate (NMDA) receptors, coordinates
learning and memory and mediates anxiety (Tyler et
al., 2017). Thus, NMDA antagonist such as
memantine and riluzole were used to treat obsessive
compulsive disorder (OCD) (Bystristsky et al.,
2013; Wiedermann, 2015). Animal models of
anxiety were developed with the intention to imitate
human pathological, physiological and behavioural
disease characteristics of anxiety (Steimer, 2011;
Cryan and Sweeney, 2011; Bourin, 2015). State
anxiety refers to the induction of an anxiety in an
animal model using external stimulus like light,
electric shock or exposure to open space.
Pathological anxiety is inherent in an animal model
71
due to their natural traits or personality (natural
aversion for light or open space). Pathological
anxiety condition could be found in transgenic mice
like Wistar Kyoto mice and genetically modified
animals with specific gene knocked-out (KO)
(Cryan and Sweeney, 2011; Steimer, 2011; Bourin,
2015). Such modification may be achieved using
gamma-aminobutyric acid transporter number one
gene (GAT-1 gene) knocked (GAT-1 KO),
Serotonin receptor knocked (5HT 1A KO), GABAA
receptor knocked (GABAAɣ2 KO), chemokine
kinase enzyme knocked (CCK2 KO) (Steimer, 2011;
Cryan and Sweeney, 2011; Bourin, 2015).
The use of plants in managing anxiety is practiced
traditionally in many parts of Nigeria. Solanum
aethiopicum L, (Solanaceae) popularly known as
garden egg or Ethiopian eggplant, Ethiopian
nightshade, mock tomato or bitter tomato is one of
such commonly used traditional anti-anxiety
remedy. In Nigeria it is called gauta by Hausa,
igbagba by Yoruba and afufa by Igbo tribes (Burkill,
2000; Chinedu et al., 2011; Anosike et al. 2012; Eze
and Kanu, 2014; Eletta et al., 2017). Solanum
aethiopicum is used as sedative and contain
solasodine which posses anxiolytic activity. It is also
used in traditional management of insomnia and
boost memory (Kumar et al., 2019). S. aethiopicum
improves cognition (Guima et al., 2015). The fruit is
reported to have anti-inflammatory (Anosike et al.,
2012), weight reducing and antidiabetic (Emiloju
and Chinedu, 2016; Okafor et al., 2016) and lipid
lowering (Chinedu et al., 2013), anti-ulcer (Chioma,
et al) and antioxidant (Eletta et al., 2017) activities.
The antifungal (Watanabe et al., 2001) and laxative
properties of the leaf have been reported (Saba et al.,
2002). The aim of this study was to evaluate the
anxiolytic activity of residual aqueous fraction of
Solanum aethiopicum.
MATERIALS AND METHODS
Animals
Swiss Albino Mice (16-20 g) of either sex were
purchased from Department of Pharmacology and
Therapeutics, Bayero University, Kano, Nigeria.
They were kept under room temperature (25 ± 2 oC)
and 12-hours light/12-hours dark circle. The relative
humidity was maintained at 60 ± 6 %. The animals
were fed on Vital Feed (Buruku, Jos) and water ad
libitum. The experiment was approved by the Ethical
Committee, College of Health Sciences Bayero
University, Kano, Nigeria. Ref No:
BUK/CHS/REC/69.
Chemicals
The chemicals used for the study included
Bicuculine (MedChem), Naloxone, (Jackson Lab),
 Trends Nat. Prod. Res. 1(2): 70-77, 2020
Chlopromazine (Sigma), Atropine (Martindale),
Ketamine (JAWA), Picrotoxin (Sigma), and
Flumazenil (Fresenius Kabi).
Collection of Plant Material and Preparation of
Extract
The whole plant material was collected from Fallau
Town, Dawakin Kudu Local Government, Kano
State, Nigeria. The plant identification and
authentication was done by Department of Plant
Biology, Bayero University, Kano, Nigeria.
Voucher number was collected as BUKHAN 0501
and kept for future references. The fruits were
purchased from same site for drying, grinding and
extraction.
The fruits were washed, shade dried, and grinded
into a coarse powder using mortar and pestle. The
powdered fruit (2 kg) was macerated in 6 L of 70 %
methanol v/v with occasional shaking for 7 days and
filtered using Whatman No10 filter paper. The
filtrate was evaporated to dryness in vacou at 40 oC
to yield residue (Deng et al., 2007). The crude
methanol extract was first dissolved in water and
transferred into separating funnel and fractionated
using n-hexane, chloroform, ethyl acetate, and n-
butanol (Deng et al., 2007).
Determination of Acute Toxicity
This test was conducted according to the OECD
guidelines 420 of 2001 (OECD, 2001). Five Swiss
albino mice weighing (16-20 g) were selected and
divided into five groups of one mouse each. Fixed
doses of 5, 50, 300, 2000 and 5000 mg/kg of n-
hexane, chloroform, ethyl acetate, n-butanol and
residual aqueous fractions (RAF) were administered
orally and intraperitoneally. The animals were
observed for signs of toxicity and mortality within
48 hours. Further observation was made for up to
two weeks for late signs of toxicity. The whole
experiment was conducted between 900 hour and
1600 hour (OECD, 2001).
Phytochemical screening
The chemical composition of crude methanol extract
and its fractions were determined using standard
method (Trease and Evans, 2002).
Anxiolytic study
This study was performed using Elevated Plus Maze
apparatus which is made up of the wooden board
comprising of two open arms (30 cm x 5 cm) without
walls. It also has two closed arms (30 cm x 5 cm x
15 cm) with walls. The two arms are connected
through a central platform (5 cm x 5 cm). The
apparatus has a wooden support at the base placed
72
50 cm above ground level (Handley and Mithani,
1984).
The mice were divided into 24 groups of 6 mice
each. The animals were treated as follows; group I,
distilled water (DW, 10 ml/kg), group II, diazepam
(0.5 mg/kg), and group III, RAF (25 mg/kg). Groups
IV to X received 25 mg/kg of the following
antagonists respectively bicuculine (2 mg/kg),
naloxone (2 mg/kg), chlorpromazine (1 mg/kg),
atropine (0.1 mg/kg), ketamine (3 mg/kg),
picrotoxin (1 mg/kg) and flumazenil (2 mg/kg).
Groups XI to XVII received the antagonists plus
DZP (0.5 mg/kg). Groups XVIII to XXIV received
the antagonists plus RAF 25 (mg/kg). Thirty minutes
after drug administration, each mouse was placed at
the centre of the maze (intersection of four arms)
with the head facing the open arm. The animal
behaviour was observed and recorded for 5 minutes
(Handley and Mithani, 1984).
Statistical Analysis
The results were presented as mean + SEM. The
statistical analyses were performed using ANOVA
(SPSS 11.5). Dunnett’s test was performed as post-
hock test. Differences between means of groups
were considered significant at p < 0.05.
RESULTS
Extraction yield
The percentage yield of the crude methanol extract
was 31.2 %. The yield of the fractions ranged from
0.2 % for n-hexane to 60.7 % for the residual
aqueous residue (Table 1)
Acute Toxicity Studies
The animals displayed no obvious signs of physical
changes. There was no death in the groups except in
n-butanol group. The oral and intraperitoneal LD 50
of the crude extract, n-hexane, chloroform,
ethylacetate and residual aqueous fraction was
above 5000 mg/kg and that of n-butanol fraction was
300 mg/kg.
Phytochemical constituents
The phytochemical screening of the crude extract
and fractions revealed the presence of saponins,
tannins, flavonoids, alkaloids, steroids and cardiac
glycosides (Table 2).
Anxiolytic effects
The residual aqueous fraction (25 mg/kg) caused
significant (p < 0.5) increase in open arm entry and
duration of stay as well as decrease in the duration
of stay in closed arm compared to DW group. In
 Trends Nat. Prod. Res. 1(2): 70-77, 2020

addition, DZP (0.5 mg/kg) evoked significant (p <
0.05) increase in the duration of stay in open arm,
and decrease in the duration of stay in closed arm
(Table 3). There was no significant change (p >
0.05) in the number of entry and duration of stay in
open and closed arms in the groups treated with the
antagonists alone. The animal groups that received
NAL plus DZP or RAF exhibited significant (p <
0.05) increase in open arm entry and duration of
stay, as well as decrease in duration of stay in the
closed arm compared to DW group (Table 3).
Conversely, treatment with BIC, CPZ or ATR plus
DZP or RAF did not produce significant (p > 0.05)
change in the number of entry duration of stay in the
closed arm compared to DW group indicating
receptor blockade (Table 3).
Treatment with KT or FLU alone or in combination
with DZP or RAF did not produce significant (p >
0.05) change in the number of entry and duration of
stay in open and closed arms indicating receptor
blockade However, PIC plus DZP or RAF resulted
in significant increase in open arm entry and
duration of stay (p < 0.05) (Table 4).

Table 1: Percentage yield of the fractions

S/N Solvent Yield (g) % Yield

1 n-hexane 0.6 0.2
2 Chloroform 0.4 0.1
3 Ethylacetate 8.4 2.2
4 n-butanol 140.1 36.8
5 Residual aqueous Fraction 231.3 60.7

Table 2: Phytochemical constituents of the extract and fractions

S/N Constituent Crude HF CHF EAF BF RAF

1 Saponins +++ ++ ++ - + ++
2 Tannins ++ + + + + +
3 Flavonoids ++ ++ ++ ++ ++ ++
4 Alkaloids + + + + + +
5 Anthraquinones - - - - - -
6 Steroids/Triterpenes
++ + + + + ++
7 Cardiac Glycosides + + + + + -
HF= n-Hexane Fraction, CHF= Chloroform Fraction, EAF= Ethylacetate Fraction, BF= n-Butanol Fraction,
RAF= Residual Aqueous Fraction.

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 Trends Nat. Prod. Res. 1(2): 70-77, 2020

Table 3: Effect of the antagonists on anxiolytic activity of DZP and RAF

S/N Treatment Open Arm Open Arm Close Arm Close Arm
Entry Duration (s) Entry Duration (s)
1 D/W 0.00 ± 0.00 00.00 ± 0.00 3.00 ± 0.55 293.00 ± 12.65
2 DZP 2.20 ± 0.58 103.60 ± 29.41* 3.60 ± 1.44 189.40 ± 30.54*
3 RAF 4.00 ± 0.45* 101.00 ± 19.41* 6.60 ± 1.40 115.60 ± 16.22*
4 BIC 1.20 ± 0.49 17.80 ± 7.17 5.60 ± 0.51 268.40 ± 7.99
5 BIC + DZP 1.40 ± 0.25 55.80 ± 25.69 4.00 ± 0.89 234.00 ± 26.61
6 BIC + RAF 1.60 ± 0.51 44.60 ± 26.00 5.00 ± 0.63 243.40 ± 26.42
7 NAL 1.60 ± 0.25 33.40 ± 10.05 4.20 ± 1.24 259.60 ± 10.17
8 NAL + DZP 3.00 ± 0.84* 93.60 ± 33.82* 3.40 ± 0.75 197.60 ± 32.75*
9 NAL + RAF 3.20 ± 0.58* 92.20 ± 25.54* 4.80 ± 0.87 200.00 ± 25.60*
10 CPZ 2.60 ± 0.60 53.80 ± 11.43 6.00 ± 0.89 232.00 ± 11.66
11 CPZ + DZP 2.20 ± 0.58 59.40 ± 18.94 4.60 ± 1.17 231.00 ± 19.46
12 CPZ + RAF 1.60 ± 0.81 22.40 ± 12.16 6.20 ± 1.62 263.40 ± 13.63
13 ATP 2.40 ± 1.44 28.00 ± 13.47 4.40 ± 0.40 258.00 ± 15.70
14 ATR + DZP 2.40 ± 0.75 65.00 ± 11.07 4.40 ± 0.75 244.00 ± 15.44
15 ATR 0. + RAF 2.20 ± 0.37 32.80 ± 5.28 3.60 ± 0.81 253.20 ± 5.07
*p< 0.05, compared to D/W (ml/kg). D/W = Distilled Water, DZP= Diazepam, BIC= Bicuculine,
NAL= Narloxone, CPZ=Chlorpromazine, ATR= Atropine.n=6

Table 4: Effect of KT, FLU and PIC on anxiolytic activity of DZP and RAF

S/N Treatment (mg/kg) Open Arm Open Arm Close Arm Close Arm
Entry Duration (s) Entry Duration (s)
1 D/W 0.72 ± 0.05 6.86 ± 2.33 3.15 ± 0.41 291.56 ± 34.92
2 DZP 4.23 ± 0.61* 126.70 ± 14.67* 4.32 ± 0.88 173.25 ± 18.6*
3 RAF 4.00 ± 0.45* 101.00 ± 19.41* 6.60 ± 1.40 115.60 ± 16.22*
4 KT 1.20 ± 1.20 50.40 ± 18.18 5.80 ± 2.13 237.00 ± 19.27
5 KT + DZP 2.60 ± 0.75 57.60 ± 16.48 5.60 ± 1.81 226.40 ± 18.13
6 KT + RAF 2.00 ± 0.84 52.60 ± 23.07 5.20 ± 0.58 227.80 ± 25.80
7 PCT 1.00 ± 0.44 11.60 ± 5.39 6.60 ± 0.40 271.20 ± 8.10
8 PIC + DZP 5.80 ± 0.73* 126.80 ±11.54* 7.40 ± 0.93 168.0 ± 12.58*
9 PIC + RAF 6.40 ± 0.68* 68.60 ± 25.73 5.80 ± 0.80 195.80 ± 23.64*
10 FLU 2.34 ± 0.73 45.40 ± 16.94 4.74 ± 0.36 253.42 ± 19.34
11 FLU + DZP 2.10 ± 0.34 32.73 ± 9.43 3.24 ± 0.55 266.17 ± 38.75
12 FLU + RAF 1.65 ± 0.17 21.60 ± 6.11 3.10 ± 0.69 277.23 ± 32.84
*p< 0.05, D/W = Distilled Water, DZP= Diazepam, KT = Ketamine, PIC= Picrotoxin,
FLU = Flumazenil. n=6

DISCUSSION

The residual aqueous fraction of S aethiopicum
displayed anxiolytic activity by increasing both
number of entry and duration of stay in the open arm
with corresponding decrease in the frequency of
entry and duration of stay in closed arm. Similar
result has been documented (Dos Santos et al., 2006;
Olayiwola et al., 2013; Bora and Pant, 2018). The
blocked of its anxiolytic effect by bicuculine
suggests an action via GABAA receptors as
previously reported by other workers (Karim et al.,
2012; Johnston, 2013, Karim et al., 2015).
Chlorpromazine abolished the anxiolytic property of
the aqueous fraction of S aethiopicum points
towards the involvement D2 dopaminergic receptors
(Brunton et al., 2010), while the effect of atropine
indicates the role M2 muscarinic receptors (Rang et
al., 2003) in the anxiolytic effect. Naloxone did not
block the anxiolytic action of the aqueous fraction
suggesting the non-involvement of opiate receptors
(Malenka et al., 2009, Aderibigbe et al., 2010). This
is in contrast with the findings of Olayiwola et al.,
(2013). The action of picrotoxin tends to imply that

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 Trends Nat. Prod. Res. 1(2): 70-77, 2020
chloride ion channels linked to GABAA receptor are
not involved in the anti-anxiety effect of the fraction
(Rho et al., 1996), also previous findings (Karim et
al., 2015; Hernandez-Leon et al., 2017) suggest
similar outcome. Ketamine and flumazenil blocked
the anxiolytic activity of the aqueous fraction
implying that N-methyl-D-aspartate receptors
(Tyler et al., 2017), and GABAA receptors
(Whitwam and Amrein, 1995) may be involved in
the anti-anxiety activity of the fraction. Similar
results were obtained in other studies (Aragao et al.,
2006; Aderibigbe et al., 2010; Olayiwola et al.,
2013; Khan et al., 2016; Aguirre-Hernández et al.,
2016).
CONCLUSION
Residual aqueous fraction of Solanum aethiopicum
was the most active fraction and its anxiolytic effect
may involve the GABAergic, cholinergic,
dopaminergic and gluterminergic pathways.
ACKNOWLEDGMENT
Special gratitude to entire staff of the Department of
Pharmacology and Therapeutics, Faculty of
Pharmaceutical Sciences, Bayero University, Kano.
Nigeria.
CONFLICT OF INTEREST
The researchers declared no conflict of interest.
FUNDING
This manuscript receives no financial support.
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