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Antimalarial potential of kolaviron, a biflavonoid from Garcinia kola seeds, against Plasmodium berghei infection in Swiss albino mice

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To investigate the antimalarial potential of kolaviron (KV), a biflavonoid fraction from Garcinia kola seeds, against Plasmodium berghei (P. berghei) infection in Swiss albino mice. The study consists of seven groups of ten mice each. Groups I, II and III were normal mice that received corn oil, KV1 and chloroquine (CQ), respectively. Groups IV, V, VI and VII were infected mice that received corn oil, CQ, KV1 and KV2, respectively. CQ, KV1 and KV2 were given at 10-, 100- and 200-mg/kg daily, respectively for three consecutive days. Administration of KV1 and KV2 significantly (P<0.05) suppressed P. berghei-infection in the mice by 85% and 90%, respectively, while CQ produced 87% suppression relative to untreated infected group after the fifth day of treatment. Also, KV2 significantly (P<0.05) increased the mean survival time of the infected mice by 175%. The biflavonoid prevented a drastic reduction in PCV from day 4 of treatment, indicating its efficacy in ameliorating anaemia. Significant (P<0.05) oxidative stress assessed by the elevation of serum and hepatic malondialdehydewere observed in untreated P. berghei-infected mice. Specifically, serum and hepatic malondialdehyde levels increased by 93% and 78%, respectively in the untreated infected mice. Furthermore, antioxidant indices, viz; superoxide dismutase, catalase, glutathione-s-transferase, gluathione peroxidase and reduced gluathione decreased significantly (P<0.05) in the tissues of untreated P. berghei-infected mice. KV significantly (P<0.05) ameliorated the P. berghei-induced decrease in antioxidant status of the infected mice. This study shows that kolaviron, especially at 200 mg/kg, has high antimalarial activities in P. berghei-infected mice, in addition to its known antioxidant properties.
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Asian Pacific Journal of Tropical Medicine (2014)97-104
Document heading doi:
Antimalarial potential of kolaviron, a biflavonoid from Garcinia kola
seeds, against Plasmodium berghei infection in Swiss albino mice
Adaramoye Oluwatosin1*, Akinpelu Tolulope2, Kosoko Ayokulehin1, Okorie Patricia2, Kehinde
Aderemi3, Falade Catherine2, Ademowo Olusegun4
1Biochemistry Department, University of Ibadan, University way, Oyo-Ojoo, Road, Ibadan , Ibadan, Oyo/South-West 20005, Nigeria
2Pharmacology Department, University of Ibadan, University way, Oyo-Ojoo, Road, Ibadan , Ibadan, Oyo/South-West 20005, Nigeria
3Medical Microbiology Department, University of Ibadan, University way, Oyo-Ojoo, Road, Ibadan , Ibadan, Oyo/South-West 20005, Nigeria
4Pharmacology and IAMRAT Department, University of Ibadan, University way, Oyo-Ojoo, Road, Ibadan , Ibadan, Oyo/South-West 20005, Nigeria
Contents lists available at ScienceDirect
Asian Pacific Journal of Tropical Medicine
journal homepage:www.elsevier.com/locate/apjtm
ART ICLE INFO AB ST RACT
Article history:
Received 10 October 2013
Received in revised form 15 December 2013
Accepted 15 January 2014
Available online 20 February 2014
Keywords:
Antimalaria
Antioxidant
Biflavonoid
Kolaviron
Plasmodium berghei
*Corresponding authors: Adaramoye Oluwatosin, Biochemistry Department,University
of Ibadan, University way, Oyo-Ojoo, Road, Ibadan, Ibadan, Oyo/South-West 20005,
Nigeria.
E-mail: aoadaramoye@yahoo.com.
1. Introduction
Malaria is a parasitic infection caused by Plasmodium
species, and is one of the oldest and greatest health
challenges affecting 40% of the worlds population[1].
Malaria deaths peaked at 1.82 million in 2004 and fell to
1.24 million in 2010 (714 000 and 524 000 deaths are children
that are less than and greater than 5 years, respectively)
and over 80% total deaths occur in sub-Sahara Africa[2]. The
disease is a major obstacle to economic advancement of
many developing and tropical nations predisposing people
to poverty. Chemotherapy remains a major means of malaria
control. However, the previously efficacious chloroquine
(CQ) is failing both as a prophylactic and therapeutic
Objective: To investigate the antimalarial potential of kolaviron (KV), a biflavonoid fraction from
Garcinia kola seeds, against Plasmodium berghei (P. berghei) infection in Swiss albino mice.
Methods: The study consists of seven groups of ten mice each. Groups , and were normal
mice that received corn oil, KV1 and chloroquine (CQ), respectively. Groups , , and
were infected mice that received corn oil, CQ, KV1 and KV2, respectively. CQ, KV1 and KV2
were given at 10-, 100- and 200-mg/kg daily, respectively for three consecutive days. Results:
Administration of KV1 and KV2 significantly (P<0.05) suppressed P. berghei-infection in the mice
by 85% and 90%, respectively, while CQ produced 87% suppression relative to untreated infected
group after the fifth day of treatment. Also, KV2 significantly (P<0.05) increased the mean survival
time of the infected mice by 175%. The biflavonoid prevented a drastic reduction in PCV from day
4 of treatment, indicating its efficacy in ameliorating anaemia. Significant (P<0.05) oxidative stress
assessed by the elevation of serum and hepatic malondialdehydewere observed in untreated P.
berghei-infected mice. Specifically, serum and hepatic malondialdehyde levels increased by
93% and 78%, respectively in the untreated infected mice. Furthermore, antioxidant indices, viz;
superoxide dismutase, catalase, glutathione-s-transferase, gluathione peroxidase and reduced
gluathione decreased significantly (P<0.05) in the tissues of untreated P. berghei-infected mice.
KV significantly (P<0.05) ameliorated the P. berghei-induced decrease in antioxidant status of
the infected mice. Conclusions: This study shows that kolaviron, especially at 200 mg/kg, has
high antimalarial activities in P. berghei-infected mice, in addition to its known antioxidant
properties.
Adaramoye Oluwatosin et al./Asian Pacific Journal of Tropical Medicine (2014)97-104
98
antimalarial drug in many endemic countries of Africa, due
to the emergence of CQ resistant Plasmodium falciparum
strains with mutant alleles for CQ resistance transporter
proteins (pfcrtT76) and multidrug resistance glycoprotein-1
(pfmdr-1Y86)[3,4]. Hence, the diminished potency of CQ in
many of the endemic countries have paved way for research
into discovery and/ or development of new antimalarial
drugs. In the last decade, several fundamental researches
have been conducted to explore antimalarial activity of
many plants, including Citrus cinensis, Carica papaya,
Swertia chirata[5], Bidens pilosa[6], Nigella sativa[7], Piper
sarmentosum, Tinospora cordifolia[8] and many others[9].
Garcinia kola Heckel (family Guttiferae) is a cultivated large
forest tree, valued in most parts of West and Central Africa
for its edible nuts[10]. The seed, known as bitter kola or false
kola, is commonly chewed and serves as an alternative to
true kola nuts (Cola nitida and Cola accuminata). Extracts of
various parts of the plant are used extensively in traditional
African medicine[11], especially for the preparation of
remedies for the treatment of laryngitis, cough and liver
diseases[12]. Chemical investigations of the seeds have shown
that they contain a complex mixture of phenolic compounds,
including GB-type biflavonoids, xanthones, benzophenones,
cycloartenol and triterpenes[13,14]. Kolaviron (KV) (Figure 1)
is a bifavonoid complex isolated from the seeds of Garcinia
kola and has been reported to possess neuroprotective, anti-
infammatory, antimicrobial, antioxidant, antigenotoxic and
hepatoprotective activities in model systems via multiple
biochemical mechanisms[15-18]. Furthermore, studies by
Adaramoye et al[19] and, Adaramoye and Medeiros[20] showed
that KV has anti-atherogenic and vasorelaxant effects in
animal model and isolated smooth muscle, respectively.
There is limited information on the effect of this biflavonoid
on the growth of Plasmodium species in animal model.
This study was therefore designed to investigate the in vivo
antimalarial effect of kolaviron in Plasmodium berghei (P.
berghei)-infected mice.
Figure 1. Structures of KV and CQ.
2. Materials and methods
2.1. Chemicals
Glutathione, Hydrogen peroxide, 5,5-dithios-bis-2-
nitrobenzoic acid and epinephrine were purchased from
Sigma Chemical Co., Saint Louis, MO USA. Absolute ethanol,
trichloroacetic acid and thiobarbituric acid were purchased
from British Drug House Chemical Ltd., Poole, UK. Other
chemicals were of analytical grade and purest quality
available.
2.2. Plant material and extraction procedure
Garcinia kola seeds (Guttiferae heckel) seeds were
purchased from a local vendor in Ibadan, Nigeria. Kolaviron
was extracted from the fresh seeds of the Kola (3.5 kg)
and characterized according to the method of Iwu et al[21].
Briefly, powdered dried seeds were extracted with light
petroleum ether (b.p. 40-60 ) in a soxhlet extractor for 24 h.
The defatted, dried marc was repacked and then extracted
with methanol. The extract was concentrated and diluted
to twice its volume with distilled water and extracted with
ethyl acetate. The concentrated ethyl acetate fraction gave a
yellow solid known as kolaviron. The yield of the preparation
was 6%.
2.3. Animals
Male adult Swiss albino mice were obtained from the
animal house of the Institute for Advanced Medical
Research and Training, College of Medicine, University of
Ibadan, Nigeria. The animals were housed in well-aerated
plastic cages, fed with standard mouse cubes (Ladokun
Feeds, Nigeria, Ltd) and supplied with clean drinking water
ad libitum. P. berghei used in this study was a donation to
the laboratory of one of us (OGA) by Malaria Research and
Reference Reagent Resource Centre (MR4). The parasites
were maintained in animals by serial passages of blood
collected from a patent donor mouse to a naive recipient.
Handling of animals and other protocols conform to the
guidelines of the National Institutes of Health and Animal
Ethical Committee of University of Ibadan, Nigeria, for care
of laboratory animals.
2.4. Course of infection and antimalarial activity
The course of infection of P. berghei following
intraperitoneal inoculation in mice was studied in each
experimental mouse that received 107 parasitized red blood
Adaramoye Oluwatosin et al./Asian Pacific Journal of Tropical Medicine (2014)97-104 99
cells in 0.2 mL inoculum. Thin blood films were prepared
from the tail vein of infected mice, fixed with methanol and
stained with 10% Giemsa stain using standard procedure.
Parasitemia was monitored daily and blood smears were
read using 100 objective of a light microscope. In vivo
antimalarial activity against P. berghei infection in mice was
done according to Ranes test as described by Elufioye and
Agbedahunsi[22]. The test relies on the ability of a standard
inoculum of Plasmodium yoelli to kill the recipient mouse
within 12 days of inoculation. Extension of survival beyond
12 days is regarded as activity.
2.5. Study design
Mice weighing between 18 and 23 g were distributed into
seven groups of ten animals each. Group : uninfected
normal mice (positive control), group : uninfected normal
mice that received KV at a dose of 100 mg/kg (KV1), group
: uninfected normal mice that received CQ, group :
untreated infected mice (Negative control), group : infected
mice treated with CQ, group : infected mice that received
KV1 and group : infected mice that received KV2 (200 mg/
kg)[23]. CQ and KV were adminstered to infected mice after
72 h of parasite inoculation when the infection was
established. CQ and KV were dissolved in distilled water and
corn oil, respectively and given daily for three consecutive
days (Days 3, 4 and 5 post-infection) to the animals by
oral gavage. The control animals received equivolume of
corn oil (vehicle), and CQ was given at dose of 10 mg/kg
body weight[24]. The levels of parasitemia in the mice were
monitored daily untill day 10 before half of the animals (n=5)
were sacrificed. The blood and liver of sacrificed animals
were obtained for biochemical assay. The remaining five
mice per group were monitored to obtain survival time.
2.6. Preparation of samples
Portion of the whole blood from each animal was collected
into heparinized bottles, stored at 4 and the red cells
were assayed for antioxidant parameters. The other portion
was taken into plain centrifuge tubes and allowed to stand
for 2 h before centrifugation to obtain serum. The serum
was used to determine the extent of lipid peroxidation and
some enzymes markers. Liver was excised after dissection
of the animals and rinsed in ice-cold 1.15% KCl, dried and
weighed. The liver samples were homogenized in 4 volumes
of 50 mM phosphate buffer, pH 7.4 using a Potter Elvehjem
homogenizer and centrifuged at 10 000 g for 15 minutes to
obtain post-mitochondrial supernatant fraction (PMF).
2.7. Biochemical and physiological assays
2.7.1. Determination of Haematocrit
The haematocrit or packed cell volume (PCV) was
determined to predict the effectiveness of the biflavonoid
in preventing anaemic conditions in malaria[25]. Blood was
drawn from the tail of the mice in the different groups into
heparinised capillary tubes. Capillary tubes were filled
to mark, sealed at one end and spun for ten minutes in a
micro-haematocrit centrifuge. The haematocrit of each
animal was subsequently read with haematocrit reader.
2.7.2. Protein
Serum and PMF protein levels were determined according
to the method of Lowry et al[26] using bovine serum albumin
as standard.
2.7.3. Alanine (ALT) and aspartate aminotransferases (AST)
The activities of serum ALT and AST were determined by
the combined methods of Mohun and Cook[27], and Reitman
and Frankel[28].
2.7.4. Total bilirubin and urea
Serum total bilirubin and urea levels were assayed by
the methods of Rutkowski and Debaare[29] and, Talke and
Schubert[30], respectively.
2.7.5. Superoxide dismutase (SOD), catalase (CAT) and
glutathione-S-transferase (GST)
SOD activity was measured by the nitroblue tetrazolium
reduction method of McCord and Fridovich[31]. The GST
activity was determined by the method of Habig et al[32], the
method is based on the rate of conjugate formation between
glutathione and 1-chloro-2,4-dinitrobenzene. The CAT
activity was assayed by measuring the rate of decomposition
of hydrogen peroxide at 240 nm as described by Aebi[33].
2.7.6. Glutathione Peroxidase (GPx), Reduced glutathione
(GSH) and lipid peroxidation
The GPx activity was determined according to the method
of Rotruck et al[34]. Reduced GSH level was assayed by
measuring the rate of formation of chromophoric product in
a reaction between 5,5-dithio-bis (2-nitrobenzoic acid) and
free sulfhydryl groups at 412 nm by the method of Moron et
al[35]. The extent of lipid peroxidation (LPO) was estimated
by the method of Walls et al[36]. The method involved the
reaction between malondialdehyde (MDA) and thiobarbituric
acid to form a pink precipitate, which was read at 535 nm
spectrophotometrically.
Adaramoye Oluwatosin et al./Asian Pacific Journal of Tropical Medicine (2014)97-104
100
2.8. Statistical analysis
The results were expressed as meanstandard deviation
(SD) of 10 mice per group. Data were analysed using one-way
analysis of variance (ANOVA) followed by post-hoc Duncans
multiple range test for analysis of biochemical data using
SPSS (12.0) statistical software. Values were considered
statistically significant at P<0.05.
3. Results
3.1. Effects of KV and CQ on parasitemia and body weight of
P. berghei infected mice
A progressive increase in average percentage parasitaemia
was observed in P. berghei infected mice, with a maximum
of 81% average parasitaemia by day 10 (post infection).
However, the results showed that CQ, KV1 and KV2 were
able to suppress parasitaemia considerably by day 6 (post
infection), while KV2 had the highest percentage suppression
of 92% at day 10 post-infection (Table 1). In addition, KV1
and KV2 extended the mean survival time of the mice to 15.8
and 28.1 days, respectively, when compared with CQ (14.6
days) and untreated infected group (10.2 days) (Table 2). In
addition, P. berghei infection caused significant (P<0.05)
decrease in the body weights-gain in the mice relative to
normal. Treatment with CQ and KV significantly (P<0.05)
increased the body weight-gain of the infected mice (Table
2).
Table 2
Effect of KV and CQ on the mean survival time and body weights in
normal and P. berghei-infected mice.
Treatment Mean
survival
time (Days)
Body weight (g) Changes in
body weight (g)
Initial Final
Normal 58.01.4 18.90.9 23.11.8 4.20.7
Normal + KV1 49.70.8 18.31.4 22.70.8 4.40.5
Normal + CQ 45.11.1 18.71.1 22.61.2 3.91.0
Infected only 10.20.5*19.31.6 17.51.0*-1.80.3*
Infected + CQ 14.60.9* 19.51.0 21.30.8 1.80.1*
Infected + KV1 15.80.7*19.21.6 23.01.1 3.80.7a
Infected + KV2 28.11.2*,a 18.51.0 22.91.0 4.40.5a
Values are reported as meanSD (n=5, 10 for mean survival time and
body weight, respectively).
* Significantly different from normal (P<0.05); a Significantly different
from infected only (P<0.05).
KV1= Kolaviron at a dose of 100 mg/kg, KV2= Kolaviron at a dose of
200 mg/kg.
3.2. Effects of KV and CQ on PCV and serum biochemical
indices of P. berghei infected mice
The PCV of untreated, infected mice decreased significantly
(P<0.05) as the infection progressess. However, treatment
with KV and CQ significantly (P<0.05) ameliorated the P.
Table 1
Effect of KV and CQ on the levels of parasitemia in normal and P. berghei-infected mice.
Treatment 3 4 5 6 7 10
P%S%P%S%P%S%P%S%P%S%P%S%
Infected only 17.00.1 0.0 23.00.4 0.0 38.00.4 0.0 71.00.8 0.0 78.01.2 0.0 81.00.7 0.0
Infected +CQ 15.00.2 11.7 20.00.6 13.1 24.00.3 36.8 12.00.3a83.1a10.00.2a87.2a12.00.6a85.2a
Infected +KV1 17.00.1 0.0 21.00.6 8.7 28.00.5 26.3 19.00.2 73.2a12.00.3a84.6a13.00.2a84.0a
Infected +KV2 16.00.2 5.9 20.00.6 13.0 23.00.5 39.5 20.00.2 71.8a 8.00.2a89.7a 6.00.3a92.6a
Values are reported as meanSD (n=10),
a Significantly different from corresponding values in days 3, 4 and 5 (P<0.05).
% P= Percentage parasitaemia, % S= Percentage suppression, KV1= Kolaviron at a dose of 100mg/kg, KV2= Kolaviron at a dose of 200mg/kg,
NOTE: Samples on day 3 were collected before commencement of treatment.
Table 3
Effect of KV and CQ on the PCV in normal and P. berghei-infected mice.
Treatment/ Days PCV(%)
3456710
Normal 53.42.5 52.81.1 52.51.2 53.22.1 53.51.4 53.71.2
Normal + KV1 51.21.3 51.32.1 52.40.9 51.51.3 52.61.0 52.21.3
Normal + CQ 52.83.9 52.01.8 52.31.4 51.92.2 52.02.0 52.02.0
Infected only 42.52.3* 43.11.3* 40.21.6* 38.71.3* 37.41.1* 32.10.9*
Infected + CQ 43.01.8* 41.62.1* 43.81.0* 48.21.7*50.71.0 52.01.1
Infected + KV1 43.71.3* 42.93.6* 45.71.7*50.42.1 50.21.1 53.52.3
Infected + KV2 44.12.1* 43.83.2* 46.02.0*51.31.8 52.31.4 52.81.0
Values are given as mean SD (n=10).
* Significantly different from normal (P<0.05). KV1= Kolaviron at a dose of 100mg/kg, KV2= Kolaviron at a dose of 200 mg/kg,
NOTE: Samples on day 3 were collected before commencement of treatment.
Adaramoye Oluwatosin et al./Asian Pacific Journal of Tropical Medicine (2014)97-104 101
berghei-induced decrease in PCV at days 6 and 7 post-
infection, respectively (Table 3). P. berghei infection also
caused significant (P<0.05) increase in the activity of serum
alanine aminotransferase (ALT) in the mice. Importantly, the
serum ALT of untreated, infected mice increased by 107%,
relative to normal, while treatment with CQ and KV reversed
the P. berghei-induced alterations in the activity of ALT.
There were no significant differences (P>0.05) in the levels
of serum urea, total bilirubin and activity of serum AST of P.
berghei infected mice when compared to others (Table 4).
Table 4
Effect of KV and CQ on serum biochemical indices of P. berghei
-infected mice.
Treatment AST (IU/L) ALT (IU/L) Urea
(mol/L)
Total bilirubin
Normal 39.0 6.8 29.6 5.9*11.8 2.1 2.59 0.17
Normal + KV1 38.5 8.0 30.4 7.2*12.0 1.9 2.83 0.20
Normal + CQ 39.4 6.3 32.8 6.4* 10.6 2.0 3.01 0.28
Infected only 36.7 8.1 61.3 8.1 12.7 2.8 2.76 0.35
Infected + CQ 38.3 7.5 33.0 6.1*11.0 2.3 2.38 0.31
Infected + KV1 40.2 9.3 34.4 7.4*13.0 2.1 2.73 0.19
Infected + KV2 38.9 9.6 32.8 6.8*10.8 2.6 2.58 0.26
Values are given as mean SD (n=5). * Significantly different from
infected only (P<0.05); KV1= Kolaviron at a dose of 100mg/kg, KV2=
Kolaviron at a dose of 200 mg/kg,
3.3. Effects of KV and CQ on the antioxidant profiles of P.
berghei infected mice
A significant (P<0.05) increase in MDA levels (lipid
peroxidation index) was observed in P. berghei infected
mice as parasitemia increased. Precisely, serum and hepatic
MDA levels were increased by 93% and 78%, respectively in
infected mice when compared to normal. Administration of
KV alone significantly (P<0.05) decreased the MDA values of
the untreated, infected mice (Figure 2). P. berghei infection
caused a significant (P<0.05) decrease in the levels of red
cell and hepatic GSH as well as the activities of SOD, CAT,
GPx and GST of untreated infected mice relative to normal
(Table 5, Figures 3 and 4). However, treatment with KV alone
completely attenuated P. berghei-induced decrease in the
GSH levels (Table 5), while administration of CQ and KV
significantly (P<0.05) ameliorated the activities of hepatic
CAT, GST and GPx of the infected mice (Figures 3 and 4).
45
40
35
30
25
20
15
10
5
0
LPO (nmol/mg protein)
Serum LPO
Hepatic LPO
Normal Normal+KV1 Normal+CQ Infected only Infected+CQ Infected+KV1 Infected+KV2
Treatemnt
Figure 2. Effects of KV and CQ on levels of serum and hepatic LPO in
P. berghei-infected mice.
* Significantly different from infected only (P<0.05).
12
10
8
6
4
2
0
U/mg protein
Hepatic SOD
Hepatic CAT
Normal Normal+KV1 Normal+CQ Infected only Infected+CQ Infected+KV1 Infected+KV2
Treatemnt
Figure 3. Effects of KV and CQ on activities of hepatic SOD and CAT
in P. berghei-infected mice.
* Significantly different from infected only (P<0.05).
Table 5
Effect of KV and CQ on enzymic and non-enzymic antioxidant profiles of P. berghei-infected mice.
Treatment Red cell Hepatic GSH (g/g tissue)
GSH (g/mL) SOD (U/mg protein) CAT (U/mg protein) GST (U/mg protein) GPx (U/mg protein)
Normal 0.680.04 1.230.15 0.720.05 0.880.06 0.630.05 1.100.15
Normal + KV1 0.610.05 1.120.15 0.680.04 0.910.05 0.660.03 0.960.10
Normal + CQ 0.590.06 1.250.17 0.700.04 0.830.07 0.540.07 0.920.08
Infected only 0.330.04* 0.710.06* 0.480.05* 0.360.04*0.280.04* 0.630.07*
Infected + CQ 0.380.05* 0.730.04*0.670.03 0.430.06* 0.310.05* 0.710.05*
Infected + KV1 0.560.03 0.980.15 0.650.05 0.790.04 0.570.03 0.900.04
Infected + KV2 0.540.06 1.130.11 0.690.04 0.840.06 0.620.06 0.950.07
Values are given as meanSD (n=5); * Significantly different from normal (P<0.05); KV1= Kolaviron at a dose of 100 mg/kg, KV2= Kolaviron at a
dose of 200 mg/kg,
Adaramoye Oluwatosin et al./Asian Pacific Journal of Tropical Medicine (2014)97-104
102
45
40
35
30
25
20
15
10
5
0
U/mg protein
Hepatic GST
Hepatic GPx
Normal Normal+KV1 Normal+CQ Infected only Infected+CQ Infected+KV1 Infected+KV2
Treatemnt
Figure 4. Effects of KV and CQ on activities of GST and GPx in P.
berghei-infected mice.
* Significantly different from infected only (P<0.05).
4. Discussion
The spread of resistance in the malaria parasite to safe,
affordable and commonly available antimalarial drugs
especially the monotherapeutic drugs such as chloroquine
and sulfadoxine-pyrimethamine[37], is a major problem in
malaria chemotherapy especially in resource poor endemic
areas. The emergence of resistance to the artemisinins
which form the backbone of the currently efficacious
artemisinin-based combination therapy in Cambodia[38]
and Myanmar[39] underscore the need to discover and
develop new antimalarial drugs. The present study has not
only validated the antiplasmodic activity of KV but has
also demonstrated its inherent antioxidant properties. In
this study, KV suppressed the growth of the established P.
bergei parasites by 93%, against 85% obtained in CQ-treated
group at day 10. This suggests that the antimalarial efficacy
of KV against P. berghei is better than CQ. The biflavonoid
did not clear the parasites completely, but it exhibited
a marked and significant reduction in multiplication of
parasites during treatment, indicating that KV may have
a direct action on the parasites. It has been reported
that several plant constituents, viz; flavonoids, tannins,
quinonoid, xanthene, polyphenols, and terpenoids possess
protein-binding and enzyme-inhibiting properties[40,41].
The likely mechanism of action of this biflavonoid may be
the inhibition of key pathogenic enzymes of the parasite
since KV is known to interfere with enzyme systems[42,43].
Anaemia is a consistent feature of Plasmodium infections[44]
caused by, among other factors, increased lipid peroxidation
as a consequence of oxidative damage to the membrane
components of erythrocytes[45]. It was observed that in
addition to the suppression of parasitemia, KV prevented a
drastic reduction in PCV values in infected mice showing
its ability to ameliorate anaemia. The amelioration of the P.
berghei induced anaemia by KV may be attributable to its
scavenging effects towards the generated ROS and thereby
reducing the oxidative attack to which the erythrocytes
membranes are exposed in the infected mice. The reduction
in anaemia was consistent with the marked decrease in
parasite load observed in the course of infection in the
groups of mice treated with 100- and 200- mg/kg doses
of the biflavonoid. This may be a subtle evidence of the
efficacy of the antimalarial effect of KV as red blood cell
lysis tends to be more severe with sustained parasitemia.
The role of oxidative stress as an important clinical and
biochemical mechanism of the disease pathogenesis is
increasingly becoming relevant[46,47]. It results from the
high metabolic rate of the rapidly growing and multiplying
parasite which produces large quantities of toxic redox
active by-products. The observed elevation in MDA values
of infected mice in this study is in concordance with the
findings of Rodrigues and Gamboa[48] and Okeola et al[7].
Increased MDA implies increase in reactive oxygen species
(ROS) levels, which are cellular renegades, and can wreak
havoc in biological systems by tissue damage, altering
biochemical compounds, corroding cell membranes and
killing out rightly[49]. This claim was further supported by
decrease in red cell and hepatic activities of SOD, CAT, GPx,
GST and levels of GSH in the infected mice, which indicate
that excess ROS probably inactivate these antioxidant
enzymes. This observation is in line with the findings of
Ibrahim et al[50], who linked the reduced activities of SOD
and CAT in P. berghei infection to excessive generation of
ROS. However, administration of KV increased the activities
of the antioxidant enzymes. It would appear therefore that
the biflavonoid kept the levels of ROS low thereby reducing
the extent of P. berghei-induced lipid peroxidation and/
or increase the levels of substrate (GSH) required for
detoxification by GPx and GST. The in vivo antioxidant
effects of KV led to the restoration of antioxidant status of
infected mice and, this would obviously provide greater
protection for cell membrane components as well as other
susceptible cellular components and hence significantly
retarding the P. berghei associated organ pathological
effects. P. berghei infection has been reported to cause
hepatomegaly and splenomegaly in the mice model[51] and
was linked to increased phagocytosis of infected cells by
macrophages and deposition of malarial pigment as well
as activation and hyperplasia of the reticulo-endothelial
system during the disease[52]. In this study, elevated levels of
serum ALT was observed in infected mice. The ability of KV
to reverse the serum ALT values in this study, could suggest
that KV may be protective against P. berghei induced
Adaramoye Oluwatosin et al./Asian Pacific Journal of Tropical Medicine (2014)97-104 103
hepatomegaly in the mice.
In conclusion, kolaviron, a biflavonoid from Garcinia kola
seeds, elicited potent antimalarial activity in P. berghei
infected mice. In addition, kolaviron at the administered
doses ameliorated the parasite-induced anaemia and body
weight alterations, possibly through interfering with lipid
peroxidation process as well as sparing endogenous primary
antioxidant enzymes reserves.
Conflict of interest statement
We declare that we have no conflict of interest.
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... Kolaviron, an established biflavonoid extracted from the seed of Garcinia kola, has displayed therapeutic effects on diverse disease conditions [17][18][19][20][21]. ...
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... Furthermore, several researchers have demonstrated through in vivo and in vitro studies that G. kola has numerous pharmacological activities such as anti-inflammatory (Popoola et al. 2016), antioxidant (Ishola et al. 2017, Oyagbemi et al. 2017, antimalarial (Oluwatosin et al. 2014); anti-asthmatic (Ibulubo et al. 2012), antiarthritis, anti-ulcer, anti-hypertensive, anti-microbial (Hioki et al. 2020, Djague et al. 2020, anti-viral, anti-diabetic (Adedara et al. 2015, Idris et al. 2020, and hepatoprotective (Badmus et al. 2014), neuroprotective (Olatunji et al. 2020), and cardioprotective (Oyagbemi et al. 2018a). ...
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... These results were consistent with previous studies (Ahmed and Hassan 2007;Mahran et al. 2020). SOD, CAT, and GSH act as supportive antioxidant enzymes that defend against ROS, and the reduction in their activities maybe because of exhaustion in counteracting the free radicals generated by the parasites (Oluwatosin et al. 2014;Surai 2018). ...
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... Garcinia kola (GK), an important seed used as snack in many parts of Africa (Atawodi et al., 1995;Hutchinson and Dalziel, 1956) has been demonstrated to be a principal source of nutritional polyphenols able to induce beneficial effects, reducing the risk of cardiovascular diseases (Adaramoye et al., 2005;Ajani et al., 2008), cancer (Oyagbemi et al., 2015) diabetes (Adaramoye and Adeyemi, 2006) and malaria (Adaramoye et al., 2014). Moreover, GK has attracted research consideration owing to its anti-inflammatory Onasanwo and Rotu, 2016) analgesic (Olaleye et al., 2000), immunomodulatory (Awogbindin et al., 2015), antioxidant (Okoko, 2009), antiproliferative (Oyagbemi et al., 2015), antimicrobial (Hussain et al., 1982) and apoptosis modulation effects (Oyagbemi et al., 2018). ...
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... The main compound in G. kola seeds (biflavonoid GB1) has been found to exhibit antiplasmodial activity with an IC 50 value of 1-10 M [19]. GB1 together with GB2 and Kolaflavanone in the biflavonoid mixture called kolaviron are described to exhibit high antimalarial activities in P. berghei-infected mice [20]. ...
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... The work of Adaramoye et al. (2014) recorded that kolaviron, a biflavonoid from G. kola seeds has high antimalarial activities against P. berghei another parasite that causes malaria, when they tested the efficacy of the kolaviron on mice. That same study also witnessed an improvement in the packed cell volume of the groups treated with kolaviron and chloroquine which was statistically significant (p<0.05). ...
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The antimalarial and antioxidant activities of methanolic extract of Nigella sativa seeds (MENS) were investigated against established malaria infection in vivo using Swiss albino mice. The antimalarial activity of the extract against Plasmodium yoelli nigeriensis (P. yoelli) was assessed using the Rane test procedure. Chloroquine (CQ)-treated group served as positive control. The extract, at a dose of 1.25 g/kg body weight significantly (p<0.05) suppressed P. yoelli infection in the mice by 94%, while CQ, the reference drug, produced 86% suppression when compared to the untreated group after the fifth day of treatment. P. yoelli infection caused a significant (p<0.05) increase in the levels of red cell and hepatic malondialdehyde (MDA), an index of lipid peroxidation (LPO) in the mice. Serum and hepatic LPO levels were increased by 71% and 113%, respectively, in the untreated infected mice. Furthermore, P. yoelli infection caused a significant (p<0.05) decrease in the activities of superoxide dismutase, catalase, glutathione-S-transferase and the level of reduced glutathione in tissues of the mice. Treatment with MENS significantly (p<0.05) attenuated the serum and hepatic MDA levels in P. yoelli-infected mice. In addition, MENS restored the activities of red cell antioxidant enzymes in the infected mice to near normal. Moreover, MENS was found to be more effective than CQ in parasite clearance and, in the restoration of altered biochemical indices by P. yoelli infection. These results suggest that N. sativa seeds have strong antioxidant property and, may be a good phytotherapeutic agent against Plasmodium infection in malaria.
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Three groups of mice viz: well fed mice, vitamin deficient mice and vitamin deficient Plasmodium berghei infected mice were studied. In these groups of mice, the weights of the liver and spleen were determined using a weighing balance and the levels of circulating immune complexes (CICS) measured spectrophotometrically using polyethylene glycol precipitation method. The mean spleen weight, liver weight and CICs of vitamin deficient mice or vitamin deficient P. berghei infected mice were reduced compared with those of well-fed mice. However, the reduction in spleen weight was significant in vitamin deficient mice from day 15-post vitamin deficiency compared with well-fed mice. Also, the reduction in liver weight was significant in vitamin deficient mice at day 5- and day 10-post vitamin deficiency compared with well-fed mice while the reduction in liver weight was significant in vitamin deficient P. berghei infected mice at day 5-, day 10-, day 15- and day 20- post P. berghei infection compared with well-fed mice. The reductions in the levels of CICs were significant in both vitamin deficient mice and vitamin deficient P. berghei infected mice compared with well-fed mice from day 5-post P. berghei infection or day 5-post vitamin deficiency. The observed decreased CICs in vitamin deficient mice accompanied by reduction in liver and spleen weights showed that vitamin is essential in mounting effective immune response against malaria. Afr. J. Clin. Exper. Microbiol. 2005; 6(2): 95-99