




































_____________________________________________________________________________________________________ 
 
*Corresponding author: E-mail: elizabeth.finbarrs-bello@esut.edu.ng; 
 
 
 

Asian Journal of Immunology 
 
3(1): 77-83, 2020; Article no.AJI.55832 
 

 
 

 

 

Evaluation of Hematological and Histopathological 
Effects of Dennettia tripetala Fruit Extract on 

Isoniazid-Induced Seizure in Wistar Rats 
 

Finbarrs-Bello E.1*, Odo C. E.1 and Ojuolape S. G.1,2 
 

1
Department of Anatomy, Faculty of Basic Medical Sciences, Enugu State University of Science and 

Technology, Parklane, Enugu State, Nigeria. 
2
Department of Anatomy, Kampala International University, Western Campus, Ishaka-Bushenyi, 

Uganda. 
 

Authors’ contributions 
 

This work was carried out in collaboration among all authors. Author FBE gave the concept, designed 
the study and did the acquisition of data. Author OCE analyzed and interpreted the data. Author OSG 
drafted the manuscript. All authors critical revised the manuscript for important intellectual content. All 

authors read and approved the final manuscript. 
 

Article Information 
 

Editor(s): 
(1) Dr. Jaffu Othniel Chilongola, Tumaini University, Tanzania. 

Reviewers: 
(1) S. Danish Kadir, University of Pharmacy, Bangladesh. 

(2) Atiq-ur-Rehman, The University of Lahore, Pakistan. 
Complete Peer review History: http://www.sdiarticle4.com/review-history/55832 

 
 
 
 

Received 27 January 2020 
Accepted 02 April 2020 
Published 07 April 2020 

 
 

ABSTRACT 
 

Seizure is one of the neurological and episodic clinical challenges and, one underutilized option for 
medication-resistant in seizure is the use of medicinal plants. Dennettia tripetala has been found to 
possess anti-seizure effects. This study estimates the hematological parameters and examines the 
histopathological effect of ethanolic extract of Dennettia tripetala fruit on Isonaizid-induced seizure 
on the temporal lobe. Twenty-four (24) adult Wistar rats were randomized into six groups (1-6) of 
four rats each (n=4). The positive and negative control groups (group 1 and 2) received Isoniazid 
300 mg/kg, i.p (inducing agent) and 1 ml, i.p normal saline (vehicle); while the rats in groups 3, 4, 5 
and 6 were induced with 300 mg/kg of Isoniazid and treated with 250 mg/kg, 500 mg/kg and 750 
mg/kg of the extract and 50 mg/kg of sodium valproate, o.p respectively. In the hematological 
study, the blood parameters RBC, PCV and HB decreased, while WBC remained normal and 
decrease eosinophils count was noted. Histopathological changes observed in the untreated 
seizure induced (positive control) group presented atrophied neurons, shrunken neurons, 

Original Research Article 



 
 
 
 

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78 

 

coagulative necrosis and microcystic spaces. The extract treated groups exhibited dose dependent 
reduction in the above histopathological features as well as the sodium valproate standard drug 
group. This implies that, Dennettia tripettala fruit extract at high dose exerts hematotoxic effect, 
while neuroprotective effect was observed at low dose. In conclusion, it is safe and effective at low 
dosage. 
 

 

Keywords: Dennettia tripettala; seizure; isoniazid; atrophy; hematotoxocity; neuroprotective. 
 

ABBREVIATIONS 
 

GABA: Gamma Amino-Butyric Acid; PCV: Packed Cell Volume; HB: Hemoglobin Concentration; 
WBC: White Blood Cell; D.P.X: Dibutylphthalate Polystyrene Xylene. 
 

1. INTRODUCTION 
 

Seizure is one of the most common neurological 
conditions in the world [1]. It has an estimated 
neuro-epidemiological index of at least 65 million 
people worldwide living with seizures with large 
proportion of sufferers’ resident within the 
developing countries [2]. Its recognizable feature 
is an excessive neuronal activity in the cortical 
areas of the brain such as the frontal and 
temporal lobes [3]. The etiology/pathogenesis is 
traceable to several factors including: Brain 
damage (traumatic brain injury, stroke, brain 
tumors), infections scarring (gliosis), hypoxia, 
severe hypoglycemia, very high fever and 
abnormal electrical activity in the brain [4]. 
Sometimes, it could be initiated by drug related 
adverse reaction or overdose, in the case with 
Isoniazid [5]. Primarily, there is loss of gamma 
amino-butyric acid (GABA) mediated inhibitory 
interneurons and increased hyper excitability of 
the neurons leading to recurrent seizure 
episodes [5,6]. 
 
Isoniazid is one of the most commonly 
prescribed tuberculosis chemotherapy regimens 
[7]. Isoniazid overdose is known to causes 
recurrent seizures, profound metabolic acidosis, 
coma and even death [7]. The Isoniazid-induced 
seizure represents a pathophysiological state of 
decrease availability of gamma aminobutyric acid 
(inhibitory neurotransmitter) and increase the 
level of glutamate (excitatory neurotransmitter) in 
the affected brain areas [8]. This dysfunctional 
milieu disrupts the glutamate and gamma 
aminobutyric acid balance which consequently 
leads to excessive excitatory signals in the brain 
and altered brain electroencephalography wave 
patterns [9]. 
 
Conventional anticonvulsants are the typical 
pharmacotherapy used for seizure which target 
different membrane channels, receptors and 
neurotransmitters in the brain. Sodium valproate 

as an anticonvulsant, acts via the voltage 
dependent sodium channels blockage and 
inhibition of gamma-aminobutyric acid 
transaminase with increases brain levels of 
GABA [10]. The increase in the turnover of 
gamma-aminobutyric acid (GABA) potentiates a 
GABAergic function which is able to be in control 
of seizure generation and propagation [11]. But, 
the refractory rate of sodium valproate is high, 
coupled to incidence of side effect and 
inadequate of curative potential. 
 
Pepper fruit botanically known as Dennettia 
tripetala of family annonaceae, is known with 
local names as: ako in Edo, opipi in Idoma, 
nkarika in Ibibio, mmimi in Igbo and ata igbere in 
Yoruba language. D. tripetala is a well-known 
medicinal in the southern parts of Nigeria and 
consumed due to the spicy taste of the fruit and 
leaf [5,12]. Phytochemical screening of the 
ethanolic extract showed the presences of 
tannins, alkaloids, steroids, flavonoids, cardiac 
glycosides, saponins, and terpenoids. It also 
contains antioxidant vitamins C and E, as well as 
the B group of vitamins B1, B6, B9 and B12 
[5,13], which provides a scientific basis for the 
use of D. tripetala in traditional medicine. 
Previous studies also documented its hypnotic, 
anticonvulsant, and anxiolytic effects in mice and 
rats [5,14]. 
 
Most synthetic anticonvulsants including sodium 
valproate had been found to have adverse 
effects on the on the targeted organs. 
Furthermore, about 30% of patients with epilepsy 
have seizures that do not react adequately to 
conventional antiepileptic drugs [11]. These 
restrictions with conventional antiepileptic drugs 
showcases the need to seek new drugs that 
could be more efficacious as the action of 
conventional antiepileptic drugs, with less side 
effects so as to achieve a better treatment 
outcome for seizures. This therefore calls the 
need to seek for an effective herbal medicine for 



 
 
 
 

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79 

 

seizure that can possibly offer the required 
opportunities for the isolation of important 
compounds which can be used in the 
development of better, affordable and well 
tolerated antiepileptic drugs. Thus, the 
ineffectiveness of these synthetic drugs, along 
with their serious side effects makes any safe 
and effective herbal medicine an attractive 
possibility. Therefore, this work investigates the 
effect of the ethanolic extract of D. tripetala fruits 
on the isoniazid induced seizure on the 
hematological parameters and temporal lobe 
histology. It showcases the comparative 
therapeutic potentials of D. tripetala extract and 
sodium valproate. This knowledge can be used 
by pharmaceutical industries to produce cheaper 
and less toxic drug for the populace or serve as 
an alternative for seizure therapy. 
 

 
 

Dennettia tripetala fruits 
 

2. MATERIALS AND METHODS 
 

2.1 Plant Collection, Identification and 
Preparation 

 
Fresh samples of D. tripetala fruit were harvested 
from farmlands, in Igbo-Eze-South local 
Government Area of Enugu State Nigeria. The 
fruits were identification and authentication by 
plant curator in the Department of Plant Science 
and Biotechnology of the University Nigeria 
Nsukka. The fruits were selected of impurities, 
washed and air dried for 7 days. The dried fruits 
were pulverized into powdered form; 863.54 g of 
the powder was soaked in 2.2 litre of 90% 
ethanol and allowed to stand for 48 hours with 
intermittent stirring. Thereafter, the mixture was 
filtered with a meshwork and what-man paper No 
1. The filtrate was left in an open space for 
ethanol to evaporate and form paste with 
percentage yield of 4.26%. It was stored in a 
refrigerator at 4°C and constituted to desired 
volume when required. 

2.2 Drugs and Chemicals 
 

Isoniazid (Isonamede India, PubChem ID: 3767) 
was procured from a registered pharmaceutical 
store and the stock solution of INH was prepared 
by dissolving 300mg of the tablets in 10 ml of 
distilled water at room temperature. 
 

2.3 Experimental Animal and Ethical 
Approval 

 

Twenty four (24) wistar rats were obtained from 
the animal house of the Zoology Department of 
University of Nigeria, Nsukka. The rat were 
housed at the animal facility of ESUT College of 
Medicine where the study was conducted, 
acclimatized for two weeks with free access to 
food and water, under light and dark phase of 12 
hours within 24 hours at a room temperature 
during the period of the experiment [15]. 
Thereafter, the rats were randomized into six 
groups of four (4) rats’ per-cage. 
 

2.4 Experimental Design 
 

Group 1 (Positive control): 300 mg/kg of 
Isoniazid (single dose, i.p). 
 

Group 2 (Negative control): 0.1 ml normal 
saline (vehicle, i.p). 
 

Group 3 (Low dose treatment): 300 mg/kg of 
Isoniazid (single dose, i.p) and 250 mg/kg of 
extract, p.o. 
 

Group 4 (Medium dose treatment): 300 mg/kg 
of Isoniazid (single dose, i.p) and 500 mg/kg of 
extract, p.o. 
 

Group 5 (High dose treatment): 300 mg/kg of 
Isoniazid (single dose, i.p) and 750 mg/kg of 
extract, p.o.  
 

Group 6 (standard treatment): 300 mg/kg of 
Isoniazid (single dose, i.p) and 50 mg/kg, p.o of 
sodium valproate. 
 

2.5 Haematological Study 
 

The rats were anesthetised by xylazine and 
ketamine (v/v); 2 ml blood samples was collected 
via the retro-orbital vessels from each rat into 
heparinized tubes and immediately used for the 
determination of RBC, PVC, HB, WBC the 
leucocytes differential counts. Total red blood cell 
(RBC) and white blood cell (WBC) counts were 
estimated using the visual method. The 
percentage packed cell volume (PCV) and blood 



 
 
 
 

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80 

 

hemoglobin concentrations (HB) and Luecocytes 
differential counts of all samples were estimated 
as specified the physiology practical manuel for 
ESUT college of medicine. The film were 
evenlycovered with leishmans’ stain and after 2 
minutes by means of a clean pipette an equal 
quantity of water added, mixedand allowed to 
stand for 10 minutes. The mixture was poured off 
and the film was washed in a gentle stream of 
water, dried with filter paper andexamined under 
a high power microscope; the different types of 
white cells (leucocytes) were systematically 
counted and categorized until a total of 100 white 
cells have been counted. 
 

2.6 Histological Studies 
 
The brain tissues were harvested at the end of 
blood sample collection and fixed in 10% neutral 

formal saline for 48 hrs, afterwards the temporal 
lobes were dissected and processed manually 
for paraffin wax embedding, sections of 5 um 
thickness were obtained using the rotary 
microtomy, deparaffinized sections were stained 
using hematoxylin and eosin (Hand E). The 
stained sections were then dried and mounted in 
Dibutylphthalate Polystyrene Xylene (D.P.X), 
micrographed and interpreted. 
 

2.7 Statistical Analysis 
 
Data was analyzed by one way analysis of 
variance (ANOVA) using the Statistical Package 
for Social Sciences (SPSS version 21) for 
windows (SPSS Inc., Chicago, USA). The results 
were presented as mean ± standard deviation 
(SD). Statistical significance was considered at 
P=.05.

 

3. RESULTS 
 

Hematological findings: 
 

Table 1. Effect of ethanolic extract of Dennettia tripetala on RBC, PCV and HB on seizure 
model 

 

Test group RBC count PCV % HB g/dl 

Isoniazid (300 mg/kg) 5.80±0.75 44.50±2.65 14.83±0.88 
Normal saline 5.00±0.82 39.75±5.56 13.25±1.86 
250 mg/kg extract &300 mg/kg Isoniazid 4.64±0.56

* 
38.25±5.06 12.53±1.82 

500 mg/Kg Extract& 300 mg/kg Isoniazid 4.39±0.47
 

36.75±4.11
* 

11.95±1.45
* 

750 mg/kg Extract& 300 mg/kg Isoniazid 6.00±0.00 50.00±0.00 16.70±0.00 
50 mg/kg Sodium Valproate & 300 mg/kg Isoniazid 2.00±0.14 47.25±2.06 16.07±0.70 

Key: *P=.05, when compared with group 1. a P=.05RBC counts showed statistically significant decrease in group 
3(P=.05),  non-significant decrease were also observed in groups 3 and 4. PCV and HB also showed a statistical 

significant decrease (P=.05) in group 4 when compared with group 1, while only group 6 showed a significant 
increase in HB (P=.05) when compared with group 2 

 

Table 2. Effect of ethanolic extract of Dennettia tripetala on total WBC and differential counts 
on test groups 

 

Test groups TWBC 
count 

Neutrophils 
% 

Lymphocytes 
% 

Monocytes 
% 

Eosinophils 
% 

Basophils 
% 

Isoniazid 
(300 mg/kg) 

6.28±3.96 51.75±7.68 41.75±8.66 3.50±0.58 2.25±0.50 0.75±0.50 

Normal saline 3.23±1.45 58.50±7.51 34.75±8.96 3.75±0.96 2.50±0.58 0.50±0.58 

250 mg/kg extract & 
300 mg/kg isoniazid 

3.33±0.48 48.25±13.72 46.75±12.37 3.75±1.50 1.25±0.50
*
 0.00±0.00 

500 mg/kg extract & 
300 mg/kg Isoniazid 

3.68±0.76 55.25±14.36 41.25±13.94 2.75±0.96 0.75±0.96
*
 0.00±0.00 

750 mg/kg extract & 
300 mg/kg Isoniazid 

4.60±0.00 37.00±0.00 60.00±0.00 3.00±0.00 0.00±0.00 0.00±0.00 

50 mg/kg valproate & 
300 mg/kg Isoniazid 

8.30±0.50 66.00±3.65
 

30.50±5.74 0.25±0.50 0.50±0.58
*
 0.00±0.00 

Key:*(P=.05) No significant effect on the WBC across the groups , for differential leucocytes counts only 
eosinophil count was significantly( P=.05) decreased in groups 3, 4 and 6 which represents the low , medium 

dose of the extract and standard drug the sodium valproate respectively 



 
 
 
 

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Histological Observations: 
 

 
 
Fig. 1. Photomicrograph of temporal lobe (A) positive control (Isoniazid 300 mg/kg) coagulative 

necrosis (white arrow), microcystic space (black arrow), neurons atrophy (green arrow) and 
shrinking neurons (SN). (B) Negative control (1 ml normal saline) normal neuronal cell (black 
arrow). (C) 250 mg/kg of D. tripetala and 300 mg/kg of Isoniazid, few atrophic neurons (white 
arrow) and intracytoplasmic inclusion (black arrow). (D) 500 mg of D. tripetala and Isoniazid 
300 mg/kg, few atrophic neurons (green arrow), intracytoplasmic inclusion (black arrow) and 

shrinking neurons (white arrow).(E) 750 mg/kg and Isoniazid reduced microcystic space (black 
arrow), atrophic neurons (green arrow) and mild shrinking neurons (white arrow). (F) Sodium 

valproate treated large nuclei and basophilic inclusions (black arrow) with few atrophic 
neurons (white arrow). H&E. x400 

 

4. DISCUSSION 
 

Hematological assessment is vital in the 
evaluation of causes, effect of treatments and 
recovery in most illnesses. Thus, the total blood 
parameter testing is carried out on seizure 
patients to access the overall health and identify 
their likely conditions such as; infections and 
anemia that might trigger seizure, and to monitor 
the possible occurrence of medication-induced 
side effects [16]. In this study, we evaluated the 
hematologic parameters and found that the RBC 
counts was significantly decreased in the low 
extract group (p<0.05), following the seizure 
induction by Isoniazid, while the diseased 
observed in the rest groups was insignificant. In 
a similar study, Daniel and Clement [17] earlier 
reported decrease in RBC counts with the D. 
tripetala fruit in the absence of seizure in rats. 

The role of the extract on the RBC is primarily 
due to the presence of certain phytochemical 
constituent like alkaloids. Although, secondary 
effect of direct bone marrow suppression might 
also be attributed to the effect on RBC count in 
the case of sodium valproate, For example, the 
aplastic anemia and pheripheral cytopenia could 
explain the characterised hematologic toxicity 
associated with sodium valproate [18,19]. 
 
Conversely, PCV and blood HB counts showed 
insignificant decreases in the treated model 
(Table 1). A direct modulatory relationship exists 
between RBC, PCV and HB concentration 
physiologically, therefore, an alteration in one 
parameter alternately impact another. Hence, the 
importance of evaluating blood parameters while 
on certain medications such as herbal and 
anticonvulsants. Hematotoxic effect has also 

A 
B 

D E 



 
 
 
 

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82 

 

been reported on Isoniazid overdose which might 
have interplayed to cause further disease in the 
treatment groups. 
 
The lack of statistical evidence on the effect of 
the total white blood count possesses a question 
of whether this suggests that the extract 
exhibited a protective effect or the harmful effect 
of Isoniazid. This is not likely the case with 
sodium valproate which has been shown to 
suppress leucocytosis, induce thrombocytopenia 
and agranulocytosis [18]. Sodium valproate 
group showed a significant increase compared 
with negative control (Table 2), This may be a 
representation of a normal physiological 
response of the body which triggers the migration 
of WBC to defend the RBC against hemolysis, 
Eosinophil counts decreased in the in sodium 
valproate, the low and medium dose of the 
extract. This effect might be attributed to the 
phytochemical components of the extracts and 
the valproate could be related to its effect on the 
hematopoietic stem cells. 
 
Consistently, loss of neurons has been a 
histopathological feature associated with focal 
temporal seizure particularly in humans [20]. The 
positive control or non treated seizure group (Fig. 
1a) revealed characteristic features of the 
neuronal degenerative changes: atrophied and 
shrunken neurons, coagulative necrosis and 
microcystic spaces. These can be attributed to 
the acute neurotoxic effect of the high dose of 
Isoniazid (INH). The atrophied neurons observed 
in the non treated seizure group were reduced 
following extract treatments with varying doses. 
Thus, the extract exhibited dose dependant 
effect, its low to medium dosages displayed 
potent property while the high dose could be 
toxic. In this regards, only the low and medium 
dose of the extract could be comparable to 
sodium valproate treatment. This implies the 
extract exerts similar activity as the standard 
drug sodium valproate by providing some 
measures of neuroprotective effects on the 
temporal lobe histology. Furthermore, Isoniazid 
toxicity is refractory to anticonvulsant and 
responsive to treatment with high dose of 
pyridoxine (vitamin B6) as demonstrated in our 
previous studies on the anticonvulsant effect of 
this extract [5]. However, the study is a pointer to 
the fact that D. tripetala fruit extract has 
promising potential in the search for an entity 
with anti-seizure activity but this might require 
further studies on the fractionated components or 
the isolated compound. 
 

5. CONCLUSION  
 
The D. tripetala extract has dose dependant 
effects on the seizure model (both 
hematologically and histologically) of the 
temporal lobe compare to sodium valproate. 
 

CONSENT 
 
It is not applicable. 
 

ETHICAL APPROVAL 
 
The study protocol was reviewed and approved 
by the ESUCOM animal research committee. 
Animals were cared for in accordance with the 
institutional and international guidelines. 
 

ACKNOWLEDGEMENT 
 
The authors would like to thank the staff of the 
physiology and histology laboratories for the 
technical assistance. 
 

COMPETING INTERESTS 
 
Authors have declared that no competing 
interests exist. 
 

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