Hematological and Biochemical parameters study of female albino rats treated with lamotrigine drug

Abstract

The present study was aimed to investigate the possible effects of the anti-epileptic drug lamotrigine (LTG) on some haematological and biochemical parameters in adult female rats. Forty-eight female rats were divided into three groups (each group=16). Group one can be considered as a control group, group two and three administrated lamotrigine drugs orally at a dose of 3.57mg/kg body weight and 7.14mg/kg body weight for 7,14,21,28 day and all groups fed with standard rat feed. The results showed that there were significant (P≤0.05) changes in haematological parameters in group two and three when compared with the control group during all period except the mean level of corpuscular haemoglobin concentration (MCHC). The liver enzyme aspartate transaminase (AST) and alanine transaminase (ALT) and serum urea, creatinine with calcium, potassium, sodium and chloride ion showed significant alteration in the treated group, the relative organ weight showed significant changes in group two and three in comparison with control group during 7,14,21 and 28 days. Estradiol level in group three increased at 7, 14 and 21 day and decreased at 28 days of treatment when compared with group two and the control group. This study suggested that treatment of healthy female albino rats with therapeutic doses of lamotrigine drug for 28 days generally affect on included parameters in this study.

Full text

Tikrit Journal of Pure Science Vol. 24 (3) 2019
23
Tikrit Journal of Pure Science
ISSN: 1813 – 1662 (Print) --- E-ISSN: 2415 – 1726 (Online)
Journal Homepage: http://tjps.tu.edu.iq/index.php/j
Hematological and Biochemical parameters study of female albino rats
treated with lamotrigine drug
Gawhar Ahmed Shekha , Kalthum Asaaf Maulood
Department of Biology, College of Education, Salahaddin University , Hawler , Kurdistan region , Iraq
https://doi.org/10.25130/tjps.v24i3.365
A r t i c l e i n f o.
Article history:
-Received: 18 / 10 / 2018
-Accepted: 26 / 12 / 2018
-Available online: / / 2019
Keywords: Lamotrigine,
Hematological, Biochemical change,
Estradiol, Female Rat.
Corresponding Author:
Name: Kalthum Asaaf Maulood
E-mail: Kalthuma5@gmail.com
Tel:
ABSTRACT
The present study was aimed to investigate the possible effects of the
anti-epileptic drug lamotrigine (LTG) on some haematological and
biochemical parameters in adult female rats. Forty-eight female rats were
divided into three groups (each group=16). Group one can be considered
as a control group, group two and three administrated lamotrigine drugs
orally at a dose of 3.57mg/kg body weight and 7.14mg/kg body weight
for 7,14,21,28 day and all groups fed with standard rat feed. The results
showed that there were significant (P≤0.05) changes in haematological
parameters in group two and three when compared with the control group
during all period except the mean level of corpuscular haemoglobin
concentration (MCHC). The liver enzyme aspartate transaminase (AST)
and alanine transaminase (ALT) and serum urea, creatinine with calcium,
potassium, sodium and chloride ion showed significant alteration in the
treated group, the relative organ weight showed significant changes in
group two and three in comparison with control group during 7,14,21
and 28 days. Estradiol level in group three increased at 7,14 and 21 day
and decreased at 28 days of treatment when compared with group two
and the control group. This study suggested that treatment of healthy
female albino rats with therapeutic doses of lamotrigine drug for 28 days
generally affect on included parameters in this study.
1. Introduction
Numerous non-epileptic central nervous system
disturbances were treated with Antiepileptic drugs
(AEDs), in both psychiatry and neurology[1]. AEDs
have many mechanisms of action, which comprise
modification of c-aminobutyric acid and
glutamatergic neurotransmission, and changes of
voltage-gated ion channels or intracellular signaling
route. These mechanisms of action may describe the
efficiency of AEDs in the treatment of epilepsy,
bipolar disturbance and neuropathic ache [2].
Lamotrigine consist of 6- (2,3- dichlorophenyl)-1,2,4-
triazine 3,5-diamine C9H7Cl2N5 is a new
antiepileptic drug derived from pyrimethamine,
which differs from ordinarily available AEDs. It has
an effective role in treating both partial and
generalized seizure [3].
Lamotrigine effort its antiepileptic activity by
blocking the release of excitatory neurotransmitters,
especially glutamate and aspartate in the central
nervous system [4]. LTG considered as the second
generation of anti-epileptic drug (AED) that has been
widely used for partial and generalized seizures in
adults and children if it's used as monotherapy or in
combination with other AEDs [5]. In addition,
because of its safety feature, it has been recognized as
a first line drug for the treatment of women during
pregnancy and childbearing age [6]. LTG display first
request linear pharmacokinetics following oral
administration, it is rapidly and completely absorbed
into the circulatory system with an extreme
concentration in plasma after 1–3 hours [7]. Hepatic
metabolism is the main path of lamotrigine
elimination, unchanged LTG excreted by renal
system accounts for less than 10% [8].
In most countries, women constitute the broadly of
users of these new AEDs [9]. In a study, mice treated
with lamotrigine 6 and 12 mg/kg-1 bm for 21 days
showed that a significant increase in total white blood
cell count [10]. Healthy rats treated with lamotrigine
for different periods noted a significant increase in
blood parameters when compared with the control
group [11]. There were no significant changes in
hematological parameters among healthy males
treated with 50mg lamotrigine [12] Milosheska et.al.

Tikrit Journal of Pure Science Vol. 24 (3) 2019
24
2016 [13] showed non-significant differences in
serum AST and ALT in patients treated with
lamotrigine at dose 50mg/day. After long-term
treatment with lamotrigine in male and female rats,
no changes were demonstrated in liver, kidney and
brain weight [14]. Lamotrigine does not alter the
serum concentrations of estradiol when used with
another ant-epileptic drug in healthy female [15].
This study aimed to quest the effect of two doses of
lamotrigine drug on some haematological,
biochemical, ions, estradiol level of a female albino
rat for different periods.
2. Materials and Methods
2.1. Drug
Lamotrigine drug was used in the present work which
manufactured by ELEA neuroscience Company,
Argentina, obtained from a local market (pharmacy)
in Hawler province-Iraq. The applied therapeutic
dose was 3.57mg/kg bw and 7.14mg/kg bw. The
applied doses were orally administrated by gavage
once daily for 7, 14, 21 and 28 days. Determination
of drug doses were depended on the animal’s body
weight [16].
2.2. Animals
Forty-eight healthy adult female albino rats of Wistar
strain, Sprague-Dawley, weighing between 125-
175gm. Obtained from the animal house in the
Department of Biology, College of Education,
University of Salahaddin-Erbil were used. The rats
were housed in plastic cages under a standard
condition at 22±2 oC temperature with, 12:12
light/dark cycle during the experimental period. They
were fed with pellet diet and tap water ad libitum at
least for 7 days before the experiment. Animals were
divided into 3 experimental groups of 16 rats per
group. The 3.57mg/kg bw and 7.14mg/kg bw dose of
LTG administrated orally by gavage to each treated
animals every morning once daily for 7,14,21,28 days
according to animal body weight, while the control
group administrated with 1 ml water for 7, 14, 21, 28
days.
Blood collection
Blood was collected from each animal through
cardiac puncture and collected into sterilized EDTA
tubes for evaluation of hematological parameters such
as white blood cell (WBC) count, red blood cell
(RBC) count, hemoglobin (Hb) concentration, Packed
cell volume (PCV) level, red blood cell indices (mean
corpuscular hemoglobin (MCH), mean corpuscular
volume (MCV), and mean corpuscular hemoglobin
concentration (MCHC)) and platelet (PLT) count by
using automated hematology analyzer (Japan).
Serum was separated using gel tube and centrifuged
at 3000 rpm for 15 minutes and then stored frozen
until used.
Liver enzymes: Serum used to determine aspartate
transaminase, alanine transaminase using the kits for
each test by Cobas E411.
Kidney function test: Serum used to estimate, urea
and creatinine using the kit for each one.
Ion evaluation: Serum used to evaluate calcium,
potassium, sodium and chloride ion levels
Hormonal Assay: Serum used to determine estradiol
level using ELISA.
Organs Weight: At the end of the treatment, each rat
was sacrificed using ketamine hydrochloride (100mg/
kg bw) the liver, kidney, brain, and lung were
removed, cleaned from adherent tissues and
weighted.
Statistical Analysis: Data was analyzed using
factorial test and Duncan according to the Statistical
Package for Social Science (SPSS) system version
20. The level of significance was accepted under level
probability 0.05. [17]
Results
Treatment of rat with two doses of lamotrigine drug
for 28 days were associated with a significant
decrease in haemoglobin concentration in group 3
(7.14mg/kg bw) in days 7, 21 and 28, in day 14
increased significantly, group2(3.57mg/kg bw)
decreased significantly in days 14 and 28 when
compared with control group. Packed cell volume
level decreased significantly in group3 in days 7, and
28, group 2 decreased significantly in days 14 and 28,
with a nonsignificant decrease in group 2 and 3 in day
21. White blood cell count decreased significantly in
group 3 in days 7 and 21 and increased significantly
in day 28 when compared with group 2 and the
control group. About platelet count, the statistical
analysis showed a significant increase in group 3 in
days 7 and 14, with a non-significant increase in both
groups in day 28 (Table 1).
Table (1): Mean ± S.E. of lamotrigine drug effect on haemoglobin concentration, packed cell volume,
white blood cell count and platelet count of rat treated with 3.57mg, 7.14mg, and control group

Tikrit Journal of Pure Science Vol. 24 (3) 2019
25
for 28 days.
Groups
M±S.E. of Haematological parameters
Hb gm/dl
PCV %
WBC 10 9 /l
Plate109 /l
Treated for 7 days
Control
12.18±0.40ef
30.85±1.93d
10.70±1.08b
624.75±24.16cd
Group2
13.08±0.28edc
35.13±0.63bc
8.80±0.35cb
676.68±9.52bc
Group 3
11.95±0.21f
30.38±1.02d
6.73±0.83d
741±34.66ba
Treated for 14 days
Control
13.50±0.14bc
36.83±0.23b
10.88±0.28b
483.71±11.65e
Group2
12.53±0.42edf
32.85±1.30c
10.43±0.72b
795.32±73.87a
Group3
13.88±0.41bac
37.15±1.15ba
10.83±0.36b
731±12.73ba
Treated for 21 days
Control
14.63±0.08a
39.95±0.22a
10.85±0.52b
643.65±38.83bcd
Group2
14.18±0.17ba
38.13±0.46ba
7.97±0.39cd
735.50±35.72ba
Group3
13.33±0.49bdc
37.63±1.51ba
6.30±0.07d
595.50±27.30cd
treated for 28 days
Control
13.73±0.36bac
37.23±0.83ba
7.25±1.13cd
566±10.09cd
Group2
12.43±0.26edf
31.38±0.34d
13.65±0.43a
573.75±11.21ed
Group3
13.68±0.28bac
36.78±0.39ba
10.85±0.67b
585.13±9.37ed
Means with the same letter are not significantly different
Red blood cell (RBC) count and indices in days 7, 14,
21 and 28 of all experimental group were
demonstrated in the table (2). RBC count in group 2
and 3 decreased significantly in days 21 and 28 and
insignificantly in day 14, and day 7. Group 2
increased significantly while group 3 decreased when
compared with the control group. Both of two groups
showed a significant decrease in the level of mean
corpuscular volume in days 21 and 28 with a
nonsignificant decrease in day 14 and non-significant
alteration in day 7, mean corpuscular haemoglobin
level decreased non-significantly in days 21 and 28,
significant differences in day 14. Mean corpuscular
haemoglobin concentration level increased
significantly in group 2 and 3 in day 28, non-
significant increase in days 7, 14 and 21.
Table (2): Mean ± S.E. of lamotrigine drug effect on red blood cell and RBC indices of rat treated with
3.57mg, 7.14mg, and control group at 28 days of treatment.
Groups
M±S.E. of Haematological parameters
RBC 1012/l
MCV fl
MCH pg
MCHC gm/dl
treated for 7 days
Control
6.05±0.16fe
52.35±0.85dc
20.43±0.59ba
38.17±0.60a
Group2
6.40±0.31dec
56.98±1.29a
20.13±0.49b
38.90±0.84ba
Group3
5.69±0.13f
54.08±1.39bac
20.90±0.27ba
39.18±1.21a
treated for 14 days
Control
6.38±0.19dec
54.78±0.13bac
20.75±0.21ba
36.38±0.23ba
Group2
6.32±0.21de
53.08±1.42c
20.23±0.39b
38.78±0.57a
Group3
6.00±0.11bdec
56.57±1.33bc
21.73±0.61a
38.50±0.56a
treated for 21 days
Control
7.20±0.17a
56.85±0.59a
21.18±0.43ba
36.83±0.17ba
Group2
6.58±0.18bdec
55.40±0.68bac
20.55±0.39ba
37.45±0.34ba
Group3
6.72±0.23bdac
53.58±0.89bc
20.13±0.42b
37.63±0.43ba
treated for 28 days
Control
6.98±0.16bac
55.15±0.81bac
20.45±0.14b
34.23±0.44ba
Group2
6.42±0.12dec
49.68±0.40d
20.28±0.74ba
36.35±3.06b
Group3
6.08±0.14ba
53.50±0.51bc
20.38±0.22ba
38.23±0.34a
Means with the same letter are not significantly different
Table (3) shows that the level of liver enzymes which
include aspartate transaminase (AST) and alanine
transaminase (ALT). AST level in group 2 increased
significantly, while in group 3 decreased significantly
in days 7,14 and 28, and both of them changed non-
significantly in day 21. The significant decrease
observed in the level of ALT in group 3 in days 14
and 21, and non-significantly in days 7and 28. Group
2 decreased non-significantly during all period except
in day 14, serum urea and creatinine level increased
significantly in group 2 and 3 in day 14, while in days
7,21 and 28 the level decreased gradually.
Table (3): Mean ± S.E. of lamotrigine drug effect on serum AST, ALT, urea and creatinine of rat treated
with 3.57mg, 7.14mg, and control group at 28 days of treatment

Tikrit Journal of Pure Science Vol. 24 (3) 2019
26
Groups
M±S.E. of Biochemical parameters
AST U/L
ALT U/L
Urea mg/dl
Creatinine mg/dl
treated for 7 days
Control
191.50±0.65bc
63±1.29a
49.50±1.55a
0.45±0.06b
Group2
211.75±23.05ba
64.25±1.38a
41.75±0.85bc
0.33±0.05c
Group3
147.48±6.28d
61.50±4.11ba
45.23±1.11ba
0.40±0.03cb
treated for 14 days
Control
154.25±1.89dc
63.75±1.93a
29.52±0.96f
0.35±0.03a
Group2
223.71±28.99ba
51.25±2.39dc
38±041edc
0.40±0.04cb
Group3
138.74±4.59d
51.75±2.87dc
43.50±1.44bac
0.42±0.06cb
treated for 21 days
Control
155.50±7.93dc
55.25±1.11bc
34.50±3.97edf
0.40±0.07cb
Group2
159.25±6.49dc
49.72±1.49dc
34.19±3.47edf
0.37±0.08cb
Group3
144.75±9.59d
45.51±5.48d
31.25±3.20ef
0.28±0.01a
treated for 28 days
Control
204.25±12.39ba
64.25±0.48a
38.24±2.81bdc
0.40±0.02cb
Group2
240.50±13.53a
61.22±1.11ba
35.71±1.26bdc
0.33±0.01c
Group3
136.50±9.12d
63.47±0.65a
37±0.41edc
0.36±0.07cb
Means with the same letter are not significantly different
A significant increase of liver weight was observed in
group 3 in days 7 and 21 and non-significantly in
group 2 and 3 in days 14 and 28. Right, and left
kidney weight increased significantly in group 3 in
day 7. Lung weight decreased significantly in group 3
in day 7 while brain weight increased significantly in
group 2 and 3 in days 14 and 28 and non-significantly
in days 7 and 21. (Table 4).
Table (4): Mean ± S.E. of lamotrigine drug effect on the liver, right and left kidney, lung, and brain of rat
treated with 3.57mg, 7.14mg and control group at 28 days of treatment.
Groups
M±S.E. of Organ weight mg
Liver
R. kidney
L. kidney
Lung
Brain
treated for 7 days
Control
5.83±0.22dc
0.62±0.04b
0.52±0.03c
1.57±0.19a
1.70±0.08cbd
Group2
6.87±0.52ba
0.70±0.05ba
0.57±0.02bc
1.30±0.07ba
1.72±0.02cbd
Group3
7.50±0.15a
0.76±.03a
0.69±0.06ba
1.19±0.12b
1.79±0.06cb
treated for 14 days
Control
6.28±0.08bdc
0.72±0.05ba
0.63±0.02bac
1.47±0.01ba
1.48±0.01e
Group2
7.31±0.39ba
0.73±0.02ba
0.67±0.03bac
1.42±0.09ba
1.70±0.02cbd
Group3
7.15±0.33ba
0.75±0.05a
0.72±0.05a
1.47±0.15ba
1.82±0.01b
treated for 21 days
Control
7.08±0.11ba
0.69±0.01ba
0.67±0.02ba
1.49±0.07ba
1.60±0.03cbd
Group2
6.39±0.10bdc
0.62±0.05b
0.58±0.04bc
1.29±0.07ba
1.65±0.03d
Group3
5.52±0.14d
0.61±0.01b
0.58±0.01bc
1.22±0.04b
1.69±0.03cd
treated for 28 days
Control
6.62±0.27bac
0.73±0.05ba
0.66±0.04ba
1.41±0.02ba
1.53±0.03a
Group2
6.99±0.67ba
0.68±0.02ba
0.64±0.05bac
1.38±0.08ba
1.68±0.04cd
Group3
7.23±0.16ba
0.72±0.03ba
0.65±0.04ba
1.40±0.07ba
1.79±0.06cb
Means with the same letter are not significantly different
Effect of lamotrigine on estradiol level observed in
fig. (1). A significant increase was shown in group 2
and 3 in day 7, nonsignificant increase in days 14 and
21 with a significant decrease in day 28 when
compared with the control group.

Tikrit Journal of Pure Science Vol. 24 (3) 2019
27
Figure (1): Effect of lamotrigine on serum estradiol level
after days 7,14,21 and 28 in female rat treated with
3.5mg,7.14mg, and control group.
Figure (2) demonstrated a significant increase in
calcium ion level in group 2 and 3 in days 14 and 21
with non-significant changes in days 7 and 28.
Figure (2): Effect of lamotrigine on serum calcium ion
level after 7, 14, 21 and 28 days in female rat treated
with 3.5mg, 7.14mg and control group.
Potassium ion level increased significantly in group 2
and 3 in day 14 and a significant decrease in day 28
with the nonsignificant change at day 21.fig. (3).
Figure (3): Effect of lamotrigine on serum potassium ion
level after 7, 14, 21 and 28 days in female rat treated
with 3.5mg, 7.14mg, and control group.
According to sodium ion level, there was a
nonsignificant increase in group 2 and 3 in days 14,
21 and 28, a significant decrease in day 7. Fig. (4).
Figure (4): Effect of lamotrigine on serum sodium ion
level after 7, 14, 21 and 28 days in female rat treated
with 3.5mg, 7.14mg, and control group.
Fig. (5) showed chloride ion level in group 2 and 3
which non-significant in days 7,21and 28 and a
significant increase in group3 in day 14.
Figure (5): Effect of lamotrigine on serum chloride ion
level after 7, 14, 21 and 28 days in female rat treated
with 3.5mg, 7.14mg, and control group.
Discussion
Antiepileptic drugs (AEDs) prescribed as typical
treatment and are widely used for not only epilepsy,
bipolar disorder, and chronic pain but also for a
diversity of nonepileptic conditions [18]. One out of
three antiepileptic drugs users used these drugs for
epilepsy [19]. A huge number of AEDs are
obtainable. Since 1990, 16 new or second-generation
AEDs have been recorded, and lamotrigine is one of
them [20]. Lamotrigine after oral administration is
quickly and completely absorbed from the
gastrointestinal tract with Tmax values of 2.2 hours.
Food does not affect the bioavailability of lamotrigine
and the pharmacokinetics are dose relative [21]. By
glucuronidation, N-2 glucuronide is considered as a
major metabolite of Lamotrigine [22].
In healthy volunteers, the elimination half-time is
32.8 hours [21]. The present study showed significant
in hematological parameters especially in hemoglobin
concentration, packed cell volume and white blood
cell count in group 2 and 3 in days 7 and 28, this
result is in agreement with Adeneye et.al. 2006 [23]
who noted that, the blood considered as an
appropriate medium of transport for numerous drugs
in the human body and for that matter components of
red blood cells, white blood cells, haemoglobin, and
platelets are exposed to notable concentrations of
toxic compounds, as damage and demolition of the
blood cells which are harmful to the normal
functioning of the body.
About 1-3 million blood cells (erythrocytes,
leucocytes, and platelets) produced in a healthy adult
and this value could be changed in abnormal
physiological or pathological condition [24]. The
normal ranges of haematological parameters and
blood formation rate were affected by these drugs
which including cytotoxic agents [25]. LTG does not
change the weights of many organs or laboratory
measures such as complete blood count and
biochemical parameters [26].
In healthy volunteers, using lower doses of
lamotrigine (25mg/day) may be hard to measure in
clinical laboratory method; while high doses cause
serious adverse events [12]. Serum AST, ALT, urea,
and creatinine were altered and the value of some of
them were significant and others were not. A

Tikrit Journal of Pure Science Vol. 24 (3) 2019
28
significant increase of liver enzymes ALT & AST
was observed at the end of 21 days of treatment with
lamotrigine in adult male Wistar rats after picrotoxin
treatment -induced convulsions [27]. Many studies
recorded that most antiepileptic drugs could cause
hepatotoxicity, LTG caused a temporary elevation of
liver enzymes without appearing symptoms or signs
of hepatic dysfunction to hepatotoxicity [28].
Serum AST and ALT are good index of liver function
and increasing of these enzymes can be used as
biomarkers to previse the possible toxicity of
lamotrigine drug [29]. These enzymes play an
important role in different metabolic routes [30].
Level of AST and ALT increased significantly in the
group treated with lamotrigine which showed the
lamotrigine effect on liver function and often
suggests the presence of liver problems [31]. While
Fayad and Choueiri,2000 [32] reported that the
discontinuous use of LTG does not affect liver
function and liver enzymes. In spite of using
lamotrigine or any medical does, dietary choline
deficiency and physical exercise may cause elevation
of liver enzymes [33].
Ali et.al.2003 [34] revealed that acute treatment with
any dose of LTG (1.3, 2.6 and 5.2 mg/kg) does not
affect many biochemical parameters, and chronic
treatment (21 days) with all doses of LTG did not
exhibit any hepatotoxic activity. Second-generation
antiepileptic drugs cause less induction of liver
enzymes in comparison to the first generation
antiepileptic drugs [35]. In this study (fig.1), showed
level of estradiol after 28 days of treatment with
lamotrigine changed significantly when compared
with control group, this result is similar with[(36]
which proved that, healthy female patients took
lamotrigine and the combined oral contraceptive,
individually or as co-therapy for 130 days, recorded
slight effect of lamotrigine on estradiol level.
Lamotrigine drug reduces estradiol level [37]. While
[11] found that, healthy rats treated with lamotrigine
for different period caused a significant increase in
the level of estradiol.
Lamotrigine is considered traditional sodium
channel–blocking antiepileptic drugs, is confirmed its
therapeutic effects by reacting with sodium channels
[38]. A large reduction of the high-voltage-activated
calcium currents produced by lamotrigine and slight
use-dependent inhibition of the sodium conductance
[39]. Sodium inward current, voltage-gated–calcium
currents and the transient potassium outward current
affected by lamotrigine drug may cause potent
mechanisms to inhibit pathological irritation in
epilepsy and a possible advantage in treating
disturbances in bipolar disorder [40].
Conclusion
Treating of female albino rats with two doses of
lamotrigine drug for 28 days have a significant effect
on altering the level of most hematological,
biochemical parameters, ions, and estradiol level
included in this study, Further studies are necessary
to investigate the high doses and long-term effect of
this drug on healthy and epileptic rats.
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
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


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37.14
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28,21,14,7
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

             28,21,14,7 
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   
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