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HISTOPATHOLOGICAL AND BIOCHEMICAL EFFECTS OF
IVERMECTIN ON KIDNEY FUNCTIONS, LUNG AND THE
AMELIORATIVE EFFECTS OF VITAMIN C IN RABBITS
(Lupus cuniculus)
Khawla Bedan Al-Jassim * , Ala Al-Deen Hassan Jawad**
Eman Aboud Al-Masoudi*** , Saleh Khadim Majeed****
*Veterinary hospital in Basrah, Basrah, Iraq.
** Department of Basic Science, College of Dentistry, University of Basrah, Basrah.
Iraq.
*** Department of Physiology, Pharmacology and Chemistry, College of Veterinary
medicine, University of Basrah, Basrah, Iraq.
**** Department of Pathology, College of Veterinary Medicine, University of Basrah,
Basrah, Iraq.
(Received 6 September 2015 , Accepted 2 November 2015)
Keywords: Ivermectin, Vitamin C, Kidney.
ABSTRACT
The objective of this study was to assess the effects of repeated
administration of ivermectin alone or with the combination of Vitamin C on kidney
function and histopathological effects on kidney and lung of rabbits. Total of 48
mature female rabbits were used in this study. The rabbits were divided into eight
groups of equal number (6). The 1st group was administered 0.9% Nacl which
considers as control. The 2nd , 3rd , and 4th groups were administered (0.5mg, 1mg,
and 2mg/Kg B.W Ivermectin) respectively. While the 5th group was administered
50mg/Kg B.W vitamin C only. The 6th , 7th , and 8th groups were given 50mg/Kg
vitamin C in combination with Ivermectin (0.5mg, 1mg, and 2mg/Kg B.W )
respectively. The ivermectin therapy was given S/C weekly, while the vitamin C was
given daily and orally. The treatment in all groups were prolonged for 8 weeks.
The results showed significant increase (P˂ 0.05) in uric acid level in the 4th
group. Also the level of urea and blood urea nitrogen were revealed significant
decrease (P˂ 0.05) in 7th group. While the creatinine level clarified significant
increase (P˂ 0.05) in the 3rd and 8th groups as compared with control group.
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The histopathological changes as a results of ivermectin treatment in kidney
included vacuolation of subcapsular tubules, atrophy of glomeruli. The lung showed
dilated alveoli, bronchioles were aggregated with lymphocyte, dilatation of
bronchioles, as well as, folding and thickening of bronchial epithelium. The
administration of vitamin C with combination of Ivermectin ameliorate the harmful
effect of ivermectin treatment. It can be conclude that the repeated administration of
ivermectin causes hazardous effects on kidney function and many of
histopathological changes were demonstrated in kidney and lung structure. The
changes were increased proportionally with the dose. The administration of vitamin
C can acts as protective agent.
INTRODUCTION
Ivermectin is abroad spectrum antihelminths drug which used to control of
ectoparasites and endoparasites in sheep and goat(1).Ivermectin is used in human in
the treatment of onchocerciasis and also it is effective against stronglyloidiasis,
Ascaraisis, Trichuriasis, Filariasis, Entrobiasis and Scabies(2). The metabolism of
ivermectin is primary via the oxidative pathway, and it has a high affinity to bind
with protein, it may reach to 93%. Also reported that the ivermectin or its
metabolites are excreted almost extensively in the faeces' but an estimated 12 days
and with less than 5% of the administered doses excreted in the urine(3,4). The (5)
showed the coadministration of ivermectin and Albendazole caused significant
increase in serum urea and creatinine in rats. The administration of vitamin E caused
reduction in urea, creatinine level in rats (6). As well as, (7) concluded that vitamin C
could prevent and relief the toxic effect of Tamoxifen therapy. Also (8) clarified that
vitamin C exhibits a protective effect against free radical induced oxidative stress
damage. The objective of this study was to assess the effects of repeated
administration of ivermectin alone or with the combination of Vitamin C on kidney
functions and histopathological effects on kidney and lung of rabbits.
MATERIALS AND METHODS
The Ivermectin 10% purchased from local market (VET Product Office, KIPRO
Company, Holland) and Vitamin C(AlShahba Labo, Syria). The uric acid was
measured according to PAP – Method,enzymatic colorimetric test for uric acid with
lipid clearing factor (LCF).The Enzymatic colorimetric test for urea was done by
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hydrolyzed of urea in the presence of water and urease to produce ammonia (NH3)
and carbon dioxide (CO2). Creatinine was measured based on Jaffe-Reaction
photometric colorimetric test for kinetic measurement, while the blood urea nitrogen
was calculated according to following equation: (absorbance of sample/ absorbance of
standard X37.28 mg/dl).
Animal housing and Experimental Design
Forty eight female rabbits (Lepus cuniculus), (1200-2000gm) body weight
and (8-12 months) of age were brought from the local market in Basra Province in
Iraq. The rabbits were housed (6 rabbits / cage) in a wire silk cages measuring (100
X 50 X 50 cm) under controlled animal house condition at temperature (25 ± 3 Co)
and relative humidity (50 ± 5 % ) in the animal house of Veterinary Medicine
College in Basra University. The rabbits were kept under observation for one month.
The animals were offered add libitiuma rabbit's diet, alfa-alfa, green leaves during all
period of the experiment.
The rabbits were divided into eight groups (6 rabbits in each group). Each
group was treated for 8week as follow: the 1stgroup was Injected (0.9 % NaCl) which
acts as a control, the 2nd , 3rd , and 4th groups were injected with ivermectin in
doses(0.5 mg/kg,1 mg/kg ,2 mg/kg B.W) respectively. While the 5thgroup was
administered 50mg/ Kg B.W Vitamin C. As well as, the 6th , 7th and 8thgroups were
administered vitamin C in addition to ivermectin (0.5mg, 1mg, 2mg/Kg B.W)
respectively. The Ivermectin were given subcutaneously and weekly, while vitamin
C were given daily and orally. At the end of experiment (8 Weeks), the blood
samples were taken directly from the heart by using disposable syringe and were put
in screw tube without anticoagulant then centrifuged at 4000 rpm for 10 minutes to
get serum for biochemical assays. After that the animals were sacrificed to get out
kidney and lung which were preserved in10% formalin for histopathological studies.
Statistical analysis
The results were analysed by one- way ANOVA test. When significant differences
were found, the means were compared using least significant difference (LSD). All
statistical calculations were carried out by the aid of the statistical SPSS V. 22 (SPSS
Inc.)
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RESULTS
In Table (1),the uric acid level showed significant increase (p< 0.05) in the 4th
group as compared with control group, while the urea and blood urine nitrogen
(BUN)levels clarified significant decrease (p< 0.05)in the 7th group. As well as, the
creatinine level reported significant increase (p< 0.05) in the 3rd and 8th groups as
compared with control group.
The examination of the kidney of control rabbits revealed normal glomeruli with
thin glomerular basement membrane, normal cellularity and patent capsular space
surrounding proximal and distal convoluted tubules (Figure 1). The 2nd group showed
vacuolation of subcapsular cortical tubules (proximal convoluted tubules) (Figure 2),
atrophy of glomerulus (Figure 3), while the 3rd group showed in addition to
vacuolated of subcapsular cortical tubules (Figure4), it undergo dilated cortical
tubules (Figure 5), and atrophic glomerulus (Figure 6).
The 4th group which treated with high dose of ivermectin (2mg/Kg) revealed
marked vacuolation of cortical tubules (Figure 7), and atrophy of glomeruli (Figure
8). Furthermore, the 5th group (50mg/Kg Vit.C) showed normal cortical tubules and
glomerulus (Figure 9). The 6th group showed minimal dilated/ vacuolation of cortical
tubules (Figure 10), as well as, the 7th and 8th groups revealed dilated/vacuolated
cortical tubules (Figure 11, 12).
The examination of the lung of control rabbits showed alveoli, bronchiole within
normal limits (Figure 13). The 2nd group showed minimal folding and thickening of
bronchiolar epithelium (Figure14). The 3rd group showed bronchioles with papillary
proliferation of mucosal epithelium, aggregate of lymphocytes and dilated alveoli
(Figure 15). The 4th group revealed thickening and folding of bronchial epithelium and
dilated alveoli (Figure 16), whereas the lung section in 5th group within normal limit
(Figure 17).The 6th group showed bronchiole with folded epithelium with proliferation
(Figure 18), as well as, the lung section of 7th group revealed peribronchial aggregated
with lymphocyte, dilated alveoli and dilated bronchiole (Figure 19), an area of alveoli
with mononuclear cell, thickening alveolar septa and congested pulmonary artery
(Figure 20). Finally the 8th group showed an area of alveoli with inflammatory cell
mostly mononuclear cell (Figure 21), bronchiole with folded proliferated bronchial
epithelium and dilated alveoli (Figure 22).
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DISCUSSION
The statistical analysis demonstrated significant increase in uric acid in 4th group
which treated with 2mg/Kg Ivermectin , as well as, the urea and blood urine nitrogen
revealed significant decrease in 7th group (1mg/Kg Ivermectin + vitamin C), while the
creatinine level showed significant increase in 3rd and 8th group (1mg/Kg IVM,
2mg/Kg IVM +Vit.C).
It is well documented that the uric acid is the end product of protein and purine
metabolism. In present study, the increase of uric acid and creatinine level it occur
may be due to nephrotoxicity due to ivermectin treatment and may suggest reduction
in glomerular filtration and dysfunction of the renal tubules and these results are
closely matching with histological changes in kidney which observed in current study
like vacuolation of cortical tubules and atrophy of glomeruli. The urea and blood
urine nitrogen level decrease in current study may be due to effect of vitamin C which
ameliorate the effects of ivermectin treatment.
Generally, (9) demonstrated the administration of 500mg/day of vitamin C for 2
months caused decrease in serum concentration of uric acid.
The results in our study is in agreement with (10) who proved the therapeutic and
double therapeutic doses of Ivermectin (0.2mg and 0.4mg/Kg S/C) when given to
male albino rats caused significant elevation in uric acid and creatinine. Similarly,
Herd and Kociba,(11) postulated the I/M injection of 0.2mg/Kg for horse caused
significant increase in urea level after 8 day of treatment, while the creatinine level
showed significant decrease from day 4 of post treatment. Some investigators (12)
found that the avermectin could interfer with the Malpighian tubules and hormones
that acts on water balance. On the other hand,(13) claimed that the supplementation of
vitamin C caused lower serum uric acid. Other group of investigators found that
vitamin is very important in preventing the oxidative renal damage and stress
(14).Moreover,Vitamin C was found to be effective in the protecting chemically
induced oxidative renal damage in animals, they reported the high dose of vitamins
significantly protect from renal damage induced by anticancerdrug (15, 16).
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Generally ,kidney is regarded a vital organ responsible for reabsorption of
substances and then excretion outside the body through urine. In present work ,the
main features which can be observed due to ivermectin therapy are vacuolation of
subcortical tubules (proximal convoluted tubules) and atrophy of glomeruli, in
addition these lesion was reduced by vitamin C administration. This finding may be
due to oxidative stress as a results of ivermectin treatment which produce free radicals
and it may be accumulated in kidney tissues and impair its function.
This results is in accordance with Abdou and Sharkawy, (17) who observed the
S/C injection of 0.2mg and 2mg/Kg of Ivermectin to goats caused pathological
changes of kidney which characterized by partial necrosis of capillary tuft and
degeneration of tubular epithelium. As well as, the administration of the 1/10 LD50 of
Abamectin for 30 consecutive days in rats caused histological changes in kidney
which includes interstitial nephritis, hyaline globules inside the tubules with
thickening of membrane (18).Moreover, the oral administration of 10mg/Kg of
Abamectin weekly to 210 day and 30mg/Kg to 30 days to rats caused
histopathological changes in kidney in both concentration which include necrosis of
renal tubular epithelium and vacuolation of endothelial lining of glomerular tufts (19
).Some investigator proved that the S/C injection of 1mg/Kg of Ivermectin to donkey
for 7day caused significant histopathological changes in kidney like hypercellular
glomeruli, glomeruli appear hypercellular tuft, as well as, pinkish deposit in Bowman
space(20). In addition, (10) demonstrated the therapeutic and double therapeutic dose
of Ivermectin (0.2mg and 0.4mg/Kg) caused several harmful changes in the kidney of
the male albino rats which includes hyper cellularity of glomerular tufts, vacuolation
and hydropic degeneration of the lining of convoluted tubules. On the other hand, the
administration of 500mg/Kg of vitamin C caused reduction in toxicity, and enhanced
the animal’s tolerance due to environmental stress (21).
In the current work, the histological examination of lung due to ivermectin therapy
revealed dilated alveoli, aggregated of lymphocyte in bronchiole, bronchiolar
dilatation and folding and thickening of bronchial epithelium. These changes occur
may be due to oxidative stress occur due to repeat administration of ivermectin and its
accumulation in lung tissue.
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This results is in line with (17) who observed the S/C injection of 0.2mg and 2mg/Kg
of Ivermectin to goats caused haemorrhage in the perivascular area of lung and
alveoli.As well as, (19) noted the Abamectin caused interstitial pneumonia in lung of
rats which treated for 30 day, while it caused diffuse focal haemorrhage associated
with atelectasis which were noted in the lung of animals exposed to Abamectin for
210 days. The ameliorative effect of vitamin C administration on lung tissue in
current study is well demonstrated.
This results is in accordance with (22) who proved the coadministration of vitamin
C and E to rats caused reduce the pulmonary fibrosis lesion in lung of rats treated with
hexavalent chromium. Also, (23) showed the vitamin C and E could reverse the
histopathological changes due to dichlovos pesticide exposure in rats.
CONCLUSION
The repeated administration of ivermectin causes hazardous effects on kidney
function and many of histopathological changes were demonstrated in kidney and
lung structure. The administration of Vitamin C can acts as protective agent.
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Table (1): Effect of ivermectin alone or with the combination of vitamin C on
kidney functions of female rabbits after 8 weeks of treatment. (Mean ± SE),
n=6/group.
Uric acid
mg/dl
Urea
mg/dl
BUN
mg/dl
Creatinine
mg/dl
1st Group Control
0.9% Nacl 7.286± 1.455
ec
41.869±2.104
a
19.490±0.982
a
0.868±0.091
b
2nd Group
0.5mg/Kg Ivermectin 5.651± 0.938
c
38.158± 3.277
ac
17.769±1.525
ac
1.136±0.125
ab
3rd Group
1mg/Kg Ivermectin 7.431± 1.330
ec
37.822± 3.964
ac
17.614±1.847
ac
2.553±0.418
c
4th Group
2mg/Kg Ivermectin 14.631± 3.377
a
44.566± 4.421
a
20.752±2.060
a
1.452±0.126
ab
5th Group
50mg/Kg Vit.C
12.909± 3.194
abe
43.677± 2.184
a
20.329±1.020
a
1.339±0.194
ab
6th Group
0.5mg/Kg Ivermectin
+
50mg/Kg Vit.C
11.431± 2.199
abc
40.858± 1.929
a
19.024±0.902
a
1.285±0.183
ab
7th Group
1mg/Kg Ivermectin
+
50mg/Kg Vit.C
10.840± 0.508
abc
31.380± 2.250
bc
14.607±1.046
bc
1.148±0.211
ab
8th Group
2mg/Kg Ivermectin
+
50mg/Kg Vit.C
10.921±1.233
abc
37.363± 1.909
ac
17.406±0.889
ac
1.505±0.140
a
*Different letters denote significant differences (P< 0.05) between groups.
* Vit.C = vitamin C
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Figure (8): Kidney of rabbit treated with 2mg/Kg Ivermectin
stained with (H&E) X500.The pointer indicate marked atrophy
of glomeruli.
Figure (7): Kidney of rabbit treated with 2mg/Kg Ivermectin
stained with (H&E) X125.The pointer indicate marked
vacuolation of cortical tubules.
D
Figure (10): Kidney of rabbit treated (0.5mg/Kg IVM + 50mg/Kg
Vit. C) Stained with (H&E) X125.The pointer indicate minimum
dilation (D), vacuolation (arrow) of cortical tubules.
Figure (11): Kidney of rabbit treated (1mg/Kg IVM +50mg/Kg
Vit. C) Stained with (H&E) X125.The pointer indicate dilated
(arrow)/vacuolated (V) cortical tubules.
V
Figure (12): Kidney of rabbit treated (2mg/Kg IVM + 50mg/Kg
Vit. C) Stained with (H&E) X125.The pointer indicate
vacuolated cortical tubules (arrow), some dilated tubule (curve
arrow).
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Figure (14): Lung of rabbit treated with 0.5mg/Kg Ivermectin
stained with (H&E) X 125.The pointer indicate minimal
folding (thickening)of bronchial epithelium.
Figure (15): Lung of rabbit treated with 1mg/Kg Ivermectin
stained with (H&E) X500.The pointer indicate bronchioles
with papillary proliferation of mucosal epithelium (arrow),
aggregated of lymphocyte(curve arrow), dilated alveoli (star),
Figure (18): Lung of rabbit treated with (0.5 mg/Kg IVM +
50mg/KgVit.C) stained with (H&E) X125.The pointer indicate
bronchiole with folded epithelium withproliferation.
Figure (17): Lung of rabbiFigure (17): Lung of rabbit treated
with 50mg/Kg Vitamin C
within normal limits stained with (H&E) X125.the pointer
Figure (13): Lung of control rabbit bronchus and alveoli within
normal limit stained with (H&E) X125. The pointer indicate
bronchiole (arrow), alveoli (star), epithelial lining (curve
arrow)
Figure (16): Lung of rabbit treated with 2mg/Kg Ivermectin
stained with (H&E) X125.The pointer indicate minimum folding
of bronchial epithelium (arrow), dilated alveoli(star), aggregated
of lymphocyte(curve arrow)
Figure (17): of rabbit treated with 50mg/Kg
Vitamin C within normal limits stained with (H&E)
X125.the pointer
indicate bronchiole (arrow), alveoli (star)
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Figure (19):Lung of rabbit treated with (1mg/Kg IVM +
50mg/KgVit.C) stained with (H&E) X50.The pointer indicate
peri bronchial aggregate of lymphocyte (arrow), dilated of
bronchiole (star) , dilated alveoli (curve arrow)
Figure (21): Lung of rabbit treated with (2mg/Kg IVM +
50mg/KgVit.C) stained with (H&E) X125.The pointer
indicate an area of mononuclear cell in alveoli.
Figure (22): Lung of rabbit treated with ( 2mg/Kg IVM +
50mg/KgVit.C) stained with (H&E) X125.The pointer
indicate bronchiole with folded proliferated
epithelium(arrow), dilated alveoli (star).
Figure (20): Lung of rabbit treated with (1mg/Kg IVM +
50mg/KgVit.C) stained with (H&E) X125.The pointer
indicate anarea of alveoli with mononuclear cell with
thickening alveolar septa and congested pulmonary
artery(star)
Figure (22): Lung of rabbit treated with ( 2mg/Kg IVM +
50mg/Kg Vit.C) stained with (H&E) X125.The pointer indicate
bronchiole with folded proliferated epithelium(arrow), dilated
alveoli (star).
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التاثیرات النسجیھ الامراضیھ والبایوکیمیائیھ للایفرمکتین على وظائف الکلى،الرئھ والدور
المحسن لفیتامین سی على الارانب
خولھ بدن الجاسم ** علاء الدین حسن جواد *** ایمان عبود المسعودی
**** صالح کاظم مجید
*المستشفى البیطری فی البصره، البصره، العراق
** کلیھ طب الاسنان، فرع العلوم الاساسیھ، البصره، العراق
*** کلیھ الطب البیطری، البصره ، العراق
الخلاصھ
تھدف ھذه الدراسھ لمعرفھ تاثیرات الجرع المتکرره من الایفرمکتین لوحده او مع فیتامین سی على وظائف
الکلى والرئھ فی الارانب. استخدمت فی ھذه الدراسھ 48 انثى ارنب بالغھ. قسمت الارانب الى ثمانیھ مجامیع
وبعدد متساو کل مجموعھ تتکون من ستھ ارانب. المجموعھ الاولى جرعت ب 0.9 % من کلورید الصودیوم
واعتبرت کمجموعھ سیطره. المجموعھ الثانیھ والثالثھ والرابعھ جرعت ب( 0.5 ملغم/کغم، 1 ملغم/کغم و 2ملغم
/کغم من وزن الجسم بالایفرمکتین) على التوالی.بینما جرعت المجموعھ الخامسھ ب 50 ملغم / کغم من وزن
الجسم بفیتامین سی فقط. المجموعھ السادسھ ، السابعھ والثامنھ اعطیت 50 ملغم/ کغم من وزن الجسم فیتامین
سی مع الایفرمکتین ( 0.5 ملغم/کغم، 1 ملغم/کغم و 2ملغم /کغم) على التوالی. اعطی عقار الایفرمکتین تحت
الجلد اسبوعیا، بینما اعطی فیتامین سی یومیا وعن طریق الفم. استمرالعلاج لمده 8 اسابیع فی کل المجامیع
المعاملھ.
فی حامض البولیک فی المجموعھ الرابعھ. کذلک اظھر مستوى (P˂ اظھرت النتائج وجود زیاده معنویھ ( 0.05
عند المجموعھ السابعھ. بینما مستوى (P˂ الیوریا و ومستوى نتروجین الیوریا فی الدم نقصان معنوی ( 0.05
فی المجموعھ الثالثھ والثامنھ عند مقارنتھا بمجموعھ السیطره. (P˂ الکریاتنیین اظھر زیاده معنویھ ( 0.05
شملت التغییرات النسجیھ الامراضیھ فی الکلى بسبب علاج الایفرمکتین تفجی فی الانابیب تحت الکبسول
للانابیب الکلویھ و ضمور الکبیبھ.اظھرت الرئھ توسع فی الاسناخ، تجمع الخلایا اللمفیھ فی القصبات، توسع
القصبات، بالاضافھ الى طی وتثخن الجدار الطلائی للقصبات. اعطاء فیتامین سی مع الایفرمکتین حسن
التاثیرات الضاره الناتجھ من المعالجھ بالایفرمکتین. یمکن ان نستنج ان الجرع المتکرره من الایفرمکتین تسبب
اضرار خطیره وخاصھ فی الجرع العالیھ على وظائف الکلى وتسبب العدید من التغییرات النسجیھ المرضیھ
فی ترکیب الکلى والرئھ. والتغییرات تزداد بالتناسب مع الجرعھ.وایضا اعطاء فیتامین سی یمکن ان یعمل
کعنصر محسن.
مفایتح الاستدلال: الایفرمکتین، فیتامین سی ، الکلى، الرئھ، الانسجھ، الارانب
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