2023.08.04.20
Files > Volume 8 > Vol 8 no 4 2023

Study of the protective effect of ginseng
against testicular oxidative stress biomarkers and its gene expression induced
by ciprofloxacin

Haitham M. Mokhimar1
, Hozaifa K. Elsawah2
,
Mohamed M. Kandiel3
, Faten E. Elsaid4, AbuBakr M.
El-Mahmoudy5




1Department of
Pharmacology, Benha College of Vet. Medicine, Benha, Qaliobia, Egypt.
2Department of
Pharmacology, Benha College of Vet. Medicine, Benha, Qaliobia, Egypt. Email: [email protected]
3Department of
Theriogenology, Benha College of Vet. Medicine, Benha, Qaliobia, Egypt. Email: [email protected]
4Department of
Pharmacology, Benha College of Vet. Medicine, Benha, Qaliobia, Egypt. Email: [email protected]
5Department of Pharmacology,
Benha College of Vet. Medicine, Benha, Qaliobia, Egypt. Email: [email protected]
Available from.
http://dx.doi.org/10.21931/RB/2023.08.04.20
ABSTRACT
Ciprofloxacin
is the first-choice member of the fluoroquinolone antibacterials for treating
testicular infections, but it may harm testicular tissue because of oxidative
stress. Many mechanisms are involved, like decreasing antioxidant enzymes and
suppressing gene expression. This study intends to investigate the possible protective
role of ginseng against ciprofloxacin-induced testicular oxidative stress and its
mechanism, if any. For this purpose, 50 adult male albino rats were randomly
divided into five groups, ten rats in each group. Rats in group 1 received only
ciprofloxacin at a daily dose of 156.46 mg/kg. Rats in groups 2, 3 and 4
received ciprofloxacin in a daily dose of 156.46 mg/kg, ginseng in two doses of
100 and 200 mg/kg, and vitamin E as a standard in a daily dose of 100 mg/kg, respectively.
Group 5 served as control and received carboxymethylcellulose in normal saline.
All these treatments were applied orally during 14 14-day experimental courses.
Half the animals in each group were euthanized on day 15 from the start of the
treatment, while the second half was euthanized on day 60. Both testes were dissected,
immediately frozen, and evaluated for oxidative stress biomarkers and gene
expression antioxidant enzymes. We found that ciprofloxacin significantly (P
≤ 0.05) increased MDA and decreased total antioxidant capacity (TAC), superoxide
dismutase (SOD) and catalase (CAT) compared to the control group. Also, the
drug downregulated gene expression of SOD and CAT. Compared to all groups, the co-administration
of ginseng or vitamin E with ciprofloxacin almost normalized antioxidant
enzymes and upregulated the tested gene expressions. It could be concluded that
ginseng ameliorates the testicular adverse effect of ciprofloxacin. So, it is highly
recommended to be used as an adjunct remedy during ciprofloxacin administration
for its antioxidant properties.
Keywords: Ciprofloxacin, Gene expression, Ginseng, Infertility, ROS,
Testicular oxidative stress, Vitamin-E.
INTRODUCTION
Reactive
oxygen species (ROS) potentially contribute to male infertility 1, leading
to defective sperm function, metabolism and motility 2, 3.
Oxidative
stress describes when a system has imbalanced oxidation and reduction reactions
leading to oxidative stress 4, which can lead to nuclear and mitochondrial DNA
damage and Y chromosomal changes 5.
Former
studies reported that ciprofloxacin harmfully impacted male fertility via
increasing testicular oxidative stress marked by depletion in SOD (Superoxide
dismutase) and GPx (glutathione peroxidase) 6-8. Ciprofloxacin is effective in the treatment of a wide
variety of infections, particularly those caused by Gram-negative
pathogens and is considered to be
the best choice for patients with complicated urinary tract infections 9, also frequently prescribed by fertility specialists
in the therapy of many types of bacterial infections when leukocytospermia or
before in vitro fertilization program 5.
Daily 400 mg/kg
of ciprofloxacin for 7 days induced elevation in oxidative stress biomarkers 10. Also, high doses of
ciprofloxacin and enrofloxacin increase blood oxidative stress 11.
Ginseng
is the most frequently used herbal medicine for immune system stimulation and
as an adjuvant with prescribed drugs12. It is effective in the treatment of male
infertility. It has been shown to induce testicular growth, increase the
production of spermatozoa and testosterone levels, and sexual activity in
animals 13. Ginseng inhibits oxidative stress in rats, which
lowers lipid peroxidation and increases antioxidant capacity 14.
So, we hypothesize that ginseng as an antioxidant could protect from
infertility caused by oxidative stress induced by ciprofloxacin.
The adverse effect of ciprofloxacin on testicular tissue via oxidative
stress has been demonstrated to achieve this objective.
MATERIALS AND METHODS
Drug
preparation
Ciprofloxacin was purchased as a
generic pharmaceutical preparation Serviflox® with a concentration of 750 mg of
ciprofloxacin in one tablet manufactured by Novartis Pharma-Cairo, under the
license of Sandoz GmbH- Australia. The tablets were crushed and diluted with
CMC (carboxymethylcellulose) in NS (normal saline) to a final volume of 1ml
/rat dose. Ginseng was purchased with the generic name Ginsana® with a
concentration of 100 mg of ginseng in one capsule manufactured by Egyptian
International Pharmaceutical Industries Company (EIPICO). The capsules were
opened and diluted with CMC in NS to a final 1ml /rat dose volume. Vitamin E
was purchased with the generic name vitamin-E 1000® with a concentration of
1000 mg of vitamin E in each capsule manufactured by Pharco Pharmaceuticals.
The tablets were opened and diluted with sunflower oil to a final 1ml /rat dose
volume.
Animals
Fifty adult Wister albino male rats,
8 weeks old and weighing 200±20g, were used. They were obtained from Animal
House, Faculty of Veterinary Medicine, Benha University. Male rats were housed
at average room temperature (30°C), humidity (40-60%) and 12h/12h dark/ light
cycle before the start of the experiment. The animals were fed laboratory
formula 15 and tap water ad libitum.
Study design
After two weeks of adaptation to a standard diet, male rats were
randomly divided into five groups, with ten in each group. Rats in group 1
received ciprofloxacin in daily doses of 156.46 mg/kg16. Rats in groups 2, 3 and 4 received ciprofloxacin in a daily doses
of 156.46 mg/kg and ginseng in two doses of 100 and 200 mg/kg17 and vitamin E in a daily doses of 100 mg/kg, respectively. Group 5
served as control and received 1 ml carboxymethyl cellulose in normal saline.
All treatments were orally administered for 14 days. Half the animals in each
group were sacrificed by euthanasia using ether 18 on day 15 from the start of the treatment (1 euthanasia).
In contrast, the second half was sacrificed by euthanasia 18 on day 60 from the beginning of the treatment (2nd
euthanasia). Testis were immediately removed, frozen, and evaluated for
oxidative stress biomarkers and gene expression antioxidant enzymes.
Sampling
Immediately after euthanasia, one testis from each animal was
dissected, weighed and divided into two parts.
1-
Testicular tissue samples for testicular oxidative stress biomarker
concentrations were collected by centrifugation of the first part of the testis
after homogenization with a phosphate buffer solution at pH 7.4 at 1500 xg for
5 minutes at 4º C 19. The supernatant was taken out and preserved at -20 C. till
used analysis of testicular oxidative stress markers: MDA (Malondialdehyde) concentration, SOD activity, total antioxidant capacity and CAT (catalase)
activity.
2- Testicular tissue samples for
testicular gene expression were collected and immediately kept at – 80oC until the expression of
testicular gene expression of antioxidant enzymes was quantified. Using
a Qiagen RNeasy® Mini kit, total RNA was extracted from the frozen samples
following the manufacturer's protocol. RNA was determined by using Spectro star
Nanodrop (BMG LABTECH®) according to the high-capacity cDNA Reverse
Transcription Kits (Applied Biosystems) protocol. Real-time polymerase chain
reaction for each gene was carried out using (Quanti Tect SYBR Green PCR
Kit, Qiagen), 1 μM of each forward and reverse primer for each gene (Table 1), and The real-time PCR equipment used the comparative CT method to
calculate the changes in gene expression20.

Table 1. Primer forward and reverse sequences for
gene expression analysis
Statistical analysis
The multi-group comparisons were carried out using the one-way
analysis of variance (ANOVA) technique, followed by post hoc Tukey's test for
pairwise comparison at a 0.05 significance level. They were using GraphPad Prism
program 21.
Ethics statement
The experiment was conducted in the Departments of Pharmacology and
Theriogenology, Faculty of Veterinary Medicine, Benha University, with the
ethical approval number BUFVTM 090422.
RESULTS
Effect of ciprofloxacin alone and with ginseng or vitamin E on testicular
oxidative stress biomarkers:
As shown in Figure 1, on the 15th
day from the start of treatment, group 1, which was treated with ciprofloxacin,
only showed a significant increase in MDA. However, adding ginseng or vitamin E
normalized MDA compared to control. However, group 3, which received a high
dose of ginseng, showed a significant decrease in MDA compared to the control. CAT,
TAC (total antioxidant capacity) and SOD enzyme activity were reduced in the
group treated with ciprofloxacin compared to the control group (P
< 0.05). However, adding ginseng or vitamin E with ciprofloxacin normalizes CAT,
TAC and SOD enzyme activity. However, the group treated with a high dose of
ginseng showed a higher increase in SOD enzyme activity than group 4, which
received vitamin E, and the control group, Figure 2A.
On the 60th day of treatment, all groups have been
approximately returned to normal figures 1-2.
Effect of ciprofloxacin alone and with ginseng or vitamin E on
antioxidant gene expression
As shown in Figure 3, on the 15th day of treatment, group 1,
which received ciprofloxacin, showed significant downregulation of relative gene
expression of CAT, GPx and SOD genes compared with all groups. However, supplementation
of ginseng or vitamin E with ciprofloxacin approximately normalized the relative
gene expression of CAT, GPx and SOD compared to the control group (P
< 0.05). Also, group
3, which received a high dose of ginseng with ciprofloxacin, showed a higher significant
upregulation of relative gene expression of CAT, GPx and SOD compared with
group 2 and group 4.
On the 60th day from the start of treatment, all groups
returned approximately to normal compared with the control group Figure 3.

Figure 1. Influence of ciprofloxacin with or without ginseng or vitamin E administration
on oxidative stress biomarker MDA obtained from rats' testis. Columns bearing
different superscript letters on the same sacrifice day differ significantly at
p < 0.05 in Tukey's multiple comparison post hoc test. (Group 1)
treated with ciprofloxacin only. (Group 2). Moreover, (group 3) was treated
with ciprofloxacin and ginseng at a low dose and ginseng at a high dose. (Group
4) treated with ciprofloxacin and vitamin E. (Group 5) serve as control. MDA:
Malondialdehyde.

Figure
2. Influence
of ciprofloxacin with or without ginseng or vitamin E administration
on antioxidant enzymes SOD, Catalase, TAC obtained from rats' testis. Columns
bearing different superscript letters on the same sacrifice day differ
significantly at p < 0.05 in Tukey's multiple comparison post hoc
test. (Group 1) treated with ciprofloxacin only. (Group 2) Moreover, (group 3)
was treated with ciprofloxacin and ginseng at a low dose and ginseng at a high
dose relatively. (Group 4) treated with ciprofloxacin and vitamin E. (Group 5)
serve as control. SOD: superoxide dismutase. TAC: total antioxidant
capacity.

Figure 3. Influence of ciprofloxacin with or without ginseng or vitamin E
administration on relative gene expression analysis of antioxidant enzymes
obtained from rats' testis. Columns bearing different superscript letters on
the same sacrifice day differ significantly at p < 0.05 in Tukey's
multiple comparison post hoc test. (Group 1) treated with ciprofloxacin only.
(Group 2)
Moreover,
(group 3) was treated with ciprofloxacin and ginseng at a low dose ginseng high
dose relatively. (Group 4) treated with ciprofloxacin and vitamin E. (Group 5)
serve as control. GPx: glutathione peroxidase. SOD: superoxide dismutase.
DISCUSSION
The presented study is to evaluate the
protective effect of ginseng against ciprofloxacin-induced oxidative stress
causing male infertility. Many previous studies have demonstrated that
ciprofloxacin-induced oxidative stress affects sperm parameters and function,
leading to male infertility. In the present study, ciprofloxacin significantly
increased MDA and decreased antioxidant enzyme activities (SOD, GPX and TAC).
These results are consistent with former reports 6-8, 22. Ciprofloxacin is mainly related to
reactive oxygen species (ROS) generation, besides metabolism-related toxicity 23. A rise in MDA indicates testicular cell
injury and a reduction in sperm motility and sperm-oocyte fusion. 24, 25. There are many possible mechanisms for
oxidative stress causing infertility related to damage of spermatozoa because
its membrane consists of polyunsaturated fatty acids, which are susceptible to
lipid peroxidation 26. Another hypothesis is that H2O2
can cross the membranes into the cells and inhibit the activity of some
enzymes, such as G6PD, which leads to the accumulation of oxidized
and reduced glutathione, which leads to lowering the antioxidant defenses of the
spermatozoa 27. Also, oxidative stress is associated with
reduced fertilization, miscarriage and congenital disabilities in the offspring
due to several modifications leading to sperm DNA damage 28-30. Ciprofloxacin also induced a significant
down-regulation of antioxidant gene expression after administration of 800
mg/kg/day for 15 days 31.
We found that groups treated with ginseng in two doses showed significant
improvement in testicular function via increasing antioxidant enzyme activity
(SOD, TAC and GPX) but decreasing in MDA with high dose only. These findings
concern previous studies 13, 14,
32, 33. Furthermore, another study found a
reduction in MDA besides an increase in SOD, CAT and GPX in rats supplemented
with ginseng 34. The ginseng root contains many amino
acids, vitamins A, B2, B12, C, and E and metals like sodium, potassium,
calcium, phosphorus, iodine, iron, zinc, copper and selenium 35. This component enhanced the antioxidant
protective role by decreasing MDA, the end product of lipid peroxidation and a
marker for tissue damage 14. The accumulation of MDA 36 evidenced the
extensive lipid peroxidation. Also, another study reported that
administering ginseng in humans for 8 weeks decreased MDA but increased SOD and
CAT activities 37. So, a decrease in MDA indicates ginseng's
antioxidant activity.
SOD defends against oxygen free radicals, which are responsible for damage
to the plasma membrane and biological structures, causing an elevation in the intracellular
Ca2+ ion concentration leading to irreversible conversion of xanthine
dehydrogenase to xanthine oxidase 38. Also, it may be due to increasing
antioxidant enzyme activities by increasing scavenger of H2O2,
preventing the formation of free radicals 39. So, the formation of free radicals is inhibited
due to the increased activity of SOD due to ginseng administration.
Catalase and GPx are essential in detoxifying H2O2
14 and indirectly protecting cells 40. The increase in CAT activity is thought
to be due to degrade H2O2 produced by SOD activity. Also,
ginseng enhanced sex hormone levels, testicular structure, and redox status and
has more antioxidant activity than Tribulus Extracts and Pollen Grains 41. Generally, these results indicated that
ginseng has protective effects against ciprofloxacin-induced oxidative stress
by increasing antioxidant activity and gene expression 42. In the same respect, another study
reported that ginseng induced a protective role against alcohol-induced hepatic
injury in mice by upregulating the gene expression of the antioxidant enzymes 43. These results are also consistent with a
previous study that suggested that ginseng inhibited cardiomyocyte apoptosis by
inhibiting the expression of the pro-apoptotic Bax gene in rats 44.
In the present study, the group treated with ciprofloxacin beside
vitamin E showed an increased antioxidant enzyme activity and upregulated its
gene expression. Consistently, a study that treated 100 Parkinson's disease
patients with vitamin E reported that it had a potential therapeutic target for
disease-modifying treatments via activating cellular pathways involved in
antioxidant and anti-inflammatory responses 45.
Furthermore, another study reported that despite ginseng 100 mg/kg/day have
superior outcomes in liver protection than vitamin E 100 mg/kg/day, their
antioxidant properties were similar, and this was evidenced by nearly absence of
differences in liver tissue MDA, SOD or CAT levels in both treated groups 46. Also, rats treated with vitamin E or
Panax ginseng concomitant with levofloxacin significantly improve biochemical
and antioxidant parameters 47.
CONCLUSIONS
Ginseng has a protective effect
against ciprofloxacin-induced oxidative stress, causing male infertility. It increases
antioxidant enzyme activities (SOD, TAC, and GPX) and decreases MDA levels.
These results are consistent with previous studies showing ginseng has
antioxidant and anti-inflammatory properties.
Vitamin E also has antioxidant
properties and can protect against ciprofloxacin-induced oxidative stress.
However, ginseng and vitamin E have similar antioxidant properties, so it is
unclear which is more effective in protecting against ciprofloxacin-induced
male infertility.
More research is needed to
determine the optimal dose and duration of ginseng or vitamin E treatment for
protecting against ciprofloxacin-induced male infertility.
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Received: 28
September 2023/ Accepted: 15 November 2023 / Published:15 December 2023
Citation: Mokhimar H M, Elsawah H K, Kandiel M M,.
Elsaid F E, El-Mahmoudy A M. Study of the
protective effect of ginseng against testicular oxidative stress biomarkers and
its gene expression induced by ciprofloxacin. Revis Bionatura 2023;8 (4) 20. http://dx.doi.org/10.21931/RB/2023.08.03.20