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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2018  |  Volume : 29  |  Issue : 1  |  Page : 19-29
Renoprotective effect of Nigella sativa against cisplatin-induced nephrotoxicity and oxidative stress in rat


1 Department of Physiology, School of Medicine, Mashhad University of Medical Sciences; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
3 Department of Pathology, Qaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran

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Date of Web Publication15-Feb-2018
 

   Abstract 

Cisplatin is one of the important antineoplastic drugs. Its clinical use has been restricted due to severe kidney toxicity. Nigella sativa (N. sativa) is an herbaceous plant with many pharmacologic effects. In the present study, we evaluated the protective effects of aqueous-ethanolic extract of N. sativa and Vitamin E on cisplatin-induced nephrotoxicity in rats. Eighty male rats were divided into eight groups: control, cisplatin (6 mg/kg; ip), preventive Vitamin E (100 mg/kg), preventive N. sativa (100,200 mg/kg), preventive + treatment Vitamin E, and preventive + treatment N. sativa (100, 200 mg/kg). Duration of this study was 11 days and cisplatin was injected on the 6th day of the experiment. Tissue damage in all groups that received N. sativa extract and Vitamin E showed a significant improvement compared with the cisplatin group. In addition, serum and tissue total thiol content in preventive and preventive + treatment N. sativa groups showed significant increase compared with cisplatin group. There was no significant difference in serum malondialdehyde concentration of the control rats compared with the preventive and preventive + treatment N. sativa groups. N. sativa extract and viamin E improved the pathology and oxidative stress in the rat kidney. However, more studies are needed to determine the mechanism of action of N. sativa on cisplatin-induced kidney toxicity.

How to cite this article:
Hosseinian S, Hadjzadeh MA, Roshan NM, Khazaei M, Shahraki S, Mohebbati R, Rad AK. Renoprotective effect of Nigella sativa against cisplatin-induced nephrotoxicity and oxidative stress in rat. Saudi J Kidney Dis Transpl 2018;29:19-29

How to cite this URL:
Hosseinian S, Hadjzadeh MA, Roshan NM, Khazaei M, Shahraki S, Mohebbati R, Rad AK. Renoprotective effect of Nigella sativa against cisplatin-induced nephrotoxicity and oxidative stress in rat. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2018 Oct 22];29:19-29. Available from: http://www.sjkdt.org/text.asp?2018/29/1/19/225208

   Introduction Top


Cisplatin (cis-diamminedichloroplatinum (II) is one of the potent chemotherapeutic agents that is specially used in the treatment of solid tumors including head and neck, testicular, ovarian, and bladder malignancies.[1] However, several adverse effects of cisplatin have been reported, mainly neurotoxicity and nephrotoxicity that limit its clinical use.[2] Despite of these toxicities, cisplatin remains one of the most important chemotherapeutic agents because of its high-therapeutic efficacy.[3] Therefore, there is an urgent need for ways to protect the kidney against complications of cisplatin administration. The kidney accumulates higher concentration of cisplatin comparing with other organs and also is the main route for the cisplatin excretion. The organic cation transporter 2 is the major transporter for cisplatin in the proximal tubular cells.[4] The mechanisms of cisplatin-induced nephrotoxicity are complex including oxidative stress, apoptosis, and inflammation.[5] Several investigations have shown that lipid peroxidation and generation of free radicals in tubular cells are involved in the pathogenesis of cisplatin nephrotoxicity. Cisplatin induces the production of reactive oxygen species (ROS) in cells through the mitochondria, xanthine-xanthine oxidase system and nicotinamide adenine dinucleotide phosphate oxidase.[6] In addition, cisplatin inhibits the renal activities of antioxidant enzymes including catalase, superoxide dismutase, and glutathione peroxidase and increases thiobarbituric acid-reactive substances (TBARS).[7] Different apoptotic pathways have been involved in cisplatin-induced cell death including the reticulum stress pathway, extrinsic pathway, and intrinsic mitochondrial pathway.[8] Recent studies also suggest that inflammation has also a major role in the renal injury induced by cisplatin. Tumor necrosis factor alpha has a critical role in mediating chemokine and cytokine expression in cisplatin-induced nephrotoxicity.[5] Several studies have provided evidence supporting the beneficial effects of a variety of antioxidants such as naringenin and dimethylthiourea in cisplatin-induced nephro-toxicity in experimental animals.[9],[10]

Nigella sativa Linn (N. sativa) is a herbaceous annual plant that commonly known as black cumin and black seed.[11] In the folk medicine, N. sativa has been recommended for a wide range of diseases including diabetes, fever, bronchitis, cough, asthma, dizziness, headache, and back pain.[12] In addition, according to the Islamic literature: “Use the black seed, because it is a cure for every disease except aging and death.” [13] Indeed, recent pharmacological studies have shown that N. sativa has anti-inflammatory,[14] anticarcinogenic,[15] and antioxidant[16] properties. The present study was undertaken to investigate whether N. sativa seeds extract as a potent free radical scavenger can protect against cisplatin-induced renal damage in rats.


   Materials and Methods Top


Chemicals

Cisplatin was purchased from the Mylan Company (Greece, Drug-bank ID: DB00515). N. sativa seeds were obtained from a local market and were identified by botanists in the herbarium of Ferdowsi University of Mashhad with herbarium number 293-0303-1. 5, 5´-dithiobis-2-nitrobenzoic acid (DTNB), 2-thiobarbituric acid (TBA), trichloroacetic acid (TCA), Tris, HCl, and potassium chloride (KCl) were obtained from the Merck Company (Germany).

Extract preparation

For the preparation of the hydroalcoholic extract, 50 g of the powdered seeds were extracted with 500 mL ethanol (70%, v/v). After the extraction, the solution purified using a rotary vacuum evaporator which yielded a blackish-brown concentrate. The prepared extract was kept at 4°C before use.

Animals

Eighty male Wistar Albino rats weighing 230–300g were purchased from the Animal House of the Mashhad Medical School, Mashhad University of Medical Sciences. The rats were housed at 23°C ± 2°C with a relative 50%–60% humidity and a 12:12 h light-dark cycle and free access to standard laboratory food and water. All experiments were carried out under the authority of the Mashhad University of Medical Sciences and approved by the local ethical committee.

Experimental design

In this study, the rats were randomly divided into eight groups of 10 each group, which received normal saline for 11 consecutive days [Figure 1]:
Figure 1: Schematic chart for experimental groups.

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Control group, which received normal saline for 11 consecutive days.

Cisplatin group, which received normal saline for 11 consecutive days and cisplatin (6 mg/kg) at the 6th day of the experiment.

Preventive (prev) Vitamin E group, which received Vitamin E (100 mg/kg) for six consecutive days[17] and cisplatin (6 mg/kg)[18] at the 6th day of the experiment.

Preventive NS100 group received N. sativa extract (100 mg/kg) for six consecutive days and cisplatin (6 mg/kg) at the 6th day of the experiment.

Preventive NS200 group received N. sativa extract (200 mg/kg) for six consecutive days and cisplatin (6 mg/kg) at the 6th day of the experiment.

Preventive + treatment (prev + treat) Vitamin E group received Vitamin E (100 mg/kg) for 11 consecutive days and cisplatin (6 mg/kg) at the 6th day of experiment.

Preventive + treatment NS100 group received N. sativa extract (100 mg/kg) for 11 consecutive days and cisplatin (6 mg/kg) at the 6th day of experiment.

Preventive + treatment NS200 group received N. sativa extract (200 mg/kg) for 11 consecutive days and cisplatin (6 mg/kg) at the 6th day of experiment.

All injections were carried out intraperitoneally. At the 12th day of the study, all animals were weighed and anesthetized with ether. Blood samples were collected from the orbital sinus and serum separated by centrifugation and stored at −20°C until assayed. Both kidneys were quickly removed, decapsulated, and weighed. The right kidney was fixed in 10% buffered formalin for histopathological examination. The left kidney was homogenized in cold KCl solution (1.5%) to give a 10% homogenate and used for measuring total thiol content and malondialdehyde (MDA) concentration.

Thiobarbituric acid reactive species measurement

MDA as an index of lipid peroxidation reacts with TBA as a TBARS to produce a red-colored complex. It has a peak absorbance at 535 nm. 15 g TCA, 0.375 g TBA, and 2 mL HCl were mixed, and 2 mL of this mixture was added to 1 mL of serum or kidney homogenate in a centrifuge tube, and the mixture was heated for 50 min in a boiling water bath. After cooling, the mixture centrifuged at 1000 rpm for 10 min. The absorbance (A) of colored layer was read at 535 nm. MDA concentration was calculated from the following equation: C (M) = A/1.56 × 105[19]

Total thiol (-SH) content assay

Total -SH groups were measured using DTNB as the reagent. This reagent reacts with the SH groups to produce a yellow colored complex which has a peak absorbance at 412 nm. 1 mL Tris-ethylenediaminetetraacetic acid (EDTA) buffer was added to 50 μL of serum or kidney homogenate and absorbance were read at 412 nm against Tris-EDTA buffer alone (A1). Then, 20 μL DTNB reagents (10 mM in methanol) was added to the mixture, and after 10 min, the sample absorbance was read again (A2). The absorbance of DTNB reagent was also read as a blank (B). Total thiol concentration (mM) was calculated from the following equation: Total thiol concentration (mM) = (A2-A1-B) × 1.07/0.05 × 13.6[20]

Histopathological examination

Right kidneys were fixed in 10% formalin, then dehydrated in graded alcohols and molded in paraffin. Tissue sections of 5 μm were prepared, and staining was carried out with hematoxylin and eosin. The renal sections were examined in light microscopy (9 random fields with a ×40 objective) for hemorrhage and necrosis, tubular swelling, and cellular vacuolization. Tubular necrosis was defined as tubular dilatation, sloughing of tubular epithetlial cells, intratubular cast formation, and naked tubular basement membrane. Tubular necrosis was scored using a scoring system ranging from 0 to 4. The scoring system was defined as follows: 0 = no damage; 1 = patchy isolated unicellular necrosis; 2 = tubular necrosis <25%; 3 = tubular necrosis between 25% and 50% and 4 = tubular necrosis >50%.[21]

Ethical issues

The research followed the tenets of the Declaration of Helsinki. The research was approved by ethical committee of Mashhad University of Medical Sciences. Before the experiment, the protocols were confirmed to be in accordance with the Guidelines of Animal Ethics Committee of Mashhad University of Medical Sciences.


   Statistical Analysis Top


The data were analyzed using the Statistical Package for Social Sciences (SPSS) version 22.0 (SPSS Inc., Chicago, IL, USA) and were expressed as mean ± standard error of the mean (SEM). Normality test (Kolmogorov–Smirnov) was done. Differences between group means were estimated using a one-way analysis of variance (ANOVA) followed by least significant difference (LSD) test for multiple comparisons. P <0.05 were considered as significant.


   Results Top


Effect of Nigella sativa and Vitamin E on the kidney injury

Renal tissue sections provided from the control group showed normal architecture [Figure 2]. Treatment with cisplatin caused a marked tubular and glomerular degenerative changes including desquamation, necrosis and vacuolation in epithelial cells, hyaline casts and necrotic epithelial cells in the lumens of tubules and intertubular hemorrhage [Figure 2]. In contrast, treatment with N. sativa extract and Vitamin E in preventive and preventive + treatment groups improved renal histopathological changes compared with the cisplatin group [Figure 2]. The percent of kidney damage in cisplatin-treated animals was significantly higher than those of the control group (P <0.001) [Figure 3]. Treatment with Vitamin E and N. sativa extract significantly reduced the percent of kidney damage in preventive and preventive + treatment groups compared with the cisplatin group (P <0.001) [Figure 3].
Figure 2: Light microscopy of renal section from all experimental groups. Control group showing normal morphology. Cisplatin group showing desquamation and necrosis in tubules (thin arrow), intertubular hemorrhage (thick arrow), congestion and swelling in tubules (double arrow), hyaline casts in tubules (star). Vitamin E and Nigella sativa extract-treated rats showing slight hyaline casts in tubules (star), mild tubular necrotic changes (thin arrow), mild hemorrhage (thick arrow), and mild congestion and swelling in tubules (double arrow) (hematoxylin and eosin, ×200).

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Figure 3: Percentage of renal tissue damage in all experimental groups of animal. Values are the mean± standard error of the mean. The data were analyzed using one-way ANOVA and post hoc least significant difference test. A significant difference was considered at P <0.05.
*** P <0.001, a: significant difference from control group, b: significant difference from cisplatin group.


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Biomarkers of oxidative stress

Tissue total thiol content

Tissue total thiol content in cisplatin group demonstrated a significant decrease compared with the control group (P <0.01) [Figure 4]a. In addition, administration of Vitamin E in preventive and preventive + treatment (P <0.001 and P <0.05, respectively) groups and N. sativa in preventive (100, 200 mg/kg) (P <0.01 and P <0.001, respectively) and preventive + treatment (100, 200 mg/kg) (P <0.05 and P <0.01, respectively) groups significantly increased the tissue total thiol content compared with the cisplatin group [Figure 4]a.
Figure 4: Tissue (a) and serum (b) total thiol content in all experimental groups of animal. Values are the Mean ± standard error of the mean. The data were analyzed using one-way ANOVA and post hoc least significant difference test. A significant difference was considered at P <0.05.
*P <0.05, **P <0.01, ***P<0.001, a: significant difference from control group, b: significant difference from cisplatin group.


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Serum total thiol content

Serum total thiol content in cisplatin group showed a significant decrease compared with the control group (P <0.01) [Figure 4]b. Administration of N. sativa extract as prevention and prevention + treatment (100, 200 mg/kg) significantly increased the serum total thiol content compared with the cisplatin group (P <0.001) [Figure 4]b. However, Vitamin E did not show a significant action on serum total thiol content in preventive and preventive + treatment groups compared with the cisplatin-treated animals [Figure 4]b.

Tissue malondialdehyde concentration

Tissue MDA concentration in cisplatin group showed no significant change compared with the control animals [Figure 5]a. However, administration of Vitamin E in preventive + treatment group significantly decreased the tissue MDA concentration compared with the control group (P <0.05) [Figure 5]a. Compared to cisplatin group, the reduction of tissue MDA concentration in preventive Vitamin E and preventive + treatment N. sativa (200 mg/ kg) groups was 14.88% and 18.71% respectively but these reductions was not significant [Figure 5]a.
Figure 5: Tissue (a) and serum (b) MDA concentration in all experimental groups of animal. Values are the Mean ± standard error of the mean. The data were analyzed using one-way ANOVA and post hoc least significant difference test. A significant difference was considered at P <0.05.
*P <0.05, **P <0.01, ***P<0.001, a: significant difference from control group, b: significant difference from cisplatin group.


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Tissue MDA concentration in preventive N. sativa (100, 200 mg/kg) groups (P <0.001) and preventive + treatment N. sativa (100 mg/kg) group (P <0.01) demonstrated a significant increase compared with the control group [Figure 5]a.

Serum malondialdehyde concentration

Serum MDA concentration in cisplatin group showed a significant increase compared with the control animals (P <0.05) [Figure 5]b. However, there was a significant decrease in serum MDA concentration in preventive Vitamin E group compared with the cisplatin group (P <0.001) [Figure 5]b. Compared to cisplatin group, the reduction of serum MDA concentration in preventive N. sativa (100, 200 mg/kg) groups was 14.86% and 16.76%, respectively and in preventive + treatment N. sativa (100, 200 mg/kg) groups was 19.77% and 8%, respectively, but these reductions was not significant [Figure 5]b.


   Discussion Top


Acute kidney injury is the most serious side effect of cisplatin as an important antitumor agent. Several studies have demonstrated that lipid peroxidation and oxygen free radicals are important mediators of cisplatin-induced nephrotoxicity.[22] Several investigations demonstrated the renoprotective effects of natural antioxidants including naringenin,[9] green tea,[23] grape seed,[24] and crocin[25] against cisplatin-induced renal toxicity. Among the medicinal plants, N. sativa is a miracle herb with a rich historical and religious background[26] and various pharmacologic effects including anti-inflammatory,[14] cytoprotective,[27] and antioxidant[16] properties. In the present study, cisplatin injection produced severe tubular and glomerular degenerative changes. These renal tissue structural changes also been reported by other investigators.[25],[28] According to the present results, administration of N. sativa extract at 100 and 200 mg/kg in preventive and preventive + treatment groups significantly decreased the morphological changes induced by cisplatin. These results are in line with previous studies described that the administration of thymoquinone and N. sativa oil before or concomitant with cisplatin injections, improved the renal injury mediated by cisplatin.[29],[30] Both in vitro and in vivo studies indicate that cisplatin generates oxygen-free radicals in the kidneys and consequently causes multiple damages in the renal tissue.[6] On the same basis, the beneficial effects of the N. sativa extract against cisplatin administration might be related to its anti-inflammatory, cytoprotective, and antioxidant actions in the kidney.[14],[16],[27] In agreement with the previous works, we showed that the administration of cisplatin to rats caused a significant decrease in serum and tissue total thiol content in comparison with the control group. Sulfhydryl (SH) groups are highly reactive constituents of protein and nonprotein molecules and are important scavengers of oxygen free radicals.[31] Our data indicated that serum and tissue total thiol content increased significantly following the administration of N. sativa extract at 100, 200 mg/kg in preventive and preventive + treatment groups compared to the cisplatin group. This finding is in agreement with Salama et al, who reported administration of N. sativa extract (50 mg/kg) and N. sativa oil (400 mg/kg) before and concomitant with alternative injections of cisplatin increased serum and tissue total thiol content.[30] There are evidences indicating that cisplatin induces ROS generation in renal epithelial cells primarily by decreasing the activity of antioxidant enzymes and by depleting intracellular concentrations of GSH.[5] Therefore, the observed protective effects of N. sativa extract in our study can be attributed to the antioxidant properties of N. sativa. It has been shown that compounds isolated from N. sativa including thymoquinone, carvacol, t-anethole, and 4-terpineol have appreciable free radical scavenging properties.[3] Indeed, this study, showed that serum MDA concentration as an indicator of the lipid peroxidation increased in the cisplatin-treated animals compared with the control group. Several investigators have reported that renal toxicity following cisplatin administration is correlated with oxidative stress.[5],[7] The present work indicated that administration of N. sativa prevented the serum MDA imbalance produced due to cisplatin injection in the rat. In this regard, preventive and preventive + treatment groups did not show a significant alteration in serum MDA concentration compared with the control animals. Indeed, the enhanced serum MDA concentration in cisplatin group was lowered by N. sativa extract (15.81% in preventive groups and 13.87% in preventive + treatment groups) but this reduction was not significant. Therefore, the beneficial action of N. sativa on serum MDA concentration of the cisplatin-treated animals might be also due to its antioxidant effects. Although several investigations have reported that cisplatin caused a significant elevation in the kidney MDA concentration,[25],[33] our results did not show this alteration in the cisplatin-treated rats compared with the control animals. In another study, intravenous administration of cisplatin caused an increase in the rat liver MDA concentration, but it was not accompanied by increase of the kidney MDA concentration.[34] Thus, it seems that the effect of cisplatin administration on the status of tissue MDA content is organ dependent. However, duration and dosage of administration may be also involved in type of cisplatin-induced oxidative stress in various organs.


   Conclusion Top


The present work supports the role of oxidative stress in the pathophysiology of cisplatin-induced nephrotoxicity. N. sativa extract and Vitamin E were able to improve the kidney tissue damage and oxidative stress caused by cisplatin in the rat kidney. However, more studies are needed to clarify mechanisms involved in N. sativa action on cisplatin-induced kidney toxicity.


   Acknowledgment Top


This study was part of a M.Sc. thesis and financially supported by Research Council of Mashhad University of Medical Sciences, Mashhad, Iran.

Conflict of interest: None declared.

 
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Correspondence Address:
Dr. Abolfazl Khajavi Rad
Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad
Iran
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DOI: 10.4103/1319-2442.225208

PMID: 29456204

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    Abstract
   Introduction
    Materials and Me...
   Statistical Analysis
   Results
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    References
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