|Ahead of print publication
Attenuation of cisplatin-induced nephrotoxicity by ethanol extract of seeds of Lens culinaris medik
Adikay Sreedevi, Kaveripakam Saisruthi
Division of Pharmaceutical Chemistry, Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam, Tirupati, Andhra Pradesh, India
Division of Pharmaceutical Chemistry, Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam, Tirupati, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Aim: The present study was undertaken to evaluate the potential role of ethanol extract of seeds of Lens culinaris in attenuation of Cisplatin-induced nephrotoxicity in male Albino rats. Materials and Methods: Seeds of Lens culinaris were powdered, defatted and ethanol extract was prepared by hot extraction method. The ethanol extract so prepared was subjected to preliminary phytochemical evaluation and fingerprint analysis using high performance thin layer chromatography. Nephroprotective potential of extract was evaluated at 200 and 400 mg/kg b.w. in both curative and prophylactic regimens in male Albino rats. Nephrotoxicity was induced by single intra peritoneal injection of Cisplatin at a dose of 5 mg/kg b.w. Nephroprotective activity was assessed by determining serum markers, urinary parameters, lipid peroxidation and antioxidant levels in renal tissue. Results: Cisplatin had induced marked acute renal toxicity as manifested by a significant increase in serum marker levels, urinary total protein, lipid peroxidation and decrease in urinary creatinine, catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH). The administration of extract significantly attenuated the Cisplatin-induced nephrotoxicity remarkably by restoring the biochemical and oxidative stress markers in both curative and prophylactic regimens in a dose dependent manner. Histological and immunohistochemical studies also substantiated the biochemical studies. Conclusion: The findings of the present study provides corroborative scientific evidence for the attenuation of Cisplatin-induced nephrotoxicity by seeds of Lens culinaris and validates the ethno-medicinal use of this seeds as renoprotective agent.
Keywords: Cisplatin, Lens culinaris, nephroprotective, serum markers
| Introduction|| |
Herbal therapeutics of the nutrition field has become one of the most popular trends because herbal products not only comprise an important group of multi-component therapeutics, but are also known to be harmless. Several lines of evidence have underlined that many medicinal herbal supplements have the potential to become valuable complementary therapy for various renal disorders.,
Nephrotoxicity is the most common renal disorder which occurs mainly due to poisonous effect of some substances including environmental contaminants, chemicals and medication on the kidneys. Cisplatin is an important chemotherapeutic agent commonly used for the treatment of several tumors, but accumulates and causes severe damage in the kidneys. Approximately 25–35% of patients develop evidence of acute kidney injury following a single dose of Cisplatin. Several studies indicate that naturally occurring dietary substances having free radical scavenging and/or antioxidant properties could have excellent scope in mitigation of drug induced nephrotoxicity. Further, many medicinal plants have been claimed to possess protective effect against renal damage and urinary disorders in folklore and traditional medicine.
Lens culinaris Medik. (F: Fabaceae) are commonly called as lentils. Seeds of Lens culinaris are being considered as one of the most beneficial legumes for health. They are good sources of essential minerals such as calcium, vitamin B and constitute an important source of food. In traditional and folklore medicine, lentils are used as blood purifier, diuretic, anti fungal and to treat various kidney and gastric ailments. Earlier reports have suggested lentils to possess anti-diabetic, anti-cancer, anti-hyperlipidemic and excellent free radical scavenging activity. The present study was designed to demonstrate the effect of ethanol extract of Lens culinaris (EELC) against Cisplatin-induced nephrotoxicity.
| Materials and Methods|| |
Collection of Seeds of Lens culinaris
Lens culinaris Medik. seeds were purchased from local market and authenticated by botanist Dr. K. Madhava Chetty, Asst. Professor, Dept. of Botany, S.V. University, Tirupati, Andhra Pradesh and a voucher specimen (1129) was deposited in Dept. of Botany, S.V. University, Tirupati.
Preparation of ethanol extract
Seeds of Lens culinaris were powdered in a Wiley mill. The powdered seeds were defatted with petroleum ether and then macerated with ethanol for 24 h. Macerated material was refluxed for 3 h and then filtered. The procedure was repeated twice and all the filtrates were combined and subjected to distillation under reduced pressure.
Preliminary phytochemical screening
Preliminary phytochemical screening was carried out for ethanol extract of Lens culinaris (EELC) for the presence of active phytochemical constituents such as alkaloids, carbohydrates, steroids, proteins, tannins, flavonoids, gums, mucilage, glycosides, saponins and terpenes.
High Performance thin layer chromatography
Ethanolic extract of Lens culinaris was dissolved in methanol and used as a test solution for HPTLC. A 8 μL aliquot of the above test solution was loaded on 10 × 10 c aluminium packed TLC plate coated with 0.2 mm layer of silica gel 60F254(E. Merck Ltd., Darmstadt, Germany) stored in a desiccator. Application was done using Hamilton micro syringe (Switzerland), mounted on a Linomat V applicator. Spotting was done on the TLC plate and the plate was kept in TLC twin trough developing chamber allowing ascending development of the plate with the migration distance 80 mm (distance to the lower edge was 10 mm) was performed at 20250 C in a Camag chamber previously saturated for 30 min. Mobile phase employed for developing chromatogram was a mixture of Chloroform, Methanol, Toulene and Ethyl acetate in the ratio of 9:1:1:1. After development, the plate was dried using hot air for five minutes to evaporate solvents from the plate. Densitometric scanning was then performed with a Camag TLC Scanner 3 equipped with WinCATS Software and the chromatograms were recorded.
Animal handling and care
Healthy Wistar strain albino rats between 2-3 months of age and weighing about 150-200g were used in the present study. They were maintained in a 12 h light/dark cycle at a constant temperature 250 C with free access to standard rat pellet diet (Hindustan Lever Limited, Bombay, India) and water ad libitum. The experimental protocol was carried out according to the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), India and approved by the Institutional Animal Ethical Committee (IAEC) (Registration No.: 1677/PO/Re/S/2012/CPCSEA; Approval letter No. 1677/PO/Re/S/2012/CPCSEA/09 dated 23-12-2014).
Acute toxicity studies
Acute toxicity studies were carried out according to OECD 423 guidelines.
Evaluation of nephroprotective activity
Nephroprotective effect of EELC was evaluated at two different dose levels i.e., 200 and 400 mg/kg body weight in curative and prophylactic regimens. Nephrotoxicity was induced by a single intraperitoneal (i.p.) Cisplatin injection (5 mg/kg b.w.). Experimental animals were systematically randomized into nine groups of six animals each and the following treatment schedule was employed:
- Group I – Normal control – vehicle for 5 days.
- Group II – Cisplatin on day 1 + vehicle from day 5 to day 9.
- Group III – Cisplatin on day 1 + EELC (200mg/kg b. w.) from day 5 to day 9.
- Group IV – Cisplatin on day 1 + EELC (400mg/kg b. w.) from day 5 to day 9.
- Group V – Vehicle from day 1 to day 5 + Cisplatin (5 mg/kg, i.p.) on day 5.
- Group VI – EELC (200mg/kg b. w.) from day 1 to day 5 + Cisplatin on day 5.
- Group VII – EELC (400mg/kg b. w.) from day 1to day 5 + Cisplatin on day 5.
- Group VIII – Cisplatin on day 1 + cystone from day 5 to day 9.
- Group IX – Only higher dose of EELC (400mg/kg b. w.) from day 1to day 5.
Urine from animals of Groups I and IX was collected on day 5 and on day 9 urine from remaining groups was collected using metabolic cages. The urine samples were subjected for estimation of urinary functional parameters. The animals were sacrificed on the respective following days by cervical decapitation and blood samples were collected by cardiac puncture and were used for estimation of serum markers.
Assessment of serum and urinary parameters
Biochemical parameters such as Blood Urea Nitrogen (BUN) by DAM method, Serum creatinine (SC) by Jaffe's Alkaline picrate method, Urinary total protein (UTP) by Turbidity method and Urinary creatinine (UCr) by Alkaline picrate method were estimated by using commercial kits. Kidneys were isolated and used for anti-oxidant and histological studies.
Renal oxidative stress markers
Kidneys were homogenized in ice cold 0.05 M phosphate buffer with a pH 7.8 to obtain a 20% (w/v) homogenate. The homogenate was centrifuged at 10,000 rpm for 15 min and the clear supernatant obtained was immediately used for the analysis of antioxidant enzymes. Anti-oxidant studies were carried out by the estimation of levels of reduced glutathione, catalase, superoxide dismutase, and lipid peroxidation.,,,
Kidneys of two animals from each group were used for histological studies. The isolated kidneys were fixed in 10% neutral buffer formalin and processed with paraffin wax. Sections (5 microns) were stained with haematoxylin and eosin and were examined under light microscope.
Sections of formalin-fixed, paraffin-embedded kidneys were obtained on poly-L-lysine coated slides. Sections were deparaffinized in xylene, then rehydrated through a graded alcohol series. Antigen retrieval was performed by incubating slides in citrate buffer (pH 6.0) (10 mM) at 95 °C for 20 min. Endogenous peroxidase activity was blocked with 3% H2O2 for 30 min. To detect active kidney injury, molecule-1 (Kim-1/Havcr1) sections were incubated under humid conditions overnight at 4 °C with the anti-Kim-1/Havcr1 antibody (1:200; R and D systems, Inc., USA). Next day, the slides were washed three times in Tris buffers (pH 6.0) and were incubated with a biotinylated Goat Anti-Polyvalent Plus (Thermo Fisher Scientific, USA) for 30 min at room temperature. This step was followed by further wash in Tris buffer and incubation of slides at room temperature with a Streptavidin Peroxidase Plus (Thermo Fisher Scientific, USA) that binds to the biotin present on the secondary antibody. After washing in Tris buffer, the immune staining reaction product was developed using 3,3-diaminobenzidine (DAB Plus substrate, Thermo Fisher Scientific, USA). After immune reactivity, slides were dipped in distilled water, counterstained with Harris haematoxylin and finally the sections were dehydrated in xylene, mounted with DPX and cover slipped. Slides prepared were examined by light microscopy.
The data was expressed as mean + standard error. Mean values between the groups was considered statistically significant P < 0.05 after analyzing by one way ANOVA and was compared using Tukey-Kramer multiple comparison tests. Graph pad prism statistical software was used for the data analysis.
| Results|| |
Preliminary phytochemical studies
Phytochemical screening of the ethanol extract of seeds of Lens culinaris revealed the presence of carbohydrates, proteins, saponins, flavonoids, tannins and phenolic compounds.
High performance thin layer chromatography
HPTLC profile of ethanol extract of Lens culinaris is shown in [Figure 1]. Ethanol extract of EELC showed six polyvalent phytoconstituents and corresponding Rf values are from 0.06 and 0.77. The Rf value of the highest concentration of phytoconstituents was found to be 82.02 and its corresponding Rf value is 0.77 and is recorded in [Table 1].
|Figure 1: HPTLC Fingerprint profile of ethanol extract of Lens culinaris|
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Acute toxicity studies
Animals which received extract at 2000 mg/kg b.w were observed for 14 days and they did not show any clinical signs of toxicity or mortality. Hence the extract is safe at 2000 mg/kg b.w.
Assessment of nephroprotective activity
Effect of seeds of Lens culinaris on Cisplatin-induced nephrotoxicity has been represented in [Table 2] and [Table 3]. Administration of high dose of ethanol extract for 5 days does not show any deteriorative effects on kidneys.
|Table 2: Effect of ethanol extract of Lens culinaris on serum and urinary parameters|
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|Table 3: Effect of ethanol extract of Lens culinaris on renal oxidative stress markers|
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Effect of ethanol extract of Lens culinaris on serum and urinary parameters
Cisplatin exhibited a significant increase (P < 0.05) in BUN, serum creatinine, urinary total protein and decrease in urinary creatinine when compared to normal control. However the levels of BUN, serum creatinine, urinary total protein were significantly decreased and urinary creatinine levels significantly increased (P < 0.05) in EELC treated groups in dose dependent manner in both curative and prophylactic regimens [Table 2].
Effect of ethanol extract of Lens culinaris on Renal oxidative stress markers
The effect of EELC on Cisplatin-induced nephrotoxicity has been depicted in [Table 3]. Cisplatin induction resulted in oxidative stress which is evident because of a significant suppression (P < 0.05) of enzymatic antioxidant activities along with an elevation in the levels of lipid peroxides in the kidney tissue. Treatment with EELC at both dose levels in both regimens caused significant increase (P < 0.05) in GSH, SOD and CAT levels and significant decrease (P < 0.05) in LPO levels.
The histological examination of proximal tubular sections from normal rats showed regular architecture of cortex without any evidence of renal damage. The kidneys of Cisplatin-treated rats showed diffuse acute tubular necrosis, tubular dilatation, congestion and vacuolization. Treatment with EELC at low dose of 200 mg/kg in both curative and prophylactic regimens exhibited mild regenerative changes while treatment with extract at higher dose in both regimens showed marked regenerative changes and reduced renal damage [Figure 2].
|Figure 2: Histological studies. (a) Section of normal rat kidney showing normal organization of tubular epithelial cells and glomeruli (Group I). (b) Section of rat kidney showing necrotic changes in kidney tissues and congestion (Curative control) (Group II). (c) Section of rat kidney showing moderate regenerative changes in kidney tissue (curative lower dose). (d) Section of rat kidney showing marked regenerative changes in renal tubule and Bowman's capsule (curative higher dose). (e) Section of rat kidney showing congestion in glomeruli, vacuolization, and necrotic changes (Prophlactic control) (Group V). (f) Section of rat kidney showing mild regeneration of kidney tissue (prophylactic lower dose) (Group VI). (g) Section of rat kidney showing regenerative changes in kidney tissue and similar to normal architecture (prophylactic higher dose) (Group VI). (h) Section of rat kidney showing regenerative changes in kidney tissue and similar to normal architecture (prophylactic higher dose) (Group VI). (i) Section of rat kidney showing almost normal organization of Bowman's capsule and distal convoluted tubule (Only higher dose of ethanol extract of Lens culinaris) (Group IX). RT: Renal tubule, BC: Bowman's capsule, PT: Proximal tubule|
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Kidney sections of rats which received Cisplatin alone showed marked expression of KIM-1 while the extract treated groups showed relatively less expression of KIM-1 compared to disease control [Figure 3].
|Figure 3: Immunohistochemical studies: (a) Normal Kidney architecture showing absence of KIM-1 expression (Group I). (b) – Kidney section showing marked expression of KIM-1 (Group II). (c) Kidney section showing moderate expression of KIM-1 (Group III). (d) Kidney section showing mild expression of KIM-1 (Group IV). (e) Kidney section showing profound expression of KIM-1 (Group V). (f) Kidney section showing moderate expression of KIM-1 (Group VI). (g) Kidney section showing reduced expression of KIM-1 (Group VII). (h) Kidney section showing mild expression of KIM-1 (Group VIII)|
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| Discussion|| |
Cisplatin is one of the most widely used cytotoxic therapeutic agents for the treatment of different cancers including testicular, head and neck, bladder, and lung cancers. It is an alkylating agent which at effective higher doses causes many adverse effects such as neurotoxicity, nephrotoxicity, and genotoxicity. Nephrotoxicity is a key complication in cancer patients undergoing Cisplatin therapy. The Cisplatin concentration in proximal tubular epithelial cells is about five times the serum concentration. The disproportionate accumulation of Cisplatin in kidney tissue contributes to Cisplatin induced nephrotoxicity. The Cisplatin-induced nephrotoxicity is a multifaceted process and involves several mechanisms such as formation of ROS,, inflammation, and mitochondrial dysfunction. However, the exact mechanism related to Cisplatin-induced nephrotoxicity is unclear.
Recently much attention has been shown in search for novel therapeutic agents with reno-protective efficacy. Traditional medicine has many herbal resources for finding potent medicinal agents. Hence in the present study we investigated the nephroprotective potential of Lens culinaris in both curative and prophylactic regimens. The nephrotoxicity is a rapid process due to the reaction with the proteins in renal tubules. The renal damage is produced within one hour after administration. Hence the presence of protective agents in the renal tissues may reduce the toxic effects of Cisplatin. This is the rationale behind the prophylactic regimen.
The main pathological feature involved in Cisplatin-induced nephrotoxicity is renal proximal tubule epithelial cell injury with increase in serum creatinine, BUN, urinary total protein levels and decline in urinary creatinine. The present study also supported the earlier findings of Naziroglu et al., Mondi et al., and Naqshbandi et al. in that, groups teated with Cisplatin (5mg/kg b.w) alone showed significant elevation in the levels of serum creatinine, BUN, urinary total protein and decline in urinary creatinine levels.,, Like Zingiber officinale, Hygrophila spinosa, Boerhavia diffusa treatment with seeds of Lens culinaris significantly (P < 0.05) reduced the elevated serum creatinine, BUN, urinary total protein and increased the declined urinary creatinine levels at both dose levels in both curative and prophylactic regimens as compared to Cisplatin-treated group., This may be due to occurrence of regenerative changes in glomeruli and renal tubules.
Oxidative stress has been recognized as an important and primary factor that contributes to Cisplatin nephrotoxicity. Formation of ROS by Cisplatin induces two main mechanisms in which the first and foremost is the hydrolysis of Cisplatin. In proximal tubular cells, the Cisplatin hydrolyzes into highly reactive form, which can rapidly react with thiol-containing molecules including glutathione (a well-recognized major cellular antioxidant). Depletion or inactivation of endogenous glutathione and other related antioxidants (SOD) by Cisplatin is expected to shift the cellular redox status, leading to the accumulation of ROS and oxidative stress within the cells., The second mechanism implicated is mitochondrial dysfunction and increase in ROS production via the disrupted respiratory chain.
Our findings revealed that the EELC administration at a dose of 200 and 400 mg/kg orally in both regimens was able to stem the decline in antioxidant enzymes (SOD, GSH) and suppressed the increase in lipid peroxidation levels. Our preliminary phytochemical studies revealed that EELC contains antioxidant principles such as phenolic (flavonoids and tannins) compounds. Presence of these phytoconstituents may efficiently combat antioxidant stress which opposes the declivity in the antioxidant enzymes.,, Histological and immuno-histochemical findings also substantiated the biochemical studies.
| Conclusion|| |
The findings of the present study reveals that seeds of Lens culinaris effectively ameliorate Cisplatin-induced nephrotoxicity in rats. Further the study provides corroborative scientific evidence and validates the ethno-medicinal use of this seeds as renoprotective agent.
The author is highly thankful to University Grant Commission for providing financial support to carry out the research work under Research Award Scheme (L. No: 30-1/2014/RA2014-16-OB-ANP-5256 [SA-II]).
Financial support and sponsorship
University Grant Commission under Research Award Scheme (L. No: 30-1/2014/RA2014-16-OB-ANP-5256 [SA-II]).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]