Defensive Role Of Rosmarinus Officinalis In Carbon Tetrachloride-Induced Nephrotoxicity And Oxidative Stress In Rats

Review Article

Defensive Role Of Rosmarinus Officinalis In Carbon Tetrachloride-Induced Nephrotoxicity And Oxidative Stress In Rats

Corresponding author: Govt. NMV Hoshangabad (Barkatullah University) Bhopal-461001, India; Email: mirajaz.777@gmail.com

Abstract

There is a growing demand for remedies from natural sources to substitute synthetic therapeutic drugs and minimize their side effects and toxicity. With the same objective, the present study was undertaken to check the defensive ability of Rosmarinus officinalis in Carbon tetrachloride CCl4-challenged male albino rats. Thirty six rats were divided into six groups (n=6).Group I (control) received distilled water for 30 days orally. Nephrotoxicity was induced by CCl4 (11 % v/v with olive oil, i.p) 2 ml/kg Body weight (b.wt.) in Group II once a week for 30 days. Group III and IV received only herb in two doses 100 and 250 mg/kg of b.wt. Respectively. Group V and VI received ethanolic extract of Rosmarinus officinalis(EERO, 100 and 250 mg/kg of b.wt.) along with 2 ml/kg b. wt. CCl4 weekly for 30 days.CCl4 treatment induced highly significant(P<0.001) elevation in kidney biomarkers i.e. blood urea nitrogen and creatinine; kidney biochemicals i.e. LPO and XOD and decrease the levels of superoxide dismutase, catalase, glutathione peroxidase and glutathione in tissue. However, EERO significantly (P<0.001) restored the altered levels of these biomarkers in a dose dependent manner. Furthermore EERO also prevents histological alteration caused due to the toxicity of CCl4. Our findings strongly support that ethanolic extract of Rosmarinus officinalisacts as potent scavenger of free radicals to prevent the toxic effect of CCl4 and hence validate its ethnomedicinal use.

Keywords: Nephrotoxicity; Rat; carbon tetrachloride; Rosmarinusofficinalis; histopathology

Introduction

Nephrotoxicity is one of the most common kidney problems and occurs when body is over exposed to a drug or toxin [1]. A number of therapeutic agents can adversely affect the kidney resulting in acute renal failure, chronic interstitial nephritis and nephritic syndrome because there is an increasing number of potent therapeutic drugs like amino glycoside antibiotics, Non-steroidal anti-inflammatory drugs(NSAID’s), chemotherapeutic agents which have been added to the therapeutic arsenal [2].  Exposure to chemical reagents like ethylene glycol, CCl4, sodium oxalate and heavy metals induce nephrotoxicity. Prompt recognition of the disease and termination of responsible drugs are usually the only necessary therapy [3].

India is experiencing a rapid health transition with large and rising burdens of chronic diseases, which are estimated to account for 53% of all deaths and 44% of disability [4]. According to World Health organization (WHO) Global Burden of Disease project, diseases of the kidney and urinary tract contribute globally with approximately 850,000 deaths every year and 115,010,107 disability adjusted life. Chronic Kidney Diseases (CKD) is 12th leading cause of death and 17th cause of disability. Treatment of kidney-related diseases is very expensive, relatively unavailable with high incidences of adverse effects and failure [5]. Due to the expensive and complex treatment system, very few patients are able to obtain adequate medicinal facility.

Therefore, medicinal plants have been used by all civilizations as a source of medicines since ancient times. In the recent times, there has been growing interest in exploiting the biological activities of different Ayurvedic medicinal herbs, due to their natural origin, cost effectiveness and lesser side effects [6]. Interest in medicinal plants as a re-emerging health aid in the maintenance of personal health and well-being has been fuelled by rising costs of prescription drugs, and the bioprospecting of new plant-derived drugs [7].

The medicinal plant Rosmarinus officinalis, commonly known as rosemary, belongs to family Lamiaceae, has been used as medicinal, culinary and cosmetics in ancient Egypt, Mesopotamia, China and India [8]. It is used as carminative, rubifacient, and stimulant and as flavouring agent for liniments, hair lotions, inhaler, soaps and cosmetics [9] and as a cholagogue, diaphoretic, digestant, diuretic, esmmenagogue, laxative and tonic [10]. It is also having potent role in treatment and prevention of diseases like bronchial asthma, spasmogenic disorders, peptic ulcer, inflammatory diseases [11], hepatotoxicity, atherosclerosis biliary upsets, as well as for tension headache, renal colic, heart disease, and poor sperm motility [12, 11]. Phytochemical screening of rosemary revealed the presence of phylobatannins, reducing sugar, flavonoids, alkaloids, carbohydrates, tannins glycosides and terpenoids [13, 14].

CCl4-induced nephrotoxic rats have been considered as a good model for evaluation of nephroprotective agents. Carbon tetrachloride, besides exerting its toxic effect on liver, also reportedly gets distributed at higher concentrations in the kidney than in the liver [15].Various studies have demonstrated that CCl4 causes free radical generation in many tissues including kidney [16]. suggested a role for reactive oxygen metabolites as one of the postulated mechanisms in the pathogenesis of CCl4 nephrotoxicity 17]. reported that CCl4 resulted in enhanced generation of trichloromethyl peroxyl radical and hydrogen peroxide in cultured hepatocytes as well as mesangial cells in kidney. In addition, report on various documented case studies established that CCl4produces renal diseases in humans [18].  In vitro and In vivo studies indicate that CCl4 enhances lipid peroxidation, reduces renal microsomal NADPH cytochrome P450, and renal reduced/oxidized glutathione ratio (GSH/GSSG) in kidney cortex as well as renal microsomes and mitochondria [19].However, not much pharmacology data regarding the nephrocurative and antioxidant effect of Rosmarinus officinalisis available. So, the present study was designed to evaluate the protective potential of Rosmarinus officinalis against carbon tetrachloride-induced nephrotoxicity and oxidative stress in rats.

Materials and Methods

Chemicals and reagents

All the chemicals used were of analytical grade obtained from Merck, Mumbai and HiMedia, Mumbai. Blood urea and creatinine investigations were performed using commercial available diagnostic kits of Erba Mannheim, Germany.

Preparation of Rosmarinus officinalis extract

Upper shoot of Rosmarinus officinaliswas purchased from Indian institute of integrative medicine, Srinagar J&K, India. The plant material was washed with double distilled water and thereafter shade-dried for the period of 3 weeks at room temperature. The fully dried plant material was powered with the help of mechanical grinder. The powder was extracted in 90% ethanol by using the Soxhlet extractor. The ethanol extract was then dried under vacuum and the semisolid material thus obtained was stored in storage vials which were kept at -4ºC for further use. The fresh stock solution of Romarinus officinalis 80 mg/ml was prepared in double distilled water just before use.

Experimental Animals

Wistar albino rats, weighing (235±15 gms.) were obtained from animal house of Pinnacle Biomedical Research Institute (PBRI), Bhopal, Madhya Pradesh and India. Animals were maintained under standard conditions of temperature 23 ± 1 ºC and with regular 12:12 hour’s light/dark cycle and allowed free access to standard laboratory food (Golden feeds, Delhi) and water ad libitum. All animal experiments were performed as per the guidelines of committee for the purpose of control and supervision on experiments on animals (CPCSEA Reg. No. – 1283/c/09/CPCSEA).Animal experiments were performed with prior permission from Institutional Animal Ethics Committee (IAEC) of PBRI, Bhopal (Approval No.  PBRI/13/IAEC/PN-296a).

Experimental Animals

The animals were divided at random into six groups of six animals each and treated as fallows.

Group I (control): received distilled water for 30 days orally.

Group II: received carbon tetrachloride (11 % v/v with olive oil) 2ml/kg b. wt. once a week for 30 days.

Group III and IV received only herb EERO (ethanolic extract of Rosmarinus officinalis) at the doses of 100   mg/kg and 250 mg/kg of b. wt. for 30 days respectively.

Group V received EERO orally 100 mg/kg of b. wt. daily followed by dose of CCl4 2 ml/kg b. wt. once a week for 30 days.

Group VI received 250 mg/kg b. wt. of EERO daily followed by dose of CCl4 2ml/kg b. wt. once a week for 30 days.

At the end of experiment, animals were fasted overnight, blood samples were collected by cardiac puncture, under light diethyl ether anesthesia into previously labeled EDTA retaining tubes and centrifuged in Remi centrifuge at 40C for 10 minutes at 5000 rpm as to get the plasma. The obtained plasma was used for the measurement of kidney markers like blood urea nitrogen (BUN) and creatinine by using commercially available kits. Then animals were dissected out and kidney was excised, washed in freshly prepared ice-cold 0.9% saline to remove blood and freed from fat. Then homogenate was prepared in phosphate and tris HCl buffers.

Biochemical Parameters

Blood urea nitrogen was determined by GLDH Urease Method, Initial Rate [20, 21] while Creatinine was estimated by Jaffe’s method [22, 23, 24].

Antioxidant Assay

The kidneys were minced separately into small pieces and homogenized with ice cold 0.05 M potassium phosphate buffer and tris HCl buffer to make 10% homogenates. The homogenates were centrifuged at 4500 rpm for 15 minutes at 4 °C. The supernatant was collected for estimations of Superoxide dismutase (SOD) by [25]. Catalase (CAT)  by [26], Glutathione Peroxidase (GPx) by [27], Glutathione (GSH)  by [28], Xanthine oxidase (XOD) by [29] and Lipid peroxidation (LPO) by [30].

Histopathological Studies

Portions of each kidney from all the experimental groups were fixed in 10% formaldehyde, dehydrated in graded alcohol, cleared in xylene and then embedded in paraffin. Microtome sections (5 μm thick) were prepared from each kidney sample and stained with heamtoxylin-eosin dye and processed further as described by [31].The sections thus obtained were then examined for the pathological findings and later on scanned in microscope (Olympus ‘CH20I’ Trinoculor) at 40X with photographic facility and photomicrographs were taken using Sony digital camera attached to the microscope.

Statistical Analysis

Data were expressed in MeanSD. Statistical comparison between different groups was done by using One Way ANOVA followed by Benferroni’s test. P<0.05 and P<0.001 were considered as levels of significance.

Results

Effect of Ethanolic Extract of Rosmarinus officinalis on CCl4 Induced Changes

The level of Blood Urea Nitrogen (BUN) and creatinine in control group of rats was 17.99 ± 1.20 mg/dL and 0.88 ± 0.14 mg/dL respectively. Intra-peritoneal administration of CCl42ml/kg b.w. once a week for 30 days caused abnormal renal function in all experimental animals. Blood urea nitrogen (BUN) and creatinine levels were highly significantly (P<0.001) elevated to 39.62 ± 3.20 mg/dL and 2.08 ± 0.21 mg/dL i.e. increased by +54.59% and +57.69% respectively of their control values.

However, the animals which received ethanolic extract of Rosmarinus officinalis at 100 mg/kg and 250 mg/kg, no significant variations in the levels of BUN and creatinine was noticed and the values of these parameters in EERO 100  mg/kg treated group of rats were as BUN19.47 ± 1.92 mg/dL, and 0.97 ± 0.10 mg/dL of creatinine and the marginal and non-significant percentage inhibition for these kidney markers against control group of rats was (+7.60%) and (+9.72%) respectively. In group of rats supplied with EERO 250 mg/kg, the levels of BUN and creatinine was18.10±1.55 and 0.96±0.21 mg/dL with percentage inhibition (+0.60%) and (+8.33%) against control group of rats respectively. Thus, these results revealed that the EERO was not having any type of side effect on kidneys. Hence, the extract was safe at selected doses. Pre-treatment with EERO at 100 mg/kg along with CCl4 restored the altered levels of BUN and creatinine to 22.19 ± 2.12 mg/dL and 1.07 ± 0.17 mg/dL and their percentage inhibition was (−43.99%) and (−48.55%) respectively, were highly significant as compared to 2 group i.e. the rats which were intoxicated with CCl4. However, in group sixth i.e. animals which received EERO at 250 mg/kg along with CCl4, the levels of BUN and creatinine was further reduced by (−53.15%) and (−50.96%) respectively (Table 1) the reduction in the levels of BUN and creatinine was highly significant when compared to that of group II. Thus the extract showed protective effect at both doses i.e. 100 and 250 mg/kg against carbon tetrachloride-induced nephrotoxicity and the protection was offered in a dose dependent manner.

Effect of Ethanolic Extract of Rosmarinus officinalis on Renal Antioxidant Profile

We also studied various enzymes in kidney homogenate which are involved in oxidative stress and the findings of our investigation with control group of rats revealed the levels of SOD, CAT,

GSH,GPx,LPO and XOD as 2.92 ± 0.10 U/mg, 24.49 ± 2.01 U/mg, 533.17 ± 11.94 nM/mg, 5.92 ± 0.19 U/mg, 0.220 ± 0.011 nM/mg, 307.86 ± 27.70 IU/g respectively. However, CCl4-intoxication significantly decreased the activity levels of SOD to 1.85 ± 0.180 U/mg (−36.64%), CAT to 12.59 ± 1.91 U/mg (−48.59%), GSH to 310.80 ± 9.92 nM/mg (−41.70%), GPx to 3.97 ± 0.27 U/mg (−32.93%) and elevated the level of LPO and XOD to 0.431 ± 0.042 nM/mg (+48.95%) and 615.61 ± 20.19 IU/gm (+49.99) respectively. In Group III of rats which received EERO at 100 mg/kg, the activity levels of SOD, CAT, GSH, GPx, LPO and XOD were near control levels viz. 2.73 ± 0.14 U/mg, 22.51 ± 2.10 U/mg, 526.88 ± 15.23 nM/mg, 5.93 ± 0.09 U/mg, 0.269±0.008 nM/mg and 321.02±16.70 IU/gm respectively. The percentage inhibition of SOD, CAT, GSH, GPx, LPO and XOD in 100 mg/kg of EERO treated group against control group was (−6.50%), (−8.08%), (−1.17%), (+0.16%), (+18.21%) and (+4.09%) respectively. However, in group IV i.e. the group of rats supplied with EERO at 250 mg/kg, the results observed were in close proximity to control levels viz. SOD 2.71 ± 0.11 U/mg, CAT 26.25 ± 2.27 U/mg, GSH 535.76 ± 11.46 nM/mg, GPx 5.94 ± 0.11 U/mg, LPO 0.257 ± 0.015 nM/mg and XOD 315.73 ± 21.76 IU/gm with percentage inhibition (−7.19%), (+6.70%), (+0.48%), (+0.33%), (+14.39%) and (+2.49%) respectively for SOD, CAT, GSH, GPx, LPO and XOD. These results clearly indicated the non-toxic nature of EERO on both selected doses.

The activity levels of SOD, CAT, GSH and GPx were significantly elevated whereas, the activity levels of LPO and XOD were significantly reduced in rats treated with both 100 mg/kg of EERO along with CCl4 (group 5th) viz. SOD 2.36 ± 0.17 U/mg (+21.61%), CAT 17.93±2.07 U/mg (+29.78%), GSH 506.90±15.48 nM/mg (+38.68%), GPx 5.75 ± 0.19 U/mg (+30.95%), LPO 0.306±0.013 nM/mg (−29.00%) and 351.27±27.12 IU/gm(−42.93%). However, further elevation in the activity levels of SOD, CAT, GSH, GPx was noticed when rats were given access to 250 mg/kg of EERO alongside with CCl4 (group 6th) viz. SOD 2.57±0.11 U/mg (+28.01%), CAT 21.04 ± 1.85 U/mg (+40.16%), GSH 520.22 ± 15.10 nM/mg (+40.25%), GPx 5.86±0.13 U/mg (+32.25%) but the levels of LPO and XOD were reduced to 0.241±0.011 nM/mg (−44.08%) and 325.69±23.72 IU/gm (−47.09%) respectively. These results obtained clearly illustrated dose -dependent working potential of ethanolic extract of Rosmarinus officinalis (EERO).

Effect of Ethanolic Extract of Rosmarinus officinalis on Renal Histopathology

The biochemical results of our investigations were fully assured by histopathological examinations of kidney micro sections. The histological inspection of the kidney of control rats(Group I) revealed that the cortex consists of several Bowman’s capsule which are double layered cup like structure inside highly anatomizing set of connections of afferent and efferent arterioles called glomerulus were present. The cortical tubules were well structured with connective tissue and inter tubular spaces. Tubular walls were made up of thick epithelial cells. Urinary space and vascular pole were well defined. On other hand, CCl4-inebriated rats (Group II) showed glomerular hypertrophy, degeneration of epithelial layer of Bowman’s capsule, prominent loss of urinary space between glomerulus and Bowman’s capsule, loss of brush border in proximal tubules, inflammatory cell infiltrations, and cast formation in renal tubules, moderate to severe necrosis of tubular epithelium, congestion and dilation of blood vessels. However, the treatments of EERO at 100 mg/kg and 250 mg/kg i.e. Group III and Group IV, showed similar structural design of micro sections of kidney as that of control group of rats.

On the other hand, when CCl4 intoxicated rats were supplied with EERO 100 mg/kg (Group V), the kidney sections showed normal architecture but still slight hyper cellularity was observed in glomerulus. However, in case group VI which received EERO at 250 mg/kg along with CCl4,normal structure of kidney was witnessed as evident from well-defined Bowman’s capsule with glomerulus, distinct urinary space, and normal proximal and distal convoluted tubules.

Table1: – Effect of ethanolic extract of upper shoot of Rosmarinus officinalis (EERO) on BUN, urea and creatinine in CCl4 induced nephrotoxicity in rats.All data presented in MeanSD (n6) and * P0.001 as compared to CCl4 treated group.

+ = increase,  = % decrease, CCl4 treated group and only herb treated were compared with control and rest of groups were compared with CCl4 treated group.

Table 2: – Effect of ethanolic extract of Rosmarinus officinalis(EERO) on, SOD, CAT,GSH, GPx, LPO and XOD in CCl4 induced nephrotoxicity in rats.

All data presented in MeanSD (n6) and * P0.001 as compared to CCl4 treated group.

+ = increase, =% decrease, CCl4 treated group and only herb treated were compared with control and rest of groups were compared with CCl4 treated group.

 All data presented in MeanSD (n6) and * P0.001 as compared to CCl4 treated group.

+ = increase, =% decrease, CCl4 treated group and only herb treated were compared with control and rest of groups were compared with CCl4 treated group.

Fig.1                                                                Fig.2


 Fig.3                                                           Fig.4

 

                                                          Fig.5                                                                Fig.6

 Photomicrographs of T.S. of kidney

Fig. 1( Group I) – control group of rats showing normal architecturewith well defined Bowman’s capsule (BW) with glomerulus(G), proximal convoluted tubules (PCT), distal convoluted tubules (DCT), urinary space (US) and vascular pole (VP) (40X, haematoxylin- eosin stain).

Fig. 2 – shows Photomicrographs of kidney of rats inebriated with CCl4 (2 ml/kg with 50% olive oil, weekly for 30 days).

Fig. 3 and 4 shows the kidney section of only EERO treated rats at the dose of 100 mg/ kg and 250 mg/kg of body weight.

Fig. 5 shows the photomicrographs of kidney of rats treated with daily dose of EERO 100mg/kg and CCl4 once a week.

Fig. 6 shows the photomicrographs of kidney of rats treated with daily dose of 250 mg/kg of EERO and CCl4 once a week.               

Discussion

Carbon tetrachloride, besides exerting its toxic effect on liver, also reportedly gets distributed at higher concentrations in the kidney than in the liver [32]. The mechanism of CCl4-renal toxicity is almost same as that of the liver, but CCl4 shows a high affinity to the kidney cortex which contains cytochrome P-450 predominantly [33, 34]. Cumulative data suggest a role for reactive oxygen metabolites as one of the postulated mechanisms in the pathogenesis of CCl4 nephrotoxicity [35]. Kidneys have some fragile responsibilities, especially when they have to deal with unwanted substances, which they have to clear from the system, especially toxins. Kidney toxicity caused a rapid decline in renal functions that is mainly attributed to decrease in glomerular filtration rate (GFR) and lack of ability of the kidney to excrete these toxic metabolites produced in our body resulting in abnormal retention of renal biomarkers i.e. blood urea nitrogen and creatinine [36]. Also increase in urea levels might indicate impairment in renal function [37]. So, it is worth to analyze these kidney biomarkers to study the carbon tetrachloride-induced nephrotoxicity.

As expected, administration of CCl4 (2 ml/kg i.p.) resulted in an obvious nephrotoxicity as evident by significant increase the levels of kidney biomarkers such as blood urea nitrogen (BUN) and creatinine. The observed nephrotoxic effect of CCl4 was similar to those of previously reported [38, 39, 13). In renal diseases, the serum urea accumulates because its rate of production exceeds the rate of clearance [40]. Also the concentration of creatinine is known to correlate inversely with the degree of glomerular filtration. Hence, creatinine is considered to be among the useful markers of the filtration task of kidneys, predominantly that creatinine is excreted only via the kidneys. Evaluation of urea and creatinine levels in the serum was taken as index of nephrotoxicity [41, 42]. In our study, the increased level of BUN and creatinine was highly significantly restored near to normal levels when CCl4-intoxicated rats were given access to EERO at 100 mg/kg and 250 mg/kg of b. wt. in a dose dependent manner. In agreement with the results of present study, various investigators reported that the increased levels of BUN, and creatinine as a result of toxicities were restored when the rats were treated with herbal extracts [43, 44, 45, 13].

Exposure to CCl4 induces acute and chronic renal injuries as well as oxidative stress and is also known to produce renal diseases in humans [46, 47]. We also studied various biochemicals in kidney homogenate which are involved in oxidative stress. Results obtained shows highly significant decrease (P<0.001) in antioxidant markers, GSH, CAT, SOD and GPx however, highly significant increase (P<0.001) was notice in the levels of XOD and LPO in the CCl4 treated group when compared with the control rats. Depletion of endogenous enzymatic and non-enzymatic antioxidants in CCl4intoxicated group could be attributed to CCl4 generated cellular ROS production and the subsequent depletion of the antioxidant cellular system [48, 49, 50, 51, 52]. On the other hand, treatment with EERO alone at 100 mg/kg and 250 mg/kg does not show any significant change in the level of these biomarkers as compared with the control group. This clearly showed nontoxic nature of EERO at both selected doses. However, the altered level of these antioxidant markers

GSH, CAT, SOD, GPx , XOD and lipid peroxidation (MDA) were highly significantly restored (P<0.001) in dose dependent manner when the rats were given access to EERO 100 mg/kg and 250 mg/kg of body weight when compared to CCl4 intoxicated group. Our findings were in concordance with other researchers [53, 54, 55,56].

The kidneys of the control and only herb treated groups showed normal histological features [Fig. 1, 3 and 4] respectively. In group II i.e. animals intoxicated with CCl4, there were apparent evidences of renal toxicity as glomerular showed hypertrophy, epithelial layer of Bowman’s capsule was degenerated with prominent loss of urinary space between glomerulus and bowman’s capsule, inflammatory cell infiltrations, cast formation in renal tubules, disappearance of tubular epithelium, moderate to severe necrosis, congestion and dilation of blood vessels [Fig. 2]. In CCl4+100mg/kg of EERO treated group, the glomeruli showed slight hypercellularity [Fig. 5]. However, in case of CCl4+250 mg/kg of body weight group kidney section revealed normal structure as that of control group [Fig. 6]. Our finding with respected to histopathology were in full agreement with [57, 58].

Conclusion

This study substantiated the scientific evidence in favour of pharmacological uses of Rosmarinus officinalis. The findings of our present investigation adequately proved the nephroprotective and antioxidant potentials of ethanolic extracts of Rosmarinus officinalisin rats challenged with CCl4, by preventing the allteration in kidney markers (BUN and Creatinine), Kidney biochemical’s (SOD, CAT, GPx, GSH and XOD) and also prevents lipid peroxidation. Furthermore, our findings with kidney biomarkers were fully supported by histopathological studies. This protective potential of EERO may be due to its high antioxidant potential.

Acknowledgement: We are highly thankful to Pinnacle Biomedical Research Institute (PBRI), Bhopal for providing us the laboratory facilities.

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