Nephroprotective and Nephrocurative Activity of Alangium Salvifolium Against Gentamicin Induced Nephrotoxicity in Albino Rats

Karra Geetha et al. / Journal of Pharmacy Research 2014,8(4),576-583 Research Article Available online through ISSN: 0974-6943 http://jprsolutions.info Nephroprotective and nephrocurative activity of Alangium salvifolium against Gentamicin induced nephrotoxicity in albino rats

Karra Geetha*1, Nadenla Ramarao 2 1CMR College of Pharmacy 1, Kandlakoya, Medchal, Hyderabad, Andhra Pradesh, India 2Chalapathi Institute of Pharmaceutical Sciences 2, Lam, Guntur, Andhra Pradesh, India

Received on:09-03-2014; Revised on: 26-03-2014; Accepted on:11-04-2014

ABSTRACT Objective:To study the nephroprotective, nephrocurative effect of Alangium salvifolium ethanolic bark extract in gentamicin induced nephrotoxicity. Materials and methods: Nephrotoxicity was induced in wistar male rats by intraperitoneal administration of gentamicin at 40mg/kgb.wt /day for 21 days. Alangium salvifolium was selected to check the effect by using ethanolic bark extract with different doses (250,500,750 mg/kg body weight respectively), was given by oral route. Serum parameters (serum creatinine, serum urea,serum proteins, and blood urea nitrogen (BUN)), urine parameters (urine creatinine and urine volume) and other parameters like body weight, in vivo antioxidants catalase, reduced glutathione (GSH) and Lipid peroxidase level were determined on 22nd day in wistar male rats .Histopathological study of kidney was studied. Results: The three doses of the extracts produced significant nephroprotective, nephrocurative activities with increased doses. The increased actions of nephroprotective, nephrocurative activity in gentamicin induced nephrotoxicity models as evident by decrease in serum creatinine, serum urea,serum proteins, urine creatinine, BUN levels and lipid peroxidation (MDA).The increased glutathione (GSH), catalase (CAT) activities when compared to gentamicin control group which was further confirmed by histopathological study. Conclusion:The study revealed that ethanolic bark extract of Alangium salvifolium reversed the nephrotoxicity induced by gentamicin experimental animals. This indicates that Alangium salvifolium bark ethanolic extract can be used as an adjuvant with gentamicin to get the therapeutic benefit of these drugs without chances of its prominent nephrotoxicity side effect.

KEYWORDS: Alangium salvifolium, nephroprotective, nephrocurative, antioxidants, gentamicin.

1. INTRODUCTION Drugs were shown to cause nephrotoxicity effects by one or more duced dose-dependent nephrotoxicity in 10-20% of therapeutic common pathogenic mechanisms. Drug-induced nephrotoxicity tends courses [3]. Gentamicin generates hydrogen peroxide in rat renal cor- to be more common among certain patients and in specific clinical tex mitochondria and it can also enhance the generation of reactive situations. Therefore, successful prevention requires knowledge of oxygen species (ROS) [4]. Abnormal production of ROS may damage pathogenic mechanisms of kidney injury, drug-related risk factors, some macromolecules to induce cellular injury, direct tubular necro- patient-related risk factors, and preventive measures, coupled with sis, without morphological changes in glomerular structures [5, 6]. Pos- vigilance and early intervention [1, 2]. sible gentamicin mechanisms to induce nephrotoxicity are peroxidation of membrane lipids, protein denaturation and DNA damage [7-9].Gen- A number of antibiotics including the tetracyclines, cephalosporins, tamicin also acts as an iron chelator and the iron-gentamicin complex penicillins, as well as aminoglycosides and sulfonamides, are poten- is a potent catalyst of free radical generation. tial nephrotoxins. Gentamicin, a typical aminoglycoside antibiotic is widely used in clinical practices for the treatment of life threatening Alangium salvifolium(L.f) Wang belongs to family Alangiaceae. Lo- gram-negative infections. This antibiotic generally causes drug-in- cally it called as Ankolam. Alangiaceae is a monogeneric family of trees and shrubs found in tropical and subtropical region.The plant is distributed in dry regions, plains and lower hills in India, Africa, Srilanka, and China. *Corresponding author. K.Geetha Alangium salvifolium wang was medicinally used in India, China and CMR College of Pharmacy, Kandlakoya (v), Medchal(M), Philippines. The parts of the plant are used to treat different diseases. Hyderabad, Andhra Pradesh, India. Root bark was used as an antidote for rabies. Fruits are sweet and it’s

Journal of Pharmacy Research Vol.8 Issue 4.April 2014 576-583 Karra Geetha et al. / Journal of Pharmacy Research 2014,8(4),576-583 used to treat burning sensation, constipation and haemorrhage. Stem Group-I (Normal control): received saline (1ml/kg b.wt, p.o). bark exerts a biphasic action on the blood pressure in cats at lower Group II (Toxic control): received gentamicin (40mg/kg b.wt for doses and marked hypotension in higher doses. 21days i.p). Group III (Plant control): received plant extract (200mg/kg b.wt for The plant has been reported for its antitubercular, antispasmodic, 21 days p.o). antiarthritis, antibacterial, anti fungal and anticholinesterase activity. Group IV (prophylactic): received gentamicin (40mg/kg b.wt, i.p) + This plant was used as antirheumatic agent by the local people of 250mg/kg b.wt of plant extract (p.o). Vellore and Tirupattur districts in Tamilnadu. Root bark was used as Group V (prophylactic): received gentamicin (40mg/kg b.wt, i.p) + an anthelmintic, antiemetic, febrifuge, hypoglycemic, purgative, 500mg/kgb.wt of plant extract (p.o). antileprotic agent and other skin diseases. The seed oil was used Group VI (prophylactic): received gentamicin (40mg/kg b.wt, i.p) + medicinally for externally and internally with palm jaggery for syphi- 750mg/kg b.wt of plant extract (p.o). litic ulcers and scabies, gonorrhea and internally for leprosy. Stem bark used to control vomiting and diarrhea. Previously ethanol ex- The IV,V, VI Prophylactic group animals were treated with gentamicin (40mg/kg b.wt, i.p),1 hr prior to administration of Alangium tract has been reported to possess anti-microbial,analgesic and anti- salvifolium bark ethanolic extract of respective doses for 13 days and inflammatory activities [10-17]. only plant extract of respective doses will be given from 14th-21st day.

2. MATERIAL AND METHODS Group VII (Curative Group): received gentamicin (40mg/kg b.wt, i.p) for 13 days and best dose of the plant extract from the prophylactic 2.1. Collection of plant materials: treatment was selected and will be given from 14th day to 21stday. Alangium salvifolium bark was collected from Hyderabad city and authenticated by P.V.Prasanna. (Scientist / officer In-charge) 2.5. Sample Collection: Botanical Survey of India bearing no. BSI/DRC/12-13/Tech./736. Rats were placed in metabolic cages over a period of 24hr and urine volume collected was measured and it was used for estimation of 2.2. Preparation of Alangium salvifolium extract: creatinine. The bark was allowed to dry under shade. The dried bark was pow- ered in a mill and extracted successively by using various solvents Animals were sacrificed on 22nd day of the study after collection of like n-hexane, ethyl acetate, ethanol, water. blood by retro orbital puncture and were centrifuged to separate the serum. It was used for estimation of creatinine, blood urea nitrogen Required quantity of ethanolic bark extract of Alangium salvifolium and total proteins. 250, 500,750mg/kg body weight of the rat was weighed and adminis- tered. 2.6. Parameters assessed:

2.3. Animals Body weight: Healthy wistar adult male albino rats weighing about 150-200gm were The weight of the animals (in grams) was noted on the 1st day and last housed in polypropylene cages and maintained at 24± 2 ºc under 12 day of the study and the difference in body weights was noted. hr light/dark and 60±5% humidity. They were fed with standard rat pellet diet and water ad libitum. Animals were acclimatized to our lab Serum creatinine: environment for about a week under laboratory conditions. All ex- Serum creatinine level was estimated by alkaline picrate method us- periments were performed according to the ethical standards of ani- ing creatinine kit and read absorbance at 520nm. mal handling and approved by Institutional Animal ethics committee (CPCSEA/1657/IAEAC/ CMRCP/PhD-l3/11-A). Blood urea Nitrogen (BUN): BUN level in serum was estimated by kit of Auto span Pvt Ltd. and 2.4. Experimental Protocol read the absorbance at 570nm. Fifty six male wistar rats were used for the study and animals were Total Proteins: divided into seven groups containing eight animals in each. Total proteins level in serum was estimated by kit of Auto span Pvt Ltd. and was read at 578nm. Journal of Pharmacy Research Vol.8 Issue 4.April 2014 576-583 Karra Geetha et al. / Journal of Pharmacy Research 2014,8(4),576-583 Urine volume: Volume of urine was measured in all groups during last 24 hrs of compared to gentamicin control group. The data was analyzed statis- experiment in all groups. tically by one way ANOVA followed by Dunnett test using graph pad prism 5.0 Software. Values are expressed as mean ± SEM (n =8). Where Urine creatinine: Urine creatinine was estimated by alkaline picrate *** (p<0.001)vs gentamicin control, ### (p<0.001) vs normal control. method using creatinine kit and read the absorbance at 520nm. 3. RESULTS GSH: GSH level in the kidney homogenate was estimated by the method of 3.1. Effect of Alangium salvifolium bark ethanolic extract on body Ellman.et al.1959. [18] weight in gentamicin induced nephrotoxicity: Table 1 Figure 1 shows effect of gentamicin on body weights. At the Catalase: end of the study, a significant weight loss (p<0.001) was observed as Catalase activity in kidney tissue was determined by measuring the a result of gentamicin administration as compared to the vehicle con- rate of decomposition of hydrogen peroxide at 240 nm, according to trol group. Alangium salvifolium ethanolic bark extract treatment sig- [19] the method given by Aebi et al 1974. nificantly attenuated gentamicin-induced changes in body weight.

Lipid peroxidation: 3.2. Effect of Alangium salvifolium bark ethanolic extract on The concentration of MDA in kidney homogenate was determined serum creatinine, blood urea nitrogen and total proteins: according to the method of Ohkawa et al. 1979. [20] Table 1 shows the levels of serum creatinine, total proteins and blood urea nitrogen increased significantly in gentamicin control animals Histopathological studies: when compared to normal animals. The level of serum creatinine, total Kidney of sacrificed rats was carefully dissected out. After rinsing in proteins and BUN was reduced significantly upon administration of normal saline the tissue was fixed in 10% formalin-saline dehydrated Alangium salvifolium ethanolic bark extracts (i.e.250mg/kg, 500mg/ with 100% ethanol solution and embedded in paraffin. Then it was kg and 750mg/kg p.o.). When compared to gentamicin control. The cut into 4-5µm thick sections stained with haematoxylin-eosin and observed under microscope (magnification power- 100X). curative group dose was selected based on the dose dependent activity of plant extract (i.e. 750mg/kg p.o.) Significantly reduced the 2.7. Statistical analysis increased level in serum creatinine, total proteins and BUN when All of the data obtained from the experimental groups have been compared with the gentamicin control. (Fig.2,3,and 4).

Table 1: Effect of Alangium salvifolium bark ethanol extract on Body weights, BUN, Serum creatinine and Total protiens against Gentamicin induced nephrotoxicity

S.No Group Difference in body BUN (mg/dl) Serum Creatinine Total Protein weights (gm) (Mean±SEM) (mg/dl) (g/dl) (Mean±SEM) (Mean±SEM) (Mean±SEM)

1 Normal control 30.90±4.89 12.39±0.36 0.15±0.00 5.43±0.22 2 Plant control 42.80±2.63*** 12.78±0.19*** 0.17±0.00*** 5.74±0.16*** 3 Gentamicin control -66.00±6.00*** 37.47±0.40## 1.52±0.09### 11.95±0.48### 4 Prophylactic (250mg/kg) 4.60±5.53*** 19.42±0.55*** 1.29±0.02* 8.60±0.28*** 5 Prophylactic (500mg/kg) 5.80±3.33*** 15.65±0.92*** 0.88±0.03*** 6.57±0.20*** 6 Prophylactic (750mg/kg) 5.80±1.24*** 13.37±0.33*** 0.70±0.03*** 5.95±0.22*** 7 Curative (750mg/kg) 10.00±3.16*** 14.92±13.66*** 0.99±0.10*** 9.05±0.61***

All of the data obtained from the experimental groups have been compared to gentamicin control group. The data was analyzed statistically by one way ANOVA followed by Dunnett test using graph pad prism 5.0 Software. Where Mean ± SEM (n=8) where *** P<0.001, **P<0.01, *P<0.05 compared to gentamicin control and ### P<0.001, ## P<0.01, # P<0.05 compared to normal control.

Journal of Pharmacy Research Vol.8 Issue 4.April 2014 576-583 Karra Geetha et al. / Journal of Pharmacy Research 2014,8(4),576-583

Body Weight Difference 40 ### 50

30 *** *** *** *** 0 20 *** *** *** *** -50 BUN (mg/dl) 10 body weig ht( gm) ### 0 -100

control control plant control plant control Gentamicin control curative(750 mg/kg) gentamicin control curative 750mg/kg prophylacticprophylact (250mg/kg)pic(rophy 500mglactic/kg) (750mg/kg) prophylacticpro 250phyla mg/kgcticprophy 500 mlacticg/kg 750mg/kg Drug treatment Drug treatment Fig.1: Effect of Alangium salvifolium bark ethanol extract on gen- Fig .3: Effect of Alangium salvifolium bark on gentamicin induced tamicin induced nephrotoxicity in terms of changes in body weight. nephrotoxicity in terms of changes in BUN.

2.0 15

### ### 1.5 10 * *** *** *** *** *** 1.0 *** *** 5 0.5 total protein (g/dl) se ru m creatinine (mg/dl) 0.0 0

control control plant control plant control

Gentamicin control curative(750 mg/kg) Gentamicin control curative(750 mg/kg) prophylacticprophylact (250mg/kg)prophyic( 500mglactic/kg) (750mg/kg) prophylacticpro (250mg/kg)phylactic(prophylactic 500mg/kg) (750mg/kg)

Drug treatment Drug treatment Fig. 2: Effect of Alangium salvifolium bark ethanol extract on gen- Fig. 4: Effect of Alangium salvifolium bark on gentamicin induced tamicin induced nephrotoxicity in terms of changes in nephrotoxicity in terms of changes in Total proteins. Serumcreatinine.

Journal of Pharmacy Research Vol.8 Issue 4.April 2014 576-583 Karra Geetha et al. / Journal of Pharmacy Research 2014,8(4),576-583 3.3. Effect of Alangium salvifolium bark ethanolic extract on urine 3.6. Effect of Alangium salvifolium bark ethanolic extract on MDA creatinine in gentamicin induced nephrotoxicity. and Glutathione Level in gentamicin induced nephrotoxicity: Table 2 and Fig. 5 shows that urine creatinine was increased in gen- Table2, Fig. 6 shows kidney tissue MDA levels were increased sig- tamicin and plant extract in prophylactic ((250 mg/kg, 500mg/kg and nificantly (p<0.001) by gentamicin administration as compared to the 750 mg/kg), curative (750 mg/kg) reduce the increased urine creati- normal control group but treatment of Alangium salvifolium bark nine significantly with the probability of *** P<0.001.It was an indi- ethanolic extract treated prophylactic groups (i.e 250mg/kg, cation of stabilization of plasma membrane as well as repair of kidney 500mg/kg, 750mg/kg.) and curative group (i.e.750mg/kg) reduced MDA tissue damage caused by gentamicin. Table 2: Effect of Alangium salvifolium bark ethanol extract on Urine creatinine, Urine volume, GSH, MDA and Catalase against Gentamicin induced toxicity. S No. Treatment Urine creatinine Urine GSH MDA Catalase (mg/dl) volume(ml) (µmole/gm of tissue) (µmole/gm of tissue) (u/mg of tissue) (Mean±SEM) (Mean±SEM) (Mean±SEM) (Mean±SEM) (Mean±SEM) 1 Normal Control 1.44±0.07 8.52±0.25 0.19±0.04 0.262±0.009 195.9±6.765 2 Plant control 1.478±0.09*** 8.01±0.20 0.05±0.002*** 0.227±0.002*** 198.7±9.141*** 3 Gentamicin Control 4.613±0.09### 5.12±0.98 0.039±0.002### 0.411±0.008## 106.4±3.473## 4 Prophylactic (250mg/Kg) 4.037±0.04*** 6.04±0.48 0.071±0.002*** 0.337±0.010*** 144.5±4.266** 5 Prophylactic (500mg/Kg) 2.763±0.08*** 7.77±0.38 0.074±0.002** 0.288±0.008*** 158.2±7.060*** 6 Prophylactic (750mg/Kg) 1.600±0.08*** 8.25±0.98 0.079±0.001*** 0.250±0.006** 193.2±2.830*** 7 Curative (750mg/Kg) 3.073±0.07*** 6.25±0.00 0.065±0.001** 0.164±0.008*** 156.6±7.615*** All of the data obtained from the experimental groups have been compared to gentamicin control group. The data was analyzed statistically by one way ANOVA followed by Dunnett test using graph pad prism 5.0 Software. Where Mean ± SEM (n=8) where *** P<0.001, **P<0.01, *P<0.05 compared to gentamicin control and ### P<0.001, ## P<0.01, # P<0.05 compared to normal control.

5 ### 0.5 ### 4 *** 0.4 *** 3 *** 0.3 *** *** *** 2 0.2 *** *** mole/ g ram of tissue)

1 m 0.1

Ur ine Cr eatini ne ( mg /d l) 0.0

0 MDA (

control

plant control plant control Normal control Gentamicin control Gentamicin control curative 750mg/kg curative(750 mg/kg)

prophylacticprophylact 250mg/kgpicrophylactic 500 mg/kg 750 mg/kg prophylacticpro (250mg/kg)phylactpicrophy (500mg/kg)lactic (750mg/kg) Drug treatment Drug treatment Drug treatment Fig .5: Effect of Alangium salvifolium bark ethanol extract on gen- Fig 6: Effect of Alangium salvifolium bark on gentamicin induced tamicin induced nephrotoxicity in terms of changes in Urine Creati- nephrotoxicity in terms of changes in MDA. nine. 3.4. Effect of Alangium salvifolium bark ethanolic extract on Urine significantly (p<0.001) as compared with gentamicin control. Table 2, volume: Fig 7 shows that Glutathione were significantly (p<0.001) decreased Table 2 shows that urine volume was significantly decreased in gen- in gentamicin treated rats compared to the normal control group. tamicin administrated group. However, it was significantly increased Whereas Alangium salvifolium bark ethanolic extract treated pro- by administration of Alangium salvifolium bark ethanolic extract (250 phylactic groups (i.e. 250mg/kg, 500mg/kg, 750mg/kg.) and curative mg/kg, 500mg/kg and 750 mg/kg) in dose related manner in prophy- group (i.e.750mg/kg) significantly increased (p<0.001) as compared lactic groups and curative group (750 mg/kg) also. with gentamicin control.

Journal of Pharmacy Research Vol.8 Issue 4.April 2014 576-583 Karra Geetha et al. / Journal of Pharmacy Research 2014,8(4),576-583 normal saline, sections were taken from each harvested kidney. The 0.10 tissue was fixed in 10% formal-saline, dehydrated with 100% ethanol 0.08 *** solution and embedded in paraffin. It was then processed into 4- 5 *** *** microns thick sections stained with haematoxylin-eosin and observed *** 0.06 under a photomicroscope (magnification power-200X). The sections of kidney treated with gentamicin showed degenerative tubular ### 0.04 structures with vacuolization, necrosis in Fig. 10,where as sections of kidneys isolated from rats treated with 250mg/kg b. wt ethanol extract mole/ g ram of tissue)

m 0.02 showed large degenerations in Fig. 12.In prophylactic medium dose 500mg/kgb.wt showed predominant normal kidney with minimal de- 0.00

GSH ( generations in Fig. 13, In prophylactic high dose 750 mg/kgb.wt ethanol extract showed predominant normal kidney in prophylactic groups in Fig. 14. In curative group sections of kidneys isolated from rats control treated with 750mg/kg b. wt showed predominant normal kidney in plant control Fig. 15.

Gentamicin control curative(750 mg/kg)

prophylacticpro (250mg/kg)phylacticprophylactic (500mg/kg) (750mg/kg) Drug treatment Fig .7: Effect of Alangium salvifolium bark ethanol extract on gentamicin induced nephrotoxicity in terms of changes in GSH. 3.7. Effect of Alangium salvifolium bark ethanolic extract on catalase activity in gentamicin induced nephrotoxicity: Table 2, (Fig. 8) shows a significant decrease in renal catalase activity Fig. 9. Control group showing Fig. 10.Gentamicin control show- was observed in gentamicin control group compared to normal con- ing degenerative tubular struc- normal glomeruli and tubules. trol. All the doses of Alangium salvifolium bark ethanolic extract tures with vacuolization,necrosis treated groups showed significant increase in catalase levels compared to gentamicin control group. 250

200 *** *** *** 150 ** ### 100

50 Fig. 11. Plant control group Fig. 12. Prophylactic group catalase(U/ mg of tissue) 0 showing normal glomeruli. (250mg/kg) Showing large degenerations.

plant control Normal control

Gentamicin control curative(750 mg/kg) prophylactic(250mg/kg)prophylactiprophyc(500mg/kg)lactic(750mg/kg) Drug treatment Fig .8:Effect of Alangium salvifolium bark ethanol extract on gentamicin induced nephrotoxicity in terms of changes in Catalase. 3.8. Histopathological studies of rat kidneys: Experimental animals were sacrificed and kidneys were identified and Fig.13. Prophylactic group (500mg/ Fig.14. Prophylactic group carefully dissected out for histopathological studies. After rinsing in kg) showing predominant normal (750mg/kg) showing pre- kidney with minimum degenerating. dominant normal kidney Journal of Pharmacy Research Vol.8 Issue 4.April 2014 576-583 Karra Geetha et al. / Journal of Pharmacy Research 2014,8(4),576-583 6. REFERENCES

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Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.8 Issue 4.April 2014 576-583