http://informahealthcare.com/phb ISSN 1388-0209 print/ISSN 1744-5116 online Editor-in-Chief: John M. Pezzuto Pharm Biol, 2014; 52(4): 428–434 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/13880209.2013.840318

ORIGINAL ARTICLE

Protective potential of Tamarindus indica against gentamicin-induced nephrotoxicity Naveed Ullah1, Mir Azam Khan1, Taous Khan2, and Waqar Ahmad1 Department of Pharmacy, University of Malakand, Chakdara, Pakistan and 2Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan Abstract

Keywords

Context: Gentamicin is an antibiotic that is effective against Gram-negative microorganisms. However, its clinical applications are often limited due to nephrotoxic effects. Objective: This study investigated the protective effects of aqueous-ethanol extract of Tamarindus indica L. (Leguminosae) fruits against gentamicin-induced renal toxicity. Materials and methods: A daily dose of 200 mg/kg of 70% aqueous-ethanol extract derived from T. indica was employed in male rabbits as a co-therapy with gentamicin (80 mg/kg) for a period of three weeks. Serum and urinary renal function parameters and histological assessments were carried out and compared with one way analysis of variance (Graphpad prism version 5.00, Graphpad Software, San Diego, CA). Results: The results showed that gentamicin-treated animals had significantly elevated blood urea nitrogen (54.1  2.6 mg/dl), serum creatinine (4.0  0.1 mg/dl), serum uric acid (2.3  0.1 mg/dl) and urinary protein excretion (3.8  0.3 mg/dl) with a fall in body weight (10  1%), creatinine clearance (0.7  0.09 ml/min), serum potassium (3.4  0.1 mEq/l), serum calcium (7.6  0.2 mg/dl), urinary volume (126  9 ml/24 h) and urinary lactate dehydrogenase secretion (103.1  4.2 U/l). However, animals treated by co-therapy with gentamicin and T. indica had significantly improved renal structure and function. Discussion and conclusion: Co-therapy of 200 mg/kg/d of T. indica for a period of three weeks successfully prevented functional and morphological derangements caused by gentamicin as assessed by different renal function parameters and histological examinations.

Aminoglycosides, antioxidant, flavonoids, Imli, nephroprotection

Introduction Medicinal plants play an important role in health-related matters and fulfill the primary healthcare needs of approximately 80% of the world’s population (WHO, 2001). Tamarindus indica L. (Leguminosae), locally known as Imli, is an important medicinal plant with widespread uses against several ailments. It is indigenous to tropical regions of Africa, United States of America and Brazil and is cultivated in India, Pakistan, China, Philippines and Spain (Alkofahi & Atta, 1999). The phytochemical study of this plant revealed the presence of phenolic compounds, tannins, fatty acids and flavones (Sudjaroen et al., 2005). The seeds are useful for the treatment of diarrhea, dysentery, vertigo, inflammation and diabetes (Alkofahi & Atta, 1999). The antioxidant property of the plant is responsible for the inhibition of oxidative changes and may serve as a hepatoprotectant (Farombi et al., 2002). A number of new antibacterial drugs, especially the thirdgeneration cephalosporins, have been developing the occurrence of resistance, which is a common clinical problem (Wright, 2010). Gentamicin is an important member of this

History Received 14 January 2013 Revised 30 July 2013 Accepted 28 August 2013 Published online 13 January 2014

group of antibiotics that has a low chance of bacterial resistance (Gonzalez & Spencer, 1998). It has broad spectrum antibacterial activity and is commonly used against Gramnegative bacteria. Despite the beneficial properties, this drug is used with caution due to its nephrotoxic effects. Researchers have tried from time to time to develop drugs that may be helpful to eradicate the nephrotoxic effects of gentamicin. Though their findings were successful to some extent, yet no drug has been proved completely effective so far. According to the literature (Farombi et al., 2002), T. indica contains flavonoids and phenolic compounds with potent antioxidant properties, which may help in the inhibition of oxidative damage and may serve to protect against gentamicin-induced nephrotoxicity. Keeping this hypothesis in mind, this study has been designed in order to investigate nephroprotective activities of this particular medicinal plant against gentamicin toxicity.

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1

Materials and methods Plant material and extraction

Correspondence: Dr. Naveed Ullah, Department of Pharmacy, University of Malakand, Chakdara, Pakistan. Tel: +92-3455910522. Fax: +92945763491. E-mail: [email protected]

The fruits of T. indica were collected from Swabi, KPK, Pakistan, in (April) 2010 after identification by Prof. Umar

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Farooq, Department of Botany, Postgraduate Degree College No. 1, Abbottabad, Pakistan. The voucher specimens (1022) were deposited in the herbarium of the same institution. The plant material was shade-dried, chopped (3 kg) and extracted with ethanol for three weeks, with stirring on alternate days. The crude extract was filtered and evaporated to dryness (416 g) in a vacuum with the help of a rotary evaporator (R-210, Germany).

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Renal protective activity A total of 24 male rabbits (of mixed breed) weighing between 1 and 1.5 kg were selected for the this study and were acclimatized for 15 d before use in experiments. All animals used in this study were handled and treated according to the rules and regulations of the University of Malakand as well as international laws and policies (National Institutes of Health Guide for the Care of Animals, NIH Publication no. 85–23, 1985) after approval of the study from Research Society of the University. These animals were maintained on the same diet and 12-h cycles of dark and light. These were then divided into four groups with six rabbits in each group. Gentamicin was administered intramuscularly while the extracts were provided orally. The doses of gentamicin and extracts were provided according to the dosage regimen given in Table 1. Collection of samples Blood and urine samples were collected on days 0, 11 and 21. Serum was separated by using a micropipette and stored in clean and dried vials for estimation of urea, creatinine, uric acid and electrolytes. Graduated cylinders were used for the measurement of 24-h urine output. Urine was also collected for estimation of urea, creatinine, protein, lactate dehydrogenase, alkaline phosphatase, pH and microscopic examination. The weight of each animal was measured three times throughout the experimental period. Both kidneys were isolated on the last day of experiment for histopathological investigations. Histopathology Animals were slaughtered after administration of the last dose of gentamicin. Both kidneys were isolated. One kidney was cut longitudinally while the other was cut transversely and fixed in 10% formalin. The tissues were then dehydrated by treating with various grades of alcohol in ascending order, i.e., 50, 70 and 90% followed by absolute alcohol. Finally, xylene was applied for clearing purposes. The tissues were then embedded in paraffin wax. Solidified blocks were cut down to a number of portions with a rotatory microtome (Micros, Hu¨ckelhoven, Germany). The tissues were stained

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with hematoxylin and eosin dyes, and the slides were examined with a light microscope (Leitz, Germany). Estimation of blood urea nitrogen, serum creatinine and serum uric acid Blood urea nitrogen, serum creatinine and serum uric acid levels were estimated with commercially available reagent kits using a Chemistry Analyzer power lab 300 (Merck, Darmstadt, Germany). Estimation of blood urea nitrogen was done by following the modified Bertholot’s indophenol assay (Burtis & Ashwood, 1999). However, estimation of serum creatinine was performed by using a Pro DIA kit by the Jaffe reaction (Friedman & Young, 2001). Estimation of electrolytes Serum calcium level was measured by the cresolphthalein complexone method (Blosser, 1985) using commercially available kits (Randox Laboratories Limited, Crumlin, UK). However, serum sodium and potassium were measured with a flame photometer (PFP-7, England) (Blosser, 1985). Estimation of urinary protein, alkaline phosphatase and lactate dehydrogenase Reagent kit (DiaSys Diagnostic system GmbH, Holzheim, Germany) was used for estimation of urinary proteins (Johnson et al., 1999), while urinary alkaline phosphatase and lactate dehydrogenase were determined by using diagnostic reagent according to the German Society of Clinical Chemistry (Deutsche, 1972). Examination of urine by reagent strip and microscopy Urine was examined under a microscope and by reagent strips for the diagnosis of renal damage. Teco Diagnostic URS-10 (Hague, Netherland) strips were used for qualitative measurement of glucose, specific gravity, bilirubin, ketone, red blood cell (RBC), pH, proteins, urobilinogen, leukocytes and nitrite. For microscopic study, first the urine was mixed and then centrifuged for 5 min. A drop of urine was then placed on a slide and examined under the light microscope. Statistical analysis The results were calculated as mean  SEM. The groups were compared by using one way analysis of variance followed by the Dunnett test with the help of the Graphpad prism version 5.00 (Graphpad Software, San Diego, CA). The difference between two groups was considered significant if the value of p was less than 0.05.

Results Table 1. Daily dosage schedule for each experimental group for a period of 21 d. Group No.

Name of group

Received

1 2 3

C (control group) G (toxic group) GTin

4

Tin

Isotonic saline 2 ml/kg/d Gentamicin 80 mg/kg/d (toxic dose) Gentamicin 80 mg/kg/d and T. indica 200 mg/kg/d T. indica 200 mg/kg/d

Mean body weight Body weights of animals were progressively decreased throughout the study period. The control group of animals lost 0.155  0.91% of body weight, while gentamicin treated (group G) lost 10.795  1.09% of body weight. T. indica extract treated (group Tin) animals lost 0.68  0.26% and gentamicin þ T. indica extract treated (group GTin) lost 3.22  0.33%, respectively. The weight loss in all

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experimental groups was significantly different when compared with the gentamicin-treated group (Figure 1). Blood urea nitrogen

Serum creatinine The serum creatinine level was significantly increased in group G animals (1.96  0.14 versus controls, 0.71  0.10 mg/ dl, p50.0001) by d 11 and further increased on the last day of the experiment (4.02  0.14 versus 0.80  0.10 mg/dl, p50.0001) (Table 2). Group GTin showed no significant increase in the serum creatinine level by d 21 of experimental period when compared with group G. Group Tin was found significantly different when compared with toxic group (0.70  0.05 versus group G, 4.02  0.14 mg/dl). Creatinine clearance Creatinine clearance decreased significantly in the group G animals (2.08  0.25 versus control, 5.08  0.82 ml/min) on

Serum uric acid Significant elevation of serum uric acid level in group G was noted when compared with the control group. A significant difference was noted among group GTin and Tin when compared with group G (Table 2). Serum electrolytes The unchanged serum sodium level was recorded in control and toxic groups on d 11 and 21, and the p values were 0.2823 and 0.1232, respectively. No significant difference was observed in group GTin and Tin in comparison with group G (Table 3). A significant decrease in the serum potassium was observed in group G animals when compared with control (3.43  0.17 mEq/l and 5.10  0.24 mEq/l, p ¼ 0.0002). However, the difference between group GTin and group G was very significant (p ¼ 0.0019). Statistically significant difference was also recorded in group Tin when compared with group G (p ¼ 0.0004). A decrease in serum calcium was observed in group G (7.68  0.21 mg/dl versus controls, 9.72  0.25 mg/dl, p ¼ 0.0001), and the difference between group C, GTin and Tin versus group G was found extremely significant. Urinary proteins

15 % loss in body weight

Elevations in the urinary protein excretion on d 21 in group G animals were noted (3.86  0.32 mg/dl versus controls, 1.81  0.22 mg/dl, p ¼ 0.0004). A statistically significant difference was observed in group GTin and Tin when compared with group G (Table 3).

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5

Urinary lactate dehydrogenase

Figure 1. Percent loss in the mean body weight on last day of study period in control-, gentamicin- and extracts-treated groups.

A significant increase in lactate dehydrogenase excretion was found in the gentamicin-treated group on d 11 of the experimental period (143.17  3.53 U/l versus control, 91.33  1.86 U/l, p ¼ 0.0001). A significant difference was also noted in group GTin and Tin when compared with the gentamicin-treated group. On d 21, lactate dehydrogenase was

Table 2. Estimation of blood urea nitrogen, serum creatinine, creatinine clearance, serum uric acid and percent loss in body weight on last day of study period.

Table 3. Estimation of serum electrolytes and urinary protein excretion in experimental groups.

Animal group C G GTin Tin

Ti n

n Ti G

C

0

G

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Blood urea nitrogen was increased significantly on d 11 of the experimental period in group G (37.78  2.14 mg/dl versus control, 13.75  1.04 mg/dl) and further increased on day 21 (54.18  2.6 mg/dl), which was statistically different from control (14.14  1.12 mg/dl) (Table 2). The blood urea nitrogen of group GTin (16.91  0.86 mg/dl) was also significantly different when compared to toxic group (54.18  2.6 mg/dl). An extreme significant difference in blood urea nitrogen was observed in the animals of group Tin (13.96  0.45 mg/dl) when compared with gentamicintreated group (54.18  2.60 mg/dl).

d 11 and further decreased on d 21 (0.76  0.09 versus control 4.99  1.16 ml/min). Creatinine clearance of Group GTin was not significantly different when compared with group G (3.08  0.49 ml/min). Moreover, group Tin was significantly different with respect to creatinine clearance of group G (5.36  0.92 ml/min versus group G, 0.76  0.09 ml/min).

Blood urea nitrogen (mg/dl)

Serum creatinine (mg/dl)

Creatinine clearance (ml/min)

Serum uric acid (mg/dl)

14.14  1.12a 54.18  2.60 16.91  0.86a 13.96  0.45a

0.80  0.1a 4.02  0.14 1.08  0.09a 0.70  0.05a

4.99  1.16b 0.76  0.09 3.08  0.49 5.36  0.92a

1.51  0.02a 2.34  0.12 1.41  0.09a 1.51  0.05a

Mean  SEM are given. a Extremely significant when compared with gentamicin-treated group. b Very significant.

Animal group C G GTin Tin

Serum sodium (mEq/l)

Serum potassium (mEq/l)

Serum calcium (mg/dl)

Urinary protein (mg/dl)

140.17  1.01 137.67  1.09 138.33  0.76 138.83  0.54

5.10  0.24a 3.43  0.17 4.46  0.18b 5.21  0.30a

9.72  0.25a 7.68  0.21 9.40  0.09a 9.83  0.16a

1.81  0.22a 3.86  0.32 1.62  0.17a 1.72  0.18a

Mean  SEM are given. a Extremely significant when compared with gentamicin-treated group. b Significant.

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decreased to 103.17  4.28 U/l in group G but was still significantly different from group Tin. No significant difference was observed in GTin when compared with group G (Table 4). Urinary alkaline phosphatase

RBC and proteins were found in group G with foul smell. Furthermore, trace amount of leukocytes and small quantity of bilirubin were also found in group G animals. No leukocytes were detected in group GTin and Tin. The pH of urine ranged between 7.5 and 8.5. Histological examination

No significant difference in urinary alkaline phosphatase level was observed in control and other treated groups when compared with group G (Table 4). Measurement of urine volume and microscopic examination of urine

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A significant decrease in urinary volume was observed on d 21 in toxic group when compared with control and Tin. The difference between gentamicin-treated group and GTin was found significant. A large number of renal casts were detected in the urine of group G animals on the last day of the experimental period. However, no significant number of renal casts was found in other experimental groups. Examination of urine by reagent strip Ketones and glucose were not diagnosed in either group on the last day of the experiment. However, a large amount of

Increased cellularity and atrophy of some glomeruli was observed in group G animals. Proximal tubular cell necrosis with loss of cellular pattern was also observed (Figure 2A and B). The lumina were seen to be filled with hyaline (Figure 2B). Flattening tubular cells were also observed and some of the tubules showed hydropic changes (Figure 2A). Dilated collecting tubules in the renal medulla with renal cast and a large number of ruptured tubules were also seen (Figure 2B). No proper tubular necrosis was found in groups GTin, Tin and control group (Figures 3A, B, 4A, B and 5A, B), while tubular damage was observed in group G animals.

Discussion This work was aimed to investigate the nephroprotectant potentials of T. indica to counteract the toxic effects of gentamicin. Gentamicin-induced cell injury is similar in both humans and animals even in therapeutic doses (Kosek et al.,

Table 4. Measurement of urinary volume and excretion of lactate dehydrogenase and alkaline phosphatase on last day study period. Urinary volume (ml/24 h) Animal group C G GTin Tin

Urinary lactate dehydrogenase (U/l)

Urinary alkaline phosphatase (U/l)

D 11

D 21

D 11

D 21

D 11

D 21

200  9.16 168  11.96 187  22.34 205.5  17.3

217  19.77a 126  9.09 206  28.76a 218  18.3c

91.33  1.8b 143.17  3.53 92.83  1.4b 89  1.59b

88.17  2.2b 103.17  4.28 94  1.21a 89  1.69b

14.2  0.9 11.9  1.1 12.7  0.8 11.8  0.8

14.1  1.2 12.4  0.6 12.9  0.9 11.4  0.6

Mean  SEM are given. Significant. b Extremely significant when compared with gentamicin-treated group. c Very significant. a

Figure 2. Photomicrographs of group G (gentamicin treated): (A) renal cortex showing renal cortex presenting glomerular atrophy with hydropic changes and proximal tubular cell necrosis and loss of cellular pattern and (B) renal medulla showing loss of cellular pattern with a number of ruptured tubules; the dilated collecting tubules also significantly present.

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Figure 3. Photomicrographs of control group: (A) renal cortex presenting no common abnormality like glomerular atrophy or necrosis and (B) renal medulla shows normal proximal and distal tubules with no significant abnormality.

Figure 4. Photomicrographs of group GTin (Gentamicin þ T. indica extract treated): (A) renal cortex presenting normal glomeruli with no evidence of necrosis, but small number of vacuoles in the proximal tubular cells and (B) renal medulla presenting normal tubules with no presence of hyaline and granular casts.

1974). However, these toxic effects are only observed when the drug is given 5–10 fold higher than therapeutic doses (Bennett et al., 1991; Tulkens, 1989). It has been reported that animals treated with 30–60 mg/kg/d for 5–10 d have proven to cause necrosis and elevated serum creatinine level (Tulkens, 1989). A daily dose of 30 mg/kg (Kapusnik & Sande, 1986), 40 mg/kg (Gilbert et al., 1989) and 60 mg/kg (Provoost et al., 1985) was selected as the toxic dose by different researchers in their experiments; however, a daily dose of 80 mg/kg of gentamicin was used in this study to produce nephrotoxicity. Increase in blood urea nitrogen, serum creatinine and decrease rate of glomerular filtration can be measured from the creatinine clearance rate (Bennett et al., 1980, 1991). In this study, elevated blood urea nitrogen, serum uric acid and serum creatinine with a significant decrease in creatinine

clearance rate was found after 21 d of gentamicin treatment when compared with control, GTin and Tin. It has also been reported that changes in glomerular function and tubular damage associated with gentamicin are not dependent on each other (Bennett et al., 1980; Luft et al., 1977). Serum creatinine and tubular necrosis were also reported (Solez, 1983). The obstruction of tubules by necrotic debris and filtrate leaking through the damaged tubules might be responsible for elevated serum creatinine level (Solez, 1983). In this study, a significant decrease in the serum potassium (p50.0001) was observed in group G, which is in agreement with previous reports (Brinker et al., 1981; Cronin et al., 1980). No significant decrease in serum potassium was found in the group GTin animals, which proved it to have nephroprotective properties. Fall in serum calcium level was

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Figure 5. Photomicrographs of group Tin (T. indica extract treated): (A) renal cortex presenting normal glomeruli and tubules. No common abnormality was identified and (B) renal medulla also presenting normal tubules with no hydropic changes or ruptured tubules.

observed in group G in this study similar to that reported previously (Cronin et al., 1980). Group GTin, Tin and control did not show any significant change in serum calcium, which proves a significant protective role. However, it has been reported that gentamicin has no effects on the serum calcium level (Brinker et al., 1981). No significant change was observed either in group G or in other treated groups like GTin. However, abnormal urinary excretion of sodium, potassium, calcium and magnesium were observed in gentamicin-treated animals (Bennett et al., 1991). Loss of body weight (p50.0001) in the gentamicin-treated group provides a condition of negative nitrogen balance, which provides a statement for potassium loss (Brinker et al., 1981). Gentamicin-treated animals have also been reported with significant loss in body weight in a dose-dependant manner (Tavafi et al., 2012). A significant increase in urinary protein excretion and fall in urinary volume was observed in the gentamicin-treated group on d 11 and 21 of study period, which was significantly different from group GTin as reported previously (AbdelRaheem et al., 2009). No significant increase in urinary protein excretion was observed in the group GTin that provide a statement of protectiveness. Estimation of tubular brush border enzyme secretion in urine was also used by a number of researchers to study nephrotoxicity (McCracken, 1986). In this study, the urinary enzymes including lactate dehydrogenase and alkaline phosphatase were also estimated, but no significant change in alkaline phosphatase was found in any group when compared with the gentamicin-treated group, which is in contrast to the previous reports (Abd El-Fattah & El-Sheikh, 2012). The urinary excretion of lactate dehydrogenase was significantly increased in group G on d 11 of experimental period, which declined on d 21 but still significant when compared with control groups. Extremely significant difference was observed when group GTin and Tin were compared with group G on d 11, which prove their protective effects. However, no significant difference was found on d 21 when group GTin was compared with group G.

An extremely significant increase of lactate dehydrogenase in group G on d 11 provides a statement of early detection of nephrotoxicity. These observations show that the plant extract has nephroprotective effects. The histological examination revealed the presence of regenerating cells and necrosis side by side in the extracttreated animals (GTin), similar to that reported by other researchers (Bennett et al., 1991; Cronin et al., 1980; Houghton et al., 1978). Leaking of proteins may be due to tubular cell degeneration caused by hyaline and granular casts in proximal and collecting tubules. The obstruction associated with casts may cause depression of glomerular filtration rate, which leads to kidney damage (Solez, 1983). In this study, Group GTin animals showed vacuoles in their proximal tubular cells, which may be due to the pinocytotic activity caused by amino acids, proteins and salts. These vacuoles, however, may not be responsible for cell injury (Gilbert et al., 1989). In this work, significant normal kidney functions were recorded in the animals having vacuoles in the proximal tubular cells. Tamarindus indica offered maximum effectiveness as assessed through kidney functional parameters like loss in body weight, blood urea nitrogen, serum creatinine, serum uric acid level, serum calcium, serum potassium, urinary volume, urinary excretion of proteins, urinary excretion of lactate dehydrogenase and histopathological investigations.

Conclusions From this work, it can be concluded that combined administration of T. indica in a daily dose of 200 mg/kg with gentamicin successfully prevented nephrotoxicity associated with gentamicin.

Acknowledgements The Higher Education Commission (HEC), Government of Pakistan is highly acknowledged for financial support to the project through indigenous scholarship.

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Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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Protective potential of Tamarindus indica against gentamicin-induced nephrotoxicity.

Abstract Context: Gentamicin is an antibiotic that is effective against Gram-negative microorganisms. However, its clinical applications are often lim...
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