protective effect of aminoguanidine against nephrotoxicity induced by cisplatin in normal rats

7/28/2019 Protective Effect of Aminoguanidine Against Nephrotoxicity Induced by Cisplatin in Normal Rats

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Comparative Biochemistry and Physiology Part C 132 (2002) 123128

1532-0456/02/$ - see front matter 2002 Elsevier Science Inc. All rights reserved.PII: S 1 532- 0456 0 2.0 0 0 6 2 - 5

Protective effect of aminoguanidine against nephrotoxicity induced

by cisplatin in normal rats

Mahmoud A. Mansour*, Adel M. Mostafa, Mahmoud N. Nagi, Mahmoud M. Khattab,Othman A. Al-Shabanah

Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia

Received 17 July 2001; received in revised form 8 February 2002; accepted 8 February 2002

Abstract

The effect of aminoguanidine (AG) on nephrotoxicity induced by cisplatin (CDDP) was investigated. A single doseof CDDP (7.5 mgykg i.p.) induced nephrotoxicity, manifested biochemically by a significant elevation in serum urea,creatinine and a severe decrease in serum albumin. Moreover, marked increases in kidney weight, urine volume andurinary excretion of albumin were observed. Nephrotoxicity was further confirmed by a significant decrease inglutathione-S-transferase (GST, E.C. 2.5.1.18), glutathione peroxidase (GSH-Px, E.C. 1.11.1.9) and catalase (E.C.1.11.1.6) and a significant increase in lipid peroxides measured as malondialdhyde (MDA) in kidney homogenates.Administration of AG (100 mgykg per day p.o.) in drinking water 5 days before and 5 days after CDDP injectionproduced a significant protection against nephrotoxicity induced by CDDP. The amelioration of nephrotoxicity wasevidenced by significant reductions in serum urea and creatinine concentrations. In addition, AG tended to normalizedecreased levels of serum albumin. Urine volume, urinary excretions of albumin and GST and kidney weight weresignificantly decreased. Moreover, AG prevented the rise of MDA and the reduction of GST and GSH-Px activities inthe kidney. These results suggest that AG has a protective effect on nephrotoxicity induced by CDDP and it maytherefore improve the therapeutic index of CDDP. 2002 Elsevier Science Inc. All rights reserved.

Keywords: Cisplatin; Aminoguanidine; Nephrotoxicity; Lipid peroxidation; Glutathione; Glutathione S-transferase; Glutathioneperoxidase; Catalase; Rat

1. Introduction

Cisplatin (Cis-dichlorodiamineplatinum wIIx

CDDP) represents a class of antineoplastic drugscontaining a heavy metal, platinum. It is effectiveagainst several human tumors, e.g. testis, ovary,head, neck and lung (Prestayko et al., 1980;

Loehrer and Einhorn, 1984) and in animal tumormodels (Rosenberg, 1977). However, several sideeffects of CDDP have been reported, mainlynephrotoxicity and myelosuppression, that limit its

*Corresponding author. Tel.: q966-1-467-7212; fax: q966-1-467-7200.

E-mail address: [email protected] (M.A. Mansour).

clinical use (Von-Hoff et al., 1979; Goldstein and

Mayor, 1983). Consequently, there is a great inter-

est in increasing the clinical usefulness of CDDP

by developing new agents to reduce its toxicity

(Walker and Gale, 1981). Thus, a combination of

various agents with CDDP have been reported.

The calcium antagonist nifedipine (Deray et al.,

1988), adenosine antagonists (Knight et al., 1991),and L-histidinol (Badary et al., 1997) have all

been shown to reduce nephrotoxicity induced by

CDDP in animals.

The exact mechanisms of CDDP-induced

nephrotoxicity are still not fully understood. How-

ever, lipid peroxidation and free radical generation


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124 M.A. Mansour et al. / Comparative Biochemistry and Physiology Part C 132 (2002) 123128

Table 1Effect of AG on CDDP-induced changes in rat serum urea, creatinine and albumin concentrations

Parameters Control AG CDDP CDDPqAGUrea (mmolyl) 6.65"0.28 6.2"0.68 16.8"12.48* 12.5"1.86Creatinine (mmolyl) 0.07"0.006 0.05"0.004 0.23"0.03* 0.14"0.02*,

Albumin (gyl) 43"4 40"1.9 29"1.4* 37.7"2.8

All data represent mean values "S.E. (ns10). AG was given in drinking water for 5 consecutive days (100 mgykg p.o.) beforeand after CDDP administration. Blood samples were obtained 5 days after CDDP (7.5 mgykg i.p).

Significant difference from control group.*

Significant difference from CDDP group. P-0.05.

in the tubular cells have been suggested to beresponsible for the nephrotoxicity (Hannemannand Baumann, 1988; Ishikawa et al., 1990; Ver-meulen and Baldew, 1992). In addition, CDDPinhibits protein synthesis in the tubular cell (Tayet al., 1988). The role of nitric oxide (NO) innephrotoxicity induced by CDDP also has been

suggested. A previous report showed that severalanti-tumor drugs stimulate NO production (Lindset al., 1997). Srivastava et al. (1996) reported thattreatment of rats with CDDP results in a significantincrease in the activity of calcium-independentnitric oxide synthase (NOS) in kidney and liverleading to enhanced NO formation. Nitric oxide isknown to react with the superoxide radical, form-ing peroxynitrite, an even more potent oxidizingagent (Ischiropoulos et al., 1992a). Peroxynitritecan react directly with sulfhydryl residues in thecell membrane leading to lipid peroxidation or

with DNA resulting in cytotoxicity(

Radi et al.,1991; Ischiropoulos et al., 1992b).Aminoguanidine (AG), a compound structurally

similar to L-arginine, inhibits inducible nitric oxidesynthase (iNOS) in a selective and competitivemanner, leading to decreased generation of NO(Misko et al., 1993). In addition, AG is endowedwith many other activities that together accountfor its beneficial effects: AG inhibits diamineoxidase (Tilton et al., 1993); binds to sites of non-enzymatic glycosylation; and prevents furtheradvanced glycosylation (Sugimoto and Yagihashi,1997). In addition, previous studies pointed to the

beneficial antioxidant effects of AG (Ihm et al.,1999) and peroxynitrite scavenger effects (Szaboet al., 1997).

The protective effects of AG have been previ-ously addressed in other models of cell damageinduced by drugs (Aoki et al., 1997; Gardner etal., 1998). In addition, the beneficial effects ofAG in various experimental models of inflamma-

tion have also been reported (Shiomi et al., 1998).Recently, Al-Shabanah et al. (2000) showed thatAG protects mice against hepatotoxicity inducedby carbon tetrachloride. Therefore, the presentwork was conducted to investigate the possibleprotective effect of AG on nephrotoxicity inducedby CDDP.

2. Materials and methods

2.1. Chemicals

Aminoguanidine (AG) was purchased from Sig-ma (St. Louis, MO, USA), while cisplatin (CDDP)was obtained from F.H. Faulding & Co. Ltd. (LexiaPlace Mulgrave, Victoria 3170, Australia).

Thiobarbituric acid (TBA) and 1-chloro-2,4-dinitrobenzene were products of Fluka (Buchs,Switzerland). All remaining chemicals were of thehighest grade commercially available.

2.2. Animals

Male Swiss albino rats, weighing 200250 gwere used. They were obtained from the Experi-mental Animal Care Center of King Saud Univer-sity, Riyadh, KSA. Animals were maintained understandard conditions of temperature 24"1 8C and55"5% RH with a regular 12:12 hlightydarkcycle and allowed free access to standard labora-tory food (Purina Chow) and water.

2.3. Animal treatments

The animals were divided at random into fourgroups of 10 animals each. The first group (con-trol) received vehicles used for CDDP (physiolog-ical saline solution, i.p.). The second group,received AG in drinking water (100 mgykg perday p.o.), the calculated dose of AG based on the


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Table 2Effect of AG on CDDP-induced changes in rat urine volume, albuminuria and urinary excretion of creatinine, urea and GST

Parameters Control AG CDDP CDDPqAG

Urine (mly24 h) 6.1"1.79 4.5"0.95 20.6"3.9* 6"2.2Urine creatinine (mmolyl) 9.8"0.62 9.6"0.33 3.2"0.36* 6.2"0.99*

Urine urea (molyl) 1.2"0.16 1.76"0.23* 0.28"0.05* 0.62"0.06*

Albuminuria (mgy24 h urine) 109"20.2 89"37 708"164* 91"13

Urinary GST activity (Uyl) n.d. n.d. 102"6*

45"11.7*

Results are expressed as mean"S.E. (ns10). Urine (24 h) was collected on the fourth day after CDDP injection (7.5 mgykg i.p.).n.d.snon-detectable.

Significant difference from control group.*

Significant difference from CDDP group.P-0.05.*

average daily intake of water. A third group wasinjected with CDDP (7.5 mgykg i.p.). The fourthgroup received AG in drinking water for 5 consec-utive days before and 5 consecutive days afterCDDP injection (7.5 mgykg i.p.). The selectedconcentration of AG and the schedule of dose

administration were chosen as guided by our ownpreliminary experiments. On the fourth day afterCDDP injection, all animals were housed separate-ly in metabolic cages to collect 24-h urine. Oneday later, blood samples were taken by cardiacpuncture, under light ether anesthesia, into non-heparinized tubes. Serum was separated by cen-trifugation for 5 min at 1000=g and stored at y20 8C until analysis. Animals were killed bycervical dislocation and the kidneys were quicklyisolated, washed with saline, blotted dry on filterpaper and weighed. A 10% (wyv) homogenate of

the kidney was prepared in ice cold saline using aBranson sonifier (250, VWR Scientific, Danbury,CT, USA).

2.4. Biochemical parameters

Creatinine and urea concentrations in serum andurine were determined colorimetrically asdescribed by Bartles et al. (1972), Patton andCrouch (1977), respectively, using diagnostic kits(bioMerieux, RCS Lyon, France). Albumin in theurine was quantified by enzyme linked immuno-sorbant assay (ELISA kit) supplied from CellTrendGmbH, Luckenwalde, Germany.

2.5. Glutathione content, lipid peroxides and

enzyme activities in kidney homogenates

Glutathione contents and lipid peroxides(Malondialdhyde wMDAx production) in the kid-

ney were determined according to the methods ofEllman (1959), Ohkawa et al. (1979), respectively.Glutathione-S-transferase (GST) activity in kidneyhomogenate and urine was determined accordingto Habig et al. (1974) using 1-chloro-2,4 dinitro-benzene as a substrate. The lower detection limit

for this assay was 12 Uyl. Catalase and glutathioneperoxidase (GSH-Px) activities were measured inkidney homogenates according to Higgins et al.(1978), Kraus and Ganther (1980), respectively.

2.6. Statistical analysis

Data are expressed as means"S.E.M. Statisticalcomparison between different groups were doneusing one-way analysis of variance (ANOVA)followed by the TukeyKramer multiple compari-

son test, to judge the difference between variousgroups. Significance was accepted at P-0.05.

3. Results

3.1. Effect of AG on CDDP-induced changes in

serum parameters

Intraperitoneal administration of CDDP (7.5mgykg i.p.) caused abnormal renal function in allrats. Serum urea and creatinine were significantlyincreased 2.5 and 3.3-fold of the control values,respectively. Also, there was a 33% decrease inserum albumin (Table 1).

Pretreatment of the animals with AG (100 mgykg p.o.) 5 days before and after single injection ofCDDP reduced the rise in the level of serum ureaand creatinine. In addition, AG tended to normalizethe decreased level of albumin (Table 1).


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Table 3Effect of AG pretreatment on CDDP induced changes on relative kidney weight, lipid peroxides (MDA), glutathione content, GST,catalase and GSH-Px

Parameters Control AG CDDP CDDPqAG

Kidney wt. % of body wt. 0.79"0.03 0.78"0.04 1.4"0.26* 0.85"0.05MDA (nmolyg) 108"5.5 109"3.7 166"10.8* 147"14.1GSH (mmolyg) 4.37"0.1 4.5"0.17 3.4"0.2* 3.2"0.29*

GST (mmolymin per g) 6.5"0.29 5.3"0.3 3.2"0.3*

5.4"0.3Catalase (mmolymin per g) 54.2"5.4 47.3"2.4 32.1"3* 33.7"4.4*

GSH-Px (mmolymin per g) 155"19.4 140"5 105"5* 128"14.5

Results are expressed as mean"S.E. (ns10).Significant difference from control group.*

Significant difference from CDDP group. * P-0.05.


urine volume and urinary excretion of albumin

and GST

CDDP treatment produced a significant increasein urine volume, urinary excretion of albumin and

GST. In addition, urine creatinine and urea weresignificantly reduced in comparison to controlanimals (Table 2). AG administrations before andafter CDDP normalized the urine volume andalbumin and significantly decreased the urinaryexcretion of GST. In addition, the marked decreasein the levels of urine urea and creatinine inducedby CDDP treatment was partially reversed in thepresence of AG, however, still statistically lowerthan controls (Table 2).


glutathione content, lipid peroxides and enzyme

activities in kidney

A single dose of CDDP-induced acute renalfailure, manifested by a significant increase inkidney mass as percent of body mass and lipidperoxides. In addition, glutathione content signifi-cantly decreased by 21% (Table 3). Moreover,reductions in GST, catalase and GSH-Px activities,respectively, were observed. Pretreatment with AGcaused a significant decrease in kidney mass andprevents the significant increase in lipid peroxides.Activities of renal GST and GSH-Px were greatly

improved. However, AG did not ameliorate thedepletion of glutathione content or the decrease incatalase activity induced by CDDP (Table 3).

4. Discussion

As predicted, administration of CDDP (7.5 mgykg i.p.) resulted in an overt nephrotoxicity as

evidenced in the serum by the marked elevationsof urea and creatinine concentration and significantdecrease in albumin. Nephrotoxicity was alsoreflected in the kidney as the depletion of gluta-thione content is accompanied by marked reduc-tion in activities of GSH-Px, GST and catalase

and significant elevation of lipid peroxides. Inaddition, urinary excretion of albumin and GSTfurther confirmed the kidney injury induced byCDDP.

The time point selected in our study was basedupon the known onset of the maximum renal injuryinduced by CDDP (Al-Harbi et al., 1995; Badaryet al., 1997). Thus, the observed nephrotoxiceffects of CDDP in rats were similar to thosepreviously reported (Choie et al., 1981; Andersonet al., 1989; Heidemann et al., 1989). In addition,enhanced urinary excretion of GST, which can be

implicated as a marker for CDDP-induced renaldamage, demonstrated in this study is consistentwith previous studies showing that CDDP admin-istration into rats leads to urinary excretion of GST(Feinfeld et al., 1986; Trakshel and Maines, 1988).

However, the nephrotoxic potential of CDDP,limits its clinical use (Hutchinson et al., 1988).The beneficial effects of AG in the prevention ofdiabetic complications in several tissues, includingkidney, have been reported (Sugimoto et al., 1999).

Treatment of rats with AG alone (100 mgykgper day p.o.) for 10 days did not induce anychanges in the measured biochemical parameters.However, administration of AG in drinking water(100 mgykg p.o.) for 5 consecutive days beforeand continued for another 5 consecutive days aftersingle dose of CDDP (7.5 mgykg i.p.) renders ratsless susceptible to kidney damage induced bytreatment with CDDP. This protection was evi-denced in the serum as the elevated level in both


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urea and creatinine concentrations were markedlylowered below those elicited by the nephrotoxicantand the severe decrease in albumin tended to benormalized. In addition, urinary excretion of albu-min and GST were greatly decreased. The attenu-ation of the nephrotoxicity was also observed inthe kidney. AG greatly ameliorated antioxidant

enzymes mainly, GSH-Px and GST and preventsthe rise in lipid peroxides in the kidney. Thesefindings may indicate an improvement in oxidantstatus and may suggest a possible antioxidantactivity for AG. These results confirm previousdata demonstrating the beneficial antioxidant effectof AG (Ihm et al., 1999). However, the docu-mented effect of AG on inducible NOS cannot beexcluded, since involvement of inducible NO inthe development of nephrotoxicity induced byCDDP has been reported. CDDP administrationproduced an increase in inducible NOS in ratpancreatic islets that may be responsible for hyper-glycemia and glucose intolerance caused by CDDP(Wang and Aggarwal, 1997). In addition, the roleof inducible NO in ototoxic side effects of CDDPhas also been reported (Watanabe et al., 2000).Moreover, CDDP treatment of rats results in asignificant increase in calcium-independent NOSin liver and kidney (Srivastava et al., 1996). Itcould be concluded that overproduction of induc-ible NO might be implicated in the pathogenesisof several toxicities induced by CDDP.

The rationale of the AG schedule of dose admin-istration was the maintainence of a steady suffi-

cient plasma concentration of AG before, duringand after the critical period of CDDP-inducedtoxicity, since the biochemical changes that occurin the kidney after CDDP administration are ofcrucial importance in determining the extent of anephrotoxic lesion (Borch and Pleasants, 1979).However, our findings showed that AG did notprevent the significant decrease in catalase activityor the depletion of glutathione content induced byCDDP administration.

GSH-Px and catalase are among the endogenousantioxidant enzymes that play a pivotal role in the

reduction of lipid peroxides and scavenge hydro-gen peroxide and thus interrupt the propagation ofthe lipid peroxidation reaction. In this process,GSH-Px requires endogenous glutathione as a co-substrate (Ketterer et al., 1983). In the presentstudy, AG tended to normalize levels in GSH-Pxand GST activities. Thus, GSH-Px and GST mayguard against the rising level of lipid peroxides

and hydrogen peroxides, leading to depletion ofendogenous glutathione. Therefore, these enzymeswere essential in cellular defense mechanismsagainst kidney damage induced by CDDP. Thismay explain, at least in part, the failure of AG toameliorate the depletion of glutathione contentinduced by CDDP administration.

In our study AG greatly afforded protectionagainst nephrotoxicity induced by CDDP treat-ment. The protective effect induced by AG maybe related to its reported antioxidant effect (Ihmet al., 1999), inhibition of inducible NOS (Miskoet al., 1993) or the peroxynitrite scavenger effect(Szabo et al., 1997). However, it is currentlydifficult to assess which of these properties of AGis responsible for this protective effect of AG,since the mechanism of nephrotoxicity induced byCDDP is still uncertain.

Our results may indicate that AG is beneficialas a protective agent against nephrotoxicityinduced by CDDP in rats. Further studies areneeded to elucidate the mechanism(s) of protectionand the effect of AG on the anti-tumor activity ofCDDP.

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protective effect of aminoguanidine against nephrotoxicity induced by cisplatin in normal rats

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