Carvedilol protects against cisplatin-induced oxidative stress, redox state unbalance and apoptosis in rat kidney mitochondria

Cisplatin is a highly effective chemotherapeutic agent which causes severe nephrotoxicity. Studies have suggested that reactive oxygen species, mainly generated in mitochondria, play a central role in cisplatin-induced renal damage. A wide range of antioxidants have been evaluated as possible protective agents against cisplatin-induced nephrotoxicity; however a safe and efficacious compound has not yet been found. The present study is the first to evaluate the protective potential of carvedilol, a beta-blocker with strong antioxidant properties, against the mitochondrial oxidative stress and apoptosis in kidney of rats treated with cisplatin. The following cisplatin-induced toxic effects were prevented by carvedilol: increased plasmatic levels of creatinine and blood urea nitrogen (BUN); lipid peroxidation, oxidation of cardiolipin; oxidation of protein sulfhydryls; depletion of the non-enzymatic antioxidant defense and increased activity of caspase-3. Carvedilol per se did not present any effect on renal mitochondria. It was concluded that carvedilol prevents mitochondrial dysfunction and renal cell death through the protection against the oxidative stress and redox state unbalance induced by cisplatin. The association of carvedilol to cisplatin chemotherapy was suggested as a possible strategy to minimize the nephrotoxicity induced by this antitumor agent.     

Comparative Study of the Possible Protective Effects of Cinnamic Acid and Cinnamaldehyde on Cisplatin‐Induced Nephrotoxicity in Rats

This study aimed to assess the protective effect of cinnamic acid (CA) and cinnamaldehyde (CD) against cisplatin‐induced nephrotoxicity. A single dose of cisplatin (5 mg/kg), injected intraperitoneally to male rats, caused significant increases in serum urea, creatinine levels, and lipid peroxides measured as the malondialdehyde content of kidney, with significant decreases in serum albumin, reduced glutathione, and the activity of antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) of kidney as compared with the control group. On the other hand, administration of CA (50 mg/kg, p.o.) or CD (40 mg/kg, p.o.) for 7 days before cisplatin ameliorated the cisplatin‐induced nephrotoxicity as indicated by the restoration of kidney function and oxidative stress parameters. Furthermore, they reduced the histopathological changes induced by cisplatin. In conclusion, CA and CD showed protective effects against cisplatin‐induced nephrotoxicity where CD was more effective than CA; affects that might be attributed to their antioxidant activities.     

Alpha lipoic acid prevents doxorubicin‐induced nephrotoxicity by mitigation of oxidative stress,inflammation, and apoptosis in rats

This study aimed to evaluate the protective effects of alpha lipoic acid (ALA) against doxorubicin (DOX)‐induced nephrotoxicity in rats. A single dose of DOX (7.5 mg/kg i.v.) induced nephrotoxicity evidenced by significant elevations in kidney weight, kidney/body weight ratio, serum urea, creatinine, tumor necrosis factor alpha, and renal contents of malondialdehyde, nitric oxide, cyclooxygenase‐2, and caspase‐3. Also, it causes significant reduction in final body weight, serum albumin, renal contents of reduced glutathione and superoxide dismutase activity. Histopathological changes in the kidney tissue confirmed the nephrotoxic effect. In contrast, pretreatment with ALA (50 mg/kg, orally) for 14 days before DOX and for 7 days after DOX administration mitigated renal toxicity evidenced by greater improvement in the examined oxidative stress, inflammation, and apoptosis parameters. In conclusion, ALA had promising protective effects against DOX‐induced nephrotoxicity that might be attributed to its antioxidant, anti‐inflammatory, and antiapoptoic activities.     

Capsaicin Ameliorates Cisplatin-Induced Renal Injury through Induction of Heme Oxygenase-1

Cisplatin is one of the most potent chemotherapy agents. However, its use is limited due to its toxicity in normal tissues, including the kidney and ear. In particular, nephrotoxicity induced by cisplatin is closely associated with oxidative stress and inflammation. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in the heme metabolism, has been implicated in a various cellular processes, such as inflammatory injury and anti-oxidant/oxidant homeostasis. Capsaicin is reported to have therapeutic potential in cisplatin-induced renal failures. However, the mechanisms underlying its protective effects on cisplatin-induced nephrotoxicity remain largely unknown. Herein, we demonstrated that administration of capsaicin ameliorates cisplatin-induced renal dysfunction by assessing the levels of serum creatinine and blood urea nitrogen (BUN) as well as tissue histology. In addition, capsaicin treatment attenuates the expression of inflammatory mediators and oxidative stress markers for renal damage. We also found that capsaicin induces HO-1 expression in kidney tissues and HK-2 cells. Notably, the protective effects of capsaicin were completely abrogated by treatment with either the HO inhibitor ZnPP IX or HO-1 knockdown in HK-2 cells. These results suggest that capsaicin has protective effects against cisplatin-induced renal dysfunction through induction of HO-1 as well as inhibition oxidative stress and inflammation.     

Protection against cisplatin-induced nephrotoxicity by Cu(II)2(3,5-diisopropylsalicylate)4

The ability of Cu(II)(2)(3,5-diisopropylsalicylate)(4), CuDIPS, which exhibits superoxide dismutase (SOD)-like activity, to prevent cisplatin-induced nephrotoxicity was examined in rats. Rats were divided into four groups and treated as follows: (i) vehicle control; (ii) cisplatin (16 mg/kg, intraperitoneally); (iii) CuDIPS (10 mg/kg, intraperitoneally); and (iv) cisplatin plus CuDIPS. Rats were sacrificed 3 days post-treatment. Cisplatin alone resulted in significantly increased plasma creatinine and urea. Administration of 10 mg/kg CuDIPS prevented the cisplatin-induced elevation of plasma creatinine and urea and protected against kidney damage. Relative to controls, rats that received cisplatin treatment displayed a decrease of reduced glutathione (GSH) and elevated platinum and thiobarbituric acid reactive substances (TBARS) levels in the kidney. In comparison with controls, activities of antioxidant enzymes (SOD, CAT, GSH-Px and GSH-Rd) were also reduced in the kidney of rats treated with cisplatin. Administration of 10 mg/kg CuDIPS prevented cisplatin-induced alterations in renal platinum, GSH, TBARS, and antioxidant enzyme activities. This study suggests that the protection offered by CuDIPS against cisplatin-induced nephrotoxicity is partly related to maintenance of renal antioxidant systems.     

卡维地洛对顺铂所致大鼠肾毒性预防作用的形态学研究

目的研究顺铂诱导大鼠肾损伤的组织病理学和超微结构变化以及卡维地洛对大鼠肾损伤的预防作用。方法雄性Wistar大鼠随机分为4组,给药后3～6d处死,取肾组织,常规石蜡切片,HE染色、PAS反应,超薄切片电镜观察。结果卡维地洛组较顺铂肾脏损伤模型组的组织病理学及超微结构变化明显减轻。结论卡维地洛预防性灌胃给与能明显减轻大鼠顺铂所致的肾损伤,其机制可能与其抗氧化和清除自由基活性有关。     

6-Gingerol prevents cisplatin-induced acute renal failure in rats

BACKGROUND: Nephrotoxicity is a major complication and a dose limiting factor for cisplatin therapy. Recent evidence suggests that enhanced oxidative stress caused by oxygen-centered free radicals may contribute to the pathogenesis of cisplatin-induced acute renal failure. 6-Gingerol is claimed to be a potent antioxidant. The present study was performed to explore the renoprotective potential of 6-gingerol on cisplatin-induced oxidative stress and renal dysfunction. METHODS: 6-Gingerol in dosages of 12.5, 25, 50 mg/kg was administered 2 days before and 3 days after cisplatin administration. Renal injury was assessed by measuring serum creatinine, blood urea nitrogen, creatinine, urea clearance and serum nitrite levels. Renal oxidative stress was assessed by determining renal malondialdehyde levels, reduced glutathione levels and enzymatic activities of superoxide dismutase and catalase. RESULTS: A single dose of cisplatin resulted in marked renal oxidative and nitrosative stress and significantly deranged renal functions. 6-Gingerol treatment significantly and dose-dependently restored renal functions, reduced lipid peroxidation and enhanced the levels of reduced glutathione and activities of superoxide dismutase and catalase. CONCLUSIONS: The present study demonstrates the renoprotective potential of 6-gingerol against cisplatin-induced oxidative stress and renal dysfunction in rats. Hence, 6-gingerol has a potential to be used as therapeutic adjuvant in cisplatin nephrotoxicity.     

Role of CFTR in oxidative stress and suicidal death of renal cells during cisplatin-induced nephrotoxicity

The clinical use of the antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the cystic fibrosis transmembrane conductance regulator protein (CFTR), a Cl⁻ channel not only involved in chloride secretion but as well in glutathione (GSH) transport. Thus, we tested whether the inhibition of CFTR could protect against cisplatin-induced nephrotoxicity. Using a renal proximal cell line, we show that the specific inhibitor of CFTR, CFTR_inh-172, prevents cisplatin-induced cell death and apoptosis by modulating the intracellular reactive oxygen species balance and the intracellular GSH concentration. This CFTR_inh-172-mediated protective effect occurs without affecting cellular cisplatin uptake or the formation of platinum-DNA adducts. The protective effect of CFTR_inh-172 in cisplatin-induced nephrotoxicity was also investigated in a rat model. Five days after receiving a single cisplatin injection (5 mg/kg), rats exhibited renal failure, as evidenced by the alteration of biochemical and functional parameters. Pretreatment of rats with CFTR_inh-172 (1 mg/kg) prior to cisplatin injection significantly prevented these deleterious cisplatin-induced nephrotoxic effects. Finally, we demonstrate that CFTR_inh-172 does not impair cisplatin-induced cell death in the cisplatin-sensitive A549 cancer cell line. In conclusion, the use of a specific inhibitor of CFTR may represent a novel therapeutic approach in the prevention of nephrotoxic side effects during cisplatin treatment without affecting its antitumor efficacy.     

In vivo evidence suggesting a role for purine-catabolizing enzymes in the pathogenesis of cisplatin-induced nephrotoxicity in rats and effect of erdosteine against this toxicity

The aim of this experimental study was to investigate the possible role of adenosine deaminase (AD) and xanthine oxidase (XO) in the pathogenesis of cisplatin-induced nephrotoxicity and the effect of erdosteine in decreasing the toxicity. The intraperitoneal injection of cisplatin (7 mg kg(-1) body weight) induced a significant increase in plasma creatinine level and blood urea nitrogen (BUN), and plasma and damaged renal tissue activities of AD and XO in rats. Co-treatment with erdosteine (10 mg kg(-1)day(-1)) attenuated the increase in the plasma creatinine and BUN levels, and significantly prevented the increase in tissue and plasma AD and XO activities (P<0.05). The results of this study revealed that XO and AD may play an important role in the pathogenesis of cisplatin-induced nephrotoxicity. The potent free radical scavenger erdosteine may have protective potential in this process and it will become a promising drug in the prevention of this undesired side-effect of cisplatin, but further studies are needed to illuminate the exact protection mechanism of erdosteine against cisplatin-induced nephrotoxicity.     

Protection by ebselen against cisplatin-induced nephrotoxicity: Antioxidant system

This study was designed to investigate the cisplatin-induced alteration in renal antioxidant system and the nephroprotection with ebselen. Male Wistar rats were injected with (1) vehicle control; (2) cisplatin; (3) ebselen; and (4) cisplatin plus ebselen. Rats were sacrificed three days post-treatment and plasma as well as kidney were isolated and analyzed. Plasma creatinine increased 598% following cisplatin administration alone which decreased by 158% with ebselen pretreatment. Cisplatin-treated rats showed a depletion of renal glutathione (GSH) levels (52% of control), while cisplatin plus ebselen injected rats had GSH values close to the controls. Antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities decreased 38, 75 and 62% of control, respectively, and malondialdehyde (MDA) levels increased 174% of control following cisplatin administration, which were restored to control levels after ebselen treatment. The renal platinum level did not significantly change with ebselen pretreatment. This study suggests that the protection offered by ebselen against cisplatin-induced nephrotoxicity is partly related to the sparing of antioxidant system.     

Amelioration of cisplatin-induced nephrotoxicity in mice by oral administration of diphenylmethyl selenocyanate

Cisplatin is one of the most potent and active cytotoxic drug in the treatment of cancer. However, side-effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the promising efficacy of cisplatin. The present study was designed to ascertain the possible in vivo protective potential of a synthetic organoselenium compound diphenylmethyl selenocyanate (3 mg/kg.b.w.) against the nephrotoxic damage induced by cisplatin (5 mg/kg.b.w. for 5 days) in Swiss albino mice. Treatment with diphenylmethyl selenocyanate markedly reduced cisplatin-induced lipid peroxidation, serum creatinine and blood urea nitrogen levels. Renal antioxidant defense systems, such as glutathione-S-transferase, glutathione peroxidase, superoxide dismutase, catalase, activities and reduced glutathione level, depleted by cisplatin therapy, were restored to normal by the selenium compound. The selenium compound also reduced renal tubular epithelial cell damage, nitric oxide levels and expression of COX-2, and iNOS in kidneys injured by cisplatin. These results demonstrate the protective effect of diphenylmethyl selenocyanate against cisplatin-induced nephrotoxicity in mice.     

Impact of Hemidesmus indicus R.Br. extract on ethanol-mediated oxidative damage in rat kidney

The antioxidant effect of the ethanolic extract of Hemidesmus indicus R.Br. root (EHI), an indigenous Ayurvedic medicinal plant in India, was studied in rats with ethanol-induced nephrotoxicity. Administering 5 g/kg body weight/day of ethanol for 60 days to male Wistar rats resulted in significantly elevated levels of serum urea, creatinine and uric acid as well as kidney thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) and conjugated dienes (CD) as compared to those of the experimental control rats. Decreased levels of kidney superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), vitamin C and vitamin E were also observed on alcohol administration as compared with those of the experimental control rats. EHI was administered at a dose of 500 mg/kg body weight/day for the last 30 days of the experiment to rats with ethanol-induced kidney injury, which significantly decreased the levels of serum urea, uric acid and creatinine as well as kidney TBARS, LOOH and CD and significantly elevated the activities of SOD, CAT, GPx, GSH, vitamin C and vitamin E in kidney as compared to that of untreated ethanol-administered rats. Histopathological observations also correlated with the biochemical parameters. Thus, the data indicate that treatment with EHI offers protection against free radical-mediated oxidative stress in kidney of animals with ethanol-induced nephrotoxicity.     

Hesperidin and Rutin,Antioxidant Citrus Flavonoids,Attenuate Cisplatin‐Induced Nephrotoxicity in Rats

This study aimed to assess the protective effect of hesperidin (HES) and rutin (RUT) against cisplatin‐induced nephrotoxicity in male rats. Cisplatin (5 mg/kg, intraperitoneal) caused significant increases in serum sodium, blood urea nitrogen, serum creatinine, total sodium and potassium excreted in urine, urine volume, and lipid peroxides measured as the malondialdehyde content of kidney, with significant decreases in serum total protein, creatinine clearance, reduced glutathione content of kidney, and kidney superoxide dismutase activity as compared with the control group. On the other hand, administration of HES (200 mg/kg, per oral [p.o.]) or RUT (30 mg/kg, p.o.) for 14 days with a single cisplatin dose on the tenth day ameliorated the cisplatin‐induced nephrotoxicity as indicated by the restoration of kidney function and oxidative stress biomarkers. Furthermore, the test drugs reduced the histopathological changes induced by cisplatin. In conclusion, HES and RUT showed protective effects against cisplatin‐induced nephrotoxicity.     

Rhus verniciflua Stokes prevents cisplatin-induced cytotoxicity and reactive oxygen species production in MDCK-I renal cells and intact mice

Cisplatin-induced oxidative stress can cause liver and kidney damage, thus limiting therapeutic efficacy. Thus, in the present study, since Rhus verniciflua Stokes (RVS) containing flavonoids has antioxidant effects, we investigated whether it can protect cisplatin-induced toxicity in vitro and in vivo, The in vitro effects of RVS on the cell viability and reactive oxygen species (ROS) production were investigated using cisplatin-treated Madin–Darby Canine kidney (MDCK)-I renal cells. Its in vivo effects were also studied in BALB/c mice inoculated with CT-26 colon adenocarcinoma cells and treated with cisplatin with or without RVS. Liver and renal functions were assessed together with indices of tissue oxidation. RVS prevented cisplatin-induced cytotoxicity and ROS release against MDCK-I cells. RVS alone exerted modest antitumor activity against CT-26 cells. When used concurrently with cisplatin, RVS prevented the increases in serum blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and NO, while reducing liver and kidney tissue MDA content, and increasing catalase, glutathione (GSH), and superoxide dismutase (SOD) activities. Moreover, the antitumor efficacy of cisplatin was not altered by concurrent administration of RVS. These findings demonstrate that RVS prevents cisplatin-induced toxicity in vitro and in vivo via an antioxidant activity without hurting its antitumor effectiveness, suggesting that RVS can be usefully applied to the neoplastic patients as a combined chemopreventive agent with cisplatin.     

Depletion of renal cortical glutathione and nephrotoxicity by cephaloridine,cephalothin and gentamicin in male sprague-dawley rats

Cephaloridine and gentamicin are selectively accumulated in renal cortex and produce necrosis of proximal tubular cells. However, the mechanisms responsible for renal cortical accumulation of these two antibiotics are quite different; therefore the early pathogenetic processes may not be the same. In the present study, effects of two cephalosporins (cephaloridine and cephalothin) and an aminoglycoside (gentamicin) on rat renal cortical glutathione were determined. Cephaloridine produced a dose-related depletion of renal cortical glutathione one hour following a single administration of the drug. In contrast, cephalothin in equivalent doses did not reduce renal cortical glutathione. Gentamicin had no effect on renal cortical glutathione, even when an acutely lethal dose (1000 mg/kg) was used. Pretreatment of rats with diethyl maleate (0.4 ml/kg) markedly depleted renal cortical glutathione and this pretreatment also potentiated cephaloridine nephrotoxicity. These results suggest that glutathione may play a protective role against cephaloridine but not gentamicin nephrotoxicity.     

Oral administration of sodium selenite minimizes cisplatin toxicity on proximal tubules of rats

Cisplatin (c-DDP) is a widely used antineoplastic drug whose main side effect is nephrotoxicity. Selenium, administered intravenously or intraperitoneally, has been shown to provided protection against c-DDP-induced nephrotoxicity in rats. In the present study, the protective effect of orally administered sodium selenite on c-DDP toxicity was further examined. Animals treated with c-DDP alone showed increased urinary volume, decreased creatinine clearance (GFR), and a rise in urinary N-acetyl-(β-d-glucosaminidase) (NAG) isoenzyme B activity. When sodium selenite was given prior to c-DDP, rats showed less GFR decline, delayed urinary volume increases, and no urinary NAG isoenzyme B activity increment. It is suggested that a single oral dose of sodium selenite given prior to c-DDP administration, although not preventing deterioration of renal function, partially protects rats from early proximal tubular injury.     

Naringenin attenuates cisplatin nephrotoxicity in rats

The effect of naringenin (NAR), a naturally occurring citrus flavanone, on the acute nephrotoxicity produced by cisplatin (7 mg/kg, i.v.) was investigated in the rat. Oral administration of NAR (20 mg/kg/day) for 10 days, starting 5 days before cisplatin single i.v. injection, produced significant protection of renal function. NAR reduced the extent of cisplatin-induced nephrotoxicity, as evidenced by significant reduction in serum urea and creatinine concentrations, decreased polyuria, reduction in body weight loss, marked reduction in urinary fractional sodium excretion and glutathione S-transferase (GST) activity, and increased creatinine clearance. Cisplatin-induced alterations in renal cortex lipid peroxides and GST activity were markedly improved by NAR. Cisplatin-induced alterations in renal cortex antioxidant defense system were greatly prevented by NAR. In cisplatin-NAR combined treatment group, antioxidant enzymes namely superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) were significantly increased to 54.5, 30.3 and 35.6%, respectively compared to cisplatin treated group. Platinum renal content was not affected by NAR treatment. The results provide further insight into the mechanisms of cisplatin-induced nephrotoxicity and confirm the antioxidant potential of NAR.     

Effect of Pre‐ and Post–Combined Multidoses of Epigallocatechin Gallate and Coenzyme Q10 on Cisplatin‐Induced Oxidative Stress in Rat Kidney

The nephroprotective effect of coenzyme Q10 and epigallocatechin gallate was investigated in rats with acute renal injury induced by a single nephrotoxic dose of cisplatin. Two days prior to cisplatin administration, epigallocatechin gallate and coenzyme Q10 alone and in four different combinations were given for 6 days. The treatment with antioxidants significantly protected the cisplatin‐induced increase in the levels of blood urea nitrogen and serum creatinine. Both the antioxidants alone or in different combinations significantly compensated the increased malondialdehyde and reduced glutathione levels. Moreover, the decrease in the activities of superoxide dismutase, catalase, and glutathione peroxidase and the concentration of selenium, zinc, and copper ions were significantly attenuated in renal tissue. In conclusion, epigallocatechin gallate and coenzyme Q10 are equally effective against cisplatin‐induced nephrotoxicity, whereas the intervention by combining these two antioxidants was found to be highly effective at low doses in attenuating oxidative stress in rat kidney.     

Taurine ameliorates potassium bromate-induced kidney damage in rats

Potassium bromate (KBrO₃) is widely used as a food additive and is a major water disinfection by-product. Several studies have shown that it causes nephrotoxicity in humans and experimental animals. We have investigated the potential role of the sulfonic amino acid taurine in protecting the kidney from KBrO₃-induced damage in rats. Animals were randomly divided into four groups: control, KBrO₃ alone, taurine alone and taurine + KBrO₃. Administration of single oral dose of KBrO₃ alone caused nephrotoxicity as evident by elevated serum creatinine and urea levels. Renal lipid peroxidation and protein carbonyls were increased while total sulfhydryl groups and reduced glutathione levels were decreased suggesting the induction of oxidative stress. The enzymes of renal brush border membrane were inhibited and those of carbohydrate metabolism were altered. There was an increase in DNA damage and DNA–protein cross-linking. Treatment with taurine, prior to administration of KBrO₃, resulted in significant attenuation in all these parameters but the administration of taurine alone had no effect. Histological studies supported these biochemical results showing extensive renal damage in KBrO₃-treated animals and greatly reduced tissue injury in the taurine + KBrO₃ group. These results show that taurine is an effective chemoprotectant against bromate-induced renal damage and this amino acid could prove to be useful in attenuating the toxicity of this compound.