Impact of peroxisome proliferator activated receptor agonist drugs in a model of nephrotoxicity in rats

Doxorubicin (DOX) is one of the basic anticancer drugs, nonetheless its use is restricted due to noxious side effects. Kidney failure is one of the main side effects that restrict its medical use. The current study assessed the nephroprotective effects of fenofibrate and pioglitazone against the renal injury induced by doxorubicin in rats and illustrated the probable mechanisms underlying these protective effects. For this purpose, Male Sprague–Dawley rats weighing (200–230 g) were allocated into seven groups treated for 15 days as following: control (50% corn oil + 50% DMSO p.o), fenofibrate (100 mg/kg p.o) and pioglitazone (10 mg/kg p.o) as well as four groups of DOX (15 mg/kg i.p on 11th day). DOX groups included DOX alone and DOX with protective drugs fenofibrate, pioglitazone or both of them. As a result of doxorubicin nephrotoxicity; serum creatinine and blood urea nitrogen were remarkably elevated. Moreover, renal glutathione was significantly reduced while tissue lipid peroxidation malondialdehyde, tumor necrosis factor-α, nuclear factor-kappa B p65 (NF-κB p65), interleukin-1β, p38 mitogen activated protein kinase (p38-MAPK) and caspase-3 (Casp-3) were significantly augmented. Treatment with fenofibrate and pioglitazone either alone or in combination markedly attenuated DOX-induced injury by suppression of oxidative stress, inflammation and apoptosis. The above-mentioned biochemical markers were affirmed by histological assessment. In conclusion, fenofibrate, pioglitazone, and their combination possess potential prophylactic effects against doxorubicin-induced renal injury through modulation of p38-MAPK/NF-κB p65 pathway with superiority to the combination.     

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.     

Antioxidant S-allylcysteine prevents gentamicin-induced oxidative stress and renal damage

Acute renal failure (ARF) is a major complication of gentamicin (GM) treatment, which is effective against gram-negative infections. Since experimental evidence suggests a role of reactive oxygen species (ROS) in GM-induced ARF, in this work we studied the effect of a garlic-derived compound, S-allylcysteine (SAC), which is a free radical scavenger, on GM-induced nephrotoxicity. In rats treated with GM (70 mg/kg/12 h/4 days/s.c.), ARF was evident by the: (i) decrease in creatinine clearance and increase in blood urea nitrogen, (ii) decrease in blood glutathione peroxidase (GPx) activity and increase in urinary excretion of N-acetyl-beta-D-glucosaminidase and total protein, and (iii) necrosis of proximal tubular cells. These alterations were prevented by SAC treatment (250 mg/kg/i.p. 24 h before the first dose of GM and 125 mg/kg/12 h/4 days along GM-treatment). Furthermore, SAC prevented the GM-induced oxidative stress (protein carbonyl groups) and the decrease in manganese superoxide dismutase (Mn-SOD), GPx, and glutathione reductase (GR) activities in renal cortex. In conclusion, SAC ameliorates the GM-induced ARF by a mechanism related, at least in part, to its ability to decrease oxidative stress and to preserve antioxidant enzymes activity in renal cortex.     

Protective effect of resveratrol against doxorubicin-induced cardiac toxicity and fibrosis in male experimental rats

The possible effectiveness of resveratrol, a polyphenol present in different plants comprising berries, grapes and peanuts, on the prevention of doxorubicin-induced cardiac toxicity and fibrosis was investigated. Forty adult male Wistar albino rats were divided into four groups. Group I received normal saline, group II gavaged with resveratrol (20 mg/kg, daily for 4 weeks), group III received doxorubicin (2.5 mg/kg i.p. in six injections for 2 weeks; accumulative dose of 15 mg/kg), and group IV received doxorubicin?+?resveratrol (starting resveratrol intake 2 weeks before doxorubicin administration). Resveratrol significantly alleviated the increase in left ventricular lipid peroxidation, hydroxyproline, and tumor necrosis factor alpha levels as well as serum creatine kinase-myocardial band (CK-MB) activity and prevented the decrease in body and heart weights in doxorubicin-treated group. However, a marked protection against reduced glutathione content depletion and superoxide dismutase activity reduction was observed in the left ventricles of rats pretreated with resveratrol in combination with doxorubicin. Resveratrol also ameliorated the up-regulation of left ventricular caspase-3 and transforming growth factor-beta1 gene expression as well as left ventricular histopathological changes including necrosis and fibrosis induced by doxorubicin. Collectively, our results suggest that resveratrol provides a significant protection against doxorubicin-induced cardiotoxicity and fibrosis in rats. Therefore, it may be used as a promising cardioprotective agent in patients treated with doxorubicin due to malignant diseases. So, further clinical trials are required to confirm these findings.     

Aged garlic extract attenuates gentamicin induced renal damage and oxidative stress in rats

Gentamicin (GM) is an antibiotic whose clinical use is limited by its nephrotoxicity. Experimental evidences suggest a role of reactive oxygen species in GM-induced nephrotoxicity. Therefore, we investigated if aged garlic extract (AGE), an antioxidant, has a protective role in this experimental model. Four groups of male Wistar rats were studied: 1) Control (CT), injected subcutaneously (s.c.) and intraperitoneally (i.p.) with saline, 2) GM, treated s.c. with GM (70 mg/kg/12 hours/4 days), 3) AGE, treated i.p with AGE (1.2 mL/kg/12 hours/6 days), and 4) GM + AGE treated with GM and AGE. The treatment with AGE started two days before the first dose of GM (GM + AGE group) or saline (AGE group). Animals were sacrificed on day 5, and blood, urine, and kidneys were obtained. Nephrotoxicity was made evident by: 1) the increase in blood urea nitrogen and plasma creatinine, 2) the decrease in plasma glutathione peroxidase (GPx) activity and the urinary increase in N-acetyl-beta-D-glucosaminidase activity and total protein, and 3) necrosis of proximal tubular cells. These alterations were prevented or ameliorated by AGE treatment. Furthermore, AGE prevented the GM-induced increase in the renal levels of oxidative stress markers: nitrotyrosine and protein carbonyl groups and the decrease in manganese superoxide dismutase (Mn-SOD), GPx, and glutathione reductase (GR) activities. The protective effect of AGE was associated with the decrease in the oxidative stress and the preservation of Mn-SOD, GPx, and GR activities in renal cortex. These data suggest that AGE may be a useful agent for the prevention of GM-nephrotoxicity.     

Proanthocyanidin from grape seeds enhances doxorubicin-induced antitumor effect and reverses drug resistance in doxorubicin-resistant K562/DOX cells

With the aim of enhancing the efficacy of chemotherapeutic agents, we investigated the antitumor actions and reversal effect on drug resistance of proanthocyanidin plus doxorubicin. The results showed that proanthocyanidin 12.5-200 mg/L significantly inhibited proliferation of K562, K562/DOX, SPC-A-1, and Lewis cells in vitro in a time- and concentration-dependent manner, as determined by microculture tetrazolium assay. A combination of proanthocyani din 12.5, or 25 mg/L and doxorubicin treatment synergistically inhibited cell proliferation with decreased IC50 values. Proanthocyanidin reverses drug resistance in doxorubicin-resistant K562/DOX cells, and IC50 values were decreased by 9.19 (3.64-23.19), 2.56 (1.48-.44), and 0.94 (0.81-1.09) mg/L, respectively, after 24 h treatment with doxorubicin 0.1-9.0 mg/L alone or in combination with proanthocyanidin 12.5 or 25 mg/L; the proanthocyanidin reversal fold was 3.6 and 9.8, respectively. Under confocal laser scanning microscope, the combination of proanthocyanidin 25 or 50 mg/L with doxorubicin 3 mg/L significantly increased the accumulation of intracellular doxorubicin, Ca2+, and Mg2+, and reduced the pH value and mitochondrial membrane potential in K562/DOX cells as compared with doxorubicin alone (p < 0.01). Additionally, the apoptosis rate was increased by 11.3% +/- 3.3%, 14.2% +/- 5.4%, and 23.8% +/- 2.8%, respectively, for doxorubicin 3 mg/L alone or with proanthocyanidin 12.5 or 25 mg/L, as compared with controls (3.0% +/- 1.4%), as demonstrated by flow cytometry. In vivo experiments demonstrated that i.p. administration of proanthocyanidin 10 mg/kg with doxorubicin 2 mg/kg had an inhibitory effect on the growth of transplantation tumor sarcoma 180 and hepatoma 22 in mice as compared with doxorubicin alone (p < 0.05). These results suggest that proanthocyanidin enhances doxorubicin-induced antitumor effect and reverses drug resistance, and its mechanism is attributed partially to the promotion of doxorubicin-induced apoptosis through an elevation of intracellular doxorubicin, and Ca2+, Mg2+ concentration, and a reduction of pH value and mitochondrial membrane potential.     

S-diclofenac protects against doxorubicin-induced cardiomyopathy in mice via ameliorating cardiac gap junction remodeling

Hydrogen sulfide (H(2)S), as a novel gaseous mediator, plays important roles in mammalian cardiovascular tissues. In the present study, we investigated the cardioprotective effect of S-diclofenac (2-[(2,6-dichlorophenyl)amino] benzeneacetic acid 4-(3H-1,2,dithiol-3-thione-5-yl)phenyl ester), a novel H(2)S-releasing derivative of diclofenac, in a murine model of doxorubicin-induced cardiomyopathy. After a single dose injection of doxorubicin (15 mg/kg, i.p.), male C57BL/6J mice were given daily treatment of S-diclofenac (25 and 50 μmol/kg, i.p.), diclofenac (25 and 50 μmol/kg, i.p.), NaHS (50 μmol/kg, i.p.), or same volume of vehicle. The cardioprotective effect of S-diclofenac was observed after 14 days. It showed that S-diclofenac, but not diclofenac, dose-dependently inhibited the doxorubicin-induced downregulation of cardiac gap junction proteins (connexin 43 and connexin 45) and thus reversed the remodeling of gap junctions in hearts. It also dose-dependently suppressed doxorubicin-induced activation of JNK in hearts. Furthermore, S-diclofenac produced a dose-dependent anti-inflammatory and anti-oxidative effect in this model. As a result, S-diclofenac significantly attenuated doxorubicin-related cardiac injury and cardiac dysfunction, and improved the survival rate of mice with doxorubicin-induced cardiomyopathy. These effects of S-diclofenac were mimicked in large part by NaHS. Therefore, we propose that H(2)S released from S-diclofenac in vivo contributes to the protective effect in doxorubicin-induced cardiomyopathy. These data also provide evidence for a critical role of H(2)S in the pathogenesis of doxorubicin-induced cardiomyopathy.     

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.     

Vitamin E and telmisartan attenuates doxorubicin induced cardiac injury in rat through down regulation of inflammatory response

ABSTRACT: BACKGROUND: The importance of doxorubicin (Dox), as a potent antitumor antibiotic, is limited by the development of life-threatening cardiomyopathy. It has been shown that free radicals are involved in acute doxorubicin-induced toxicity. The aim of this study was to determine the protective effect of vitamin E and telmisartan in acute doxorubicin induced cardiotoxicity. METHODS: Thirty two male Sprague - Dawly rats were involved in this study and were randomly separated into 4 groups, eight rats in each group, one group received normal saline I.P as control and second group received doxorubicin 20 mg/kg I.P, the other two groups also received doxorubicin 20 mg/kg I.P as single dose after seven cumulative doses (for seven days) of vitamin E (100 mg/kg) and telmisartan (1 mg/kg) respectively. Immunofluorescent staining for monocytes infiltration and analyses of plasma by (ELISAs) for MCP-1and troponin I. Western immunoblotting assay for ICAM-1, while left ventricular function was analyzed by microcatheter, also estimated the level of oxidative stress parameters (MDA and Catalase) and cardiac enzymes activities (CK-MB and LDH) before starting drugs treatment and after treatment period by 48 hours. RESULTS: The immunofluorescent staining showed that administration of vitamin E and telmisartan are attenuated of mononuclear cell infiltration; (p < 0.05 vs. Dox group), also reduced the level of chemokines MCP-1 and ICAM-1 expression compared with Dox group only, and there is marked reduction of myocardial troponin-I levels with improved LV function in vitamin E and telmisartan treated group. Doxorubicin treatment increased MDA, LDH, CK-MB levels significantly (P < 0.01), and were counteracted by administration of vitamin E and telmisartan, but did not significantly affect serum catalase activity. CONCLUSIONS: Antioxidant effect (Vitamin E and telmisartan) have been shown to decrease doxorubicininduced cardiotoxicity.     

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.     

Cardioprotective activity of melatonin and its novel synthesized derivatives on doxorubicin-induced cardiotoxicity

This study aimed at evaluation of melatonin and some of its novel synthesized derivatives 3, 4, 9 and 10b as cardioprotective agents against doxorubicin-induced acute cardiac toxicity in rats. Also, this work was extended to study the potential role of each synthesized derivative in comparison with the parent compound melatonin. Intraperitoneal injection of a single dose (15mg/kg B.W.) of doxorubicin resulted in significant increase in serum troponin I, leptin, triglycerides, cholesterol and LDL-cholesterol levels with concomitant decrease in serum T(3), T(4) and IL-1alpha levels. In contrast, intraperitoneal injection of melatonin or its synthesized derivatives especially compounds 3 and 10b in a dose of 5mg/kg B.W./day for 10days reversed doxorubicin-induced changes in the above mentioned parameters towards the normal values. The present data revealed that doxorubicin exerts its action mainly through the oxidative stress. This appeared from the significant elevation in serum nitric oxide level and cardiac lipid peroxidation level with concomitant decrease in cardiac antioxidative enzymes activity. Treatment with melatonin and its derivatives 3 and 10b could reduce the markers of oxidative stress and restore the activity of the antioxidative enzymes in the heart tissue. In conclusion, the cardioprotective effect of melatonin and its derivatives may be mediated through the antioxidant and free radical scavenging activity of these compounds.     

Renoprotective effects of montelukast in an experimental model of cisplatin nephrotoxicity in rats

Renal toxicity is one of the most severe complications that can occur with cisplatin (CIS) administration in cancer patients. Montelukast (ML) renoprotective outcome contrary to CIS‐drawn nephrotoxicity remains obscure. Therefore, adult male Sprague–Dawley rats were orally given ML (10 and 20 mg/kg/day) 5 days before and after single CIS (5 mg/kg; i.p.) treatment. ML returned blood urea nitrogen, as well as serum creatinine and gamma glutamyl transferase that were elevated by CIS to normal level. The improved kidney function tests corroborated the attenuation of CIS renal injury at the microscopical level. It also reduced serum/renal nitric oxide and renal hemeoxygenase‐1. Meanwhile, ML hindered the raised levels of serum endothelin‐1, serum and renal tumor necrosis factor‐α, and monocyte chemoattractant protein‐1. These effects were associated by deceased caspase‐3 expression in kidney after ML treatment. In conclusion, ML guards against CIS‐induced nephrotoxicity via anti‐inflammatory and antiapoptotic properties.     

Cyclosporine A-induced alterations in magnesium homeostasis in the rat

The immunosuppressive drug cyclosporine A (CsA) exhibits significant nephrotoxicity. Disturbance of magnesium (Mg) homeostasis may be an important component of this nephrotoxicity. It has been suggested that transmigration of Mg from plasma to tissues may be an important component of CsA-induced alterations in Mg homeostasis. In this study, CsA nephrotoxicity in male Wistar rats was investigated and alterations in Mg homeostasis along with other indices of toxicity were assessed. Animals were dosed daily for 14 days i.p. with CsA (20 mg/kg body weight). Control animals received vehicle alone. CsA toxicity was evidenced by i) lower gain in body weight, ii) reduced thymus/body weight ratio, iii) increased blood urea nitrogen and creatinine, iv) a tendency for reduced plasma magnesium and v) increased urinary Mg excretion and greatly increased fractional excretion of Mg. Tissue Mg analysis did not reveal any changes in thymus or skeletal muscle Mg while Mg in kidney tissue tended to be reduced. Electron microscopy revealed some damage in renal tubules of rats treated with cyclosporine including translucent cytoplasm, vacuolization, rounded and swollen mitochondria, damage to brush border and disruption of basal infoldings. These results indicate that direct renal tubular damage may result from CsA exposure. No evidence was found for CsA-induced movement of Mg from plasma to tissues. CsA-induced altered renal handling of Mg and this renal Mg wasting may be an important consequence of the nephrotoxicity.     

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

The effect of aminoguanidine (AG) on nephrotoxicity induced by cisplatin (CDDP) was investigated. A single dose of CDDP (7.5 mg/kg 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 and urinary excretion of albumin were observed. Nephrotoxicity was further confirmed by a significant decrease in glutathione-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 mg/kg per day p.o.) in drinking water 5 days before and 5 days after CDDP injection produced a significant protection against nephrotoxicity induced by CDDP. The amelioration of nephrotoxicity was evidenced by significant reductions in serum urea and creatinine concentrations. In addition, AG tended to normalize decreased levels of serum albumin. Urine volume, urinary excretions of albumin and GST and kidney weight were significantly decreased. Moreover, AG prevented the rise of MDA and the reduction of GST and GSH-Px activities in the kidney. These results suggest that AG has a protective effect on nephrotoxicity induced by CDDP and it may therefore improve the therapeutic index of CDDP.     

Effects of thymic hormone on reactive oxygen species-scavengers and renal function in tacrolimus-induced nephrotoxicity

The effects of a thymic hormone (Facteur thymique serique; FTS) on renal reactive oxygen species-scavenging enzymes or substances in heminephrectomized rats with and without tacrolimus-induced nephrotoxicity were studied. Rats received both oral dose of tacrolimus (5 mg/kg/day) and subcutaneous administration of three dosages of FTS (5, 50, and 250 microg/kg/day) over 28 days (Group A). In Group B, they received three dosages of FTS alone (0.5, 5, and 50 microg/kg/day) or FTS 50 microg/kg/day with tacrolimus over 28 days. Each dose of FTS (Group A) partially elevated renal creatinine clearances. Tacrolimus enhanced renal glutathione reductase (GSH-R) activities and glutathione (GSH) and depressed catalase (CAT) activities. FTS increased GSH levels and GSH-R activities. Although FTS alone did not change CAT activities, CAT activities recovered as a result of concomitant use of FTS (Groups A and B). A significant positive correlation was found between CAT activity and creatinine clearance. These findings suggest that FTS is useful for the prevention of tacrolimus-induced nephrotoxicity, and that the increase of renal CAT activity in the defense mechanism of FTS might be important for cell protection against active oxygen species.     

Effect of oral administration of Arabic gum on cisplatin-induced nephrotoxicity in rats

It has been recently postulated from our laboratory that Arabic gum (AG) offers a protective effect in the kidney of rats against nephrotoxicity induced by gentamicin via inhibiting lipid peroxidation. It has also recently shown a powerful antioxidant effect through scavenging superoxide anions. In this study we utilized a rat model of cisplatin (CP)-induced nephrotoxicity to determine its peak time following (1, 2, 5, and 7 days) of a single CP (7.5 mg/kg, i.p.) injection. Also, a possible protective effect of cotreatment with AG (7.5 g/kg/day p.o.) on CP-induced nephrotoxicity was investigated. Biochemical as well as histological assessments were carried out. CP-induced nephrotoxicity was manifested by significant elevations of the functional parameters blood urea, serum creatinine, and kidney/body weight ratio. Maximum toxic effects of CP were observed 5 days after its injection, while it started after day 1 in the biochemical parameters, such as glutathione depletion in the kidney tissue with concomitant increases in lipid peroxides and platinum content. Additionally, severe necrosis and desquamation of tubular epithelial cells in renal cortex as well as interstitial nephritis were observed after 5 days in CP-treated animals. Five days after AG cotreatment with CP did not protect the kidney from the damaging effects of CP. However, it significantly reduced CP-induced lipid peroxidation. These findings suggest that lipid peroxidation is not the main cause of CP-induced nephrotoxicity but it is rather more dependent on other factors such as platinum disposition in renal interstitial tubules.     

Carvedilol: a beta blocker with antioxidant property protects against gentamicin-induced nephrotoxicity in rats

Gentamicin is an antibiotic effective against gram negative infections, whose clinical use is limited by its nephrotoxicity. Since the pathogenesis of gentamicin-induced nephrotoxicity involves oxygen free radicals, the antioxidant carvedilol may protect against gentamicin-induced renal toxicity. We therefore tested this hypothesis using a rat model of gentamicin nephrotoxicity. Carvedilol (2 mg/kg) was administered intraperitoneally 3 days before and 8 days concurrently with gentamicin (80 mg/kg BW). Estimations of urine creatinine, glucose, blood urea, serum creatinine, plasma and kidney tissue malondialdehyde (MDA) were carried out, after the last dose of gentamicin. Kidneys were also examined for morphological changes. Gentamicin caused marked nephrotoxicity as evidenced by increase in blood urea, serum creatinine and decreased in creatinine clearance. Blood urea and serum creatinine was increased by 883% and 480% respectively with gentamicin compared to control. Carvedilol protected the rats from gentamicin induced nephrotoxicity. Rise in blood urea, serum creatinine and decrease in creatinine clearance was significantly prevented by carvedilol. There was 190% and 377% rise in plasma and kidney tissue MDA with gentamicin. Carvedilol prevented the gentamicin induced rise in both plasma and kidney tissue MDA. Kidney from gentamicin treated rats, histologically showed necrosis and desquamation of tubular epithelial cells in renal cortex, whereas it was very much comparable to control with carvedilol. In conclusion, carvedilol with its antioxidant property protected the rats from gentamicin-induced nephrotoxicity.     

Inhibition of PARP activation by enalapril is crucial for its renoprotective effect in cisplatin-induced nephrotoxicity in rats

Oxidative stress-induced PARP activation has been recognized to be a main factor in the pathogenesis of cisplatin-induced nephrotoxicity. Accumulating literature has revealed that ACE inhibitors may exert beneficial effect in several disease models via preventing PARP activation. Based on this hypothesis, we have evaluated the renoprotective effect of enalapril, an ACE inhibitor, and its underlying mechanism(s) in cisplatin-induced renal injury in rats. Male Albino Wistar rats were orally administered normal saline or enalapril (10, 20 and 40?mg/kg) for 10 days. Nephrotoxicity was induced by a single dose of cisplatin (8?mg/kg; i.p.) on the 7th day. The animals were thereafter sacrificed on the 11th day and both the kidneys were excised and processed for biochemical, histopathological, molecular, and immunohistochemical studies. Enalapril (40?mg/kg) significantly prevented cisplatin-induced renal dysfunction. In comparison to cisplatin-treated group, the elevation of BUN and creatinine levels was significantly less in this group. This improvement in kidney injury markers was well substantiated with reduced PARP expression along with phosphorylation of MAPKs including JNK/ERK/p38. Enalapril, in a dose-dependent fashion, attenuated cisplatin-induced oxidative stress as evidenced by augmented GSH, SOD and catalase activities, reduced TBARS and oxidative DNA damage (8-OHDG), and Nox-4 protein expression. Moreover, enalapril dose dependently inhibited cisplatin-induced inflammation (NF-κB/IKK-β/IL-6/Cox-2/TNF-α expressions), apoptosis (increased Bcl-2 and reduced p53, cytochrome c, Bax and caspase-3 expressions, and TUNEL/DAPI positivity) and preserved the structural integrity of the kidney. Thus, enalapril attenuated cisplatin-induced renal injury via inhibiting PARP activation and subsequent MAPKs/TNF-α/NF-κB mediated inflammatory and apoptotic response.     

Effect of pre-treatment with St John's Wort on nephrotoxicity of cisplatin in rats

An herbal health care supplement, St John's Wort (SJW, Hypericum perforatum) has become widely used in the treatment of depression, and is known to interact with therapeutic drugs. Here we report a preventive effect of SJW on cisplatin nephrotoxicity in rats. Rats were given SJW (400 mg/kg/day, p.o.) for 10 consecutive days, and were injected with cisplatin (5 mg/kg, i.v.) on the day after the final SJW treatment. Cisplatin treatment increased the serum creatinine level, which is an index of nephrotoxicity, to 1.51+/-0.22 mg/dl (mean+/-SE) from 0.28+/-0.05 mg/dl (control) on day 5 after the cisplatin injection. This increase fell significantly to 0.86+/-0.13 mg/dl by pre-treatment with SJW. Cisplatin-induced histological abnormality of the kidney was blocked by pre-treatment with SJW. When SJW was administered for 10 days, the amounts of renal metallothionein (MT) and hepatic multidrug resistance protein 2 (Mrp2) were increased to 164.8+/-13.0% and 220.8+/-39.3% (mean+/-SE) of controls, respectively. GSH levels in the kidney and liver were not changed. Total and free cisplatin concentration in serum was not influenced by SJW treatment. In conclusion, the results suggest that pre-treatment with SJW may diminish cisplatin nephrotoxicity.