L-carnitine protects against cyclosporine-induced pancreatic and renal injury in rats.

BACKGROUND: L-carnitine has protective effects against various types of injury. This study was designed to evaluate the beneficial effects of L-carnitine on pancreatic and renal injuries caused by cyclosporine (CsA). METHODS: Rats maintained on a low sodium diet were given vehicle (olive oil, 1 mL/kg/d), CsA (15 mg/kg/d), L-carnitine (50 or 200 mg/kg/d), or a combination of CsA and L-carnitine for 4 weeks. The impact of L-carnitine on pancreatic injury was assessed by blood glucose levels, plasma insulin concentrations, and hemoglobulin A1c (HbA1c). In addition, the protective effects of L-carnitine against CsA-induced kidney injury were evaluated in terms of renal function, histopathology (inflammatory cell influx and tubulointerstitial fibrosis), oxidative stress (8-hydroxy 2'-deoxyguanosine, 8-OHdG), transforming growth factor-betal (TGF-ß1), apoptosis (caspase-3), and autophagy (LC3-II). RESULTS: CsA treatment caused diabetes, renal dysfunction, tubulointerstitial inflammation (ED-1-positive cells), and fibrosis, which were accompanied by an increase in 8-OHdG production and upregulation of TGF-ß1, caspase-3, and LC3-II. Concomitant administration of L-carnitine increased plasma insulin concentrations, decreasing plasma glucose and HbA1c levels. In the kidney, L-carnitine induced dose-dependent improvement of renal function, inflammation, and fibrosis in parallel with suppression of the expression of TGF-ß1 and 8-OHdG. Furthermore, the administration of L-carnitine at a high dose inhibited the expression of caspase-3 and LC3-II. CONCLUSION: These findings suggest that L-carnitine has a protective effect against CsA-induced pancreatic and renal injuries.

Effects of tomato extract on oxidative stress induced toxicity in different organs of rats.

Tomato products containing lycopene are believed to be associated with decreased risk of chronic diseases including cancer, and its effects are suggested to be due to antioxidant effect of lycopene. The aim of this research was to study the effects of tomato extract on acetaminophen (APAP), amiodarone (ADN) and cyclosporine A (CsA)-induced liver, lung and kidney toxicity, respectively. Previous studies have shown that free radical reactions may play important roles in toxicity of these drugs. Rats received a single dose of APAP (750mg/kg, i.p.) before treatment with tomato extract (5mg/kg, oral) for seven consecutive days, ADN (100mg/kg, i.p.) plus tomato extract (5mg/kg, oral) for 10 consecutive days, or CsA (250mg/kg, i.p.) plus tomato extract (5mg/kg, oral) for 14 consecutive days. At the end of each treatment, the animals were sacrificed and the related organ tissues were collected for biochemical and histopathological examinations. Simultaneous treatment of tomato extract ameliorated tissue damage, biochemical indices, and oxidative stress parameters against APAP-induced acute hepatotoxicity, but had less beneficial effects on ADN-induced lung toxicity and little effect against CsA-induced nephrotoxicity. Therefore, tomato products may be beneficial for the prevention and therapy of toxicity induced by ADN and APAP.

Heteropterys aphrodisiaca infusion reduces the collateral effects of cyclosporine A on the testis.

Cyclosporine A (CsA) is known to have testicular toxicity, leading to male infertility. Stimulant and aphrodisiac properties have been attributed to the plant, Heteropterys aphrodisiaca. Thus, the present work was undertaken to evaluate the association of the drug and the medicinal herb in Wistar rats, applying testicular morphometry and ultrastructure. Twenty-four rats were used, divided into four groups: I, control; II, CsA; III, simultaneous use of CsA and H. aphrodisiaca; IV, H. aphrodisiaca. Daily administration by gavage was carried out, during 56 days, of water (sham), CsA in a dose of 15 mg/kg per day and/or H. aphrodisiaca in a dose of 0.5 ml of the infusion prepared with 25 g of roots/100 ml of boiling water. Increased body weight was observed for all groups, but the animals that received only CsA showed the smallest body weight gain. Morphometry showed increased connective tissue volumetric proportion and decreased Leydig cell volumetric proportion in CsA-treated rats. Using transmission electron microscopy, it was possible to ascertain that CsA caused seminiferous epithelium degeneration, resulting in Sertoli cell vacuolization, abnormal round and elongated spermatids and large accumulation of residual cytoplasm at the epithelium border next to the lumen. Expanded intercellular spaces between germ cells were still observed in H. aphrodisiaca-treated rat testes. The administration of H. aphrodisiaca infusion to CsA-treated rats diminished nearly all the CsA-induced damage to the testis ultrastructure, suggesting that H. aphrodisiaca infusion may be used combined with CsA to reduce CsA-induced injuries in the testis.

Beneficial effect of shallot (Allium ascalonicum L.) extract on cyclosporine nephrotoxicity in rats.

The clinical use of an immunosuppressive cyclosporine A (CsA) is limited by its serious nephrotoxic effect. Evidences have suggested the role of oxidative stress in its pathogenesis. Shallot (Allium ascalonicum L.) has recently been shown to possess antioxidative and free radical scavenging abilities. The present study was undertaken to investigate the possible beneficial effect of shallot extract on renal injury caused by CsA. Male Wistar rats were treated orally with vehicle, CsA (25 mg/kg), shallot extract (1 g/kg), and CsA plus shallot extract for 21 days. Renal function, histopathology, tissue malondialdehyde (MDA) and glutathione (GSH) levels were evaluated 24 h after the last treatment. CsA-induced nephrotoxicity was evidenced by increased blood urea nitrogen and serum creatinine, but decreased urea and creatinine clearance. The kidney of CsA treated rats exhibited severe vacuolations and tubular necrosis. CsA also induced oxidative stress, as indicated by increased renal MDA and reduced GSH concentrations. Administration of shallot extract along with CsA counteracted the deleterious effects of CsA on renal dysfunction, oxidative stress markers, and morphological changes. These data indicate the protective potential of shallot extract against CsA nephrotoxicity and suggest a significant contribution of its antioxidant property to this beneficial effect.

Possible therapeutic effect of lipid supplementation on neurological complications in liver transplant recipients.

Neurological complications (NCs) represent a serious problem following liver transplantation and may develop either because of various peri-operative factors or the toxicity of immunosuppression. Although the causality assessment of NCs can be particularly difficult in the setting of organ transplantation, calcineurin inhibitors (CNIs) might influence NCs to a certain extent, regardless of the etiology. Therefore, minimizing the influence of CNIs could be a reasonable strategy for alleviating NCs. Based on our hypothesis that lipid supplementation prevents lipophilic CNIs from crossing the blood-brain barrier, soybean oil was administered to five liver transplant patients with NCs. In all of these patients, the neurological symptoms improved without discontinuing or reducing the dose of CNIs. Thus, lipid supplementation might be able to reduce the adverse neurological effects of CNIs.

Discovery and synthesis of new immunosuppressive alkaloids from the stem of Fissistigma oldhamii (Hemsl.) Merr.

Three new alkaloids (1-3) and twenty-one known compounds were isolated from the stem of Fissistigma oldhamii (Hemsl.) Merr. which was the ruler herb in an approved Traditional Chinese herbal formula used for treatment of rheumatoid arthritis in China and synthesis of one new immunosuppressive alkaloid was achieved. These compounds, including the crude extracts of this herb, exhibited strong activities in the inhibition of T and B cell proliferation.

Involvement of oxidative stress induction in Na+ toxicity and its relation to the inhibition of a Ca2+ -dependent but calcineurin-independent mechanism in Saccharomyces cerevisiae.

Uridine 5'-hexadecylphosphate (UMPC16) inhibited the growth of Saccharomyces cerevisiae under a hypersaline stress condition with Na+ more strongly than the calcineurin inhibitor cyclosporine A (CsA). Additional Ca2+ supplementation similarly suppressed the inhibitory activities of UMPC16 and CsA on yeast cell growth in a medium with Na+. UMPC16, but not CsA, accelerated mitochondrial reactive oxygen species (ROS) generation in combination with Na+, suggesting its inhibition of a Ca2+ -dependent but calcineurin-independent mechanism for protection against Na+ toxicity.

Taurine attenuates hypertension and renal dysfunction induced by cyclosporine A in rats.

Cyclosporine A (CsA) is the first-line immunosuppressant used for the management of solid organ transplantation and autoimmune diseases. Nephrotoxicity is the major limitation of CsA use. Recent evidence suggests that reactive oxygen species (ROS) play an important role in mediating CsA-induced hypertension and nephrotoxicity. Taurine, the major intracellular free beta-amino acid, is known to be an endogenous anti-oxidant and membrane-stabilizing agent. The present study was designed to investigate the effects of taurine on CsA-induced oxidative stress, hypertension and renal dysfunction. 2. Animals were assigned into four groups of seven rats each as follows: (i) control group, receiving vehicle (olive oil; 1 mL/kg, s.c.); (ii) CsA group, given CsA (25 mg/kg per day, s.c.) for 21 days; (iii) taurine group, supplemented with taurine (1% in the drinking water); and (iv) taurine + CsA group, treated with taurine 3 days before and concurrently during CsA injections for 21 days. 3. Cyclosporine A administration elevated blood pressure, reduced serum nitric oxide (NO) levels and deteriorated renal function, as assessed by increased serum creatinine levels and proteinuria and reduced urine flow rate and creatinine clearance compared with vehicle-treated rats. Cyclosporine A induced oxidative stress, as indicated by increased renal tissue concentrations of thiobarbituric acid-reactive substances and reduced concentrations of renal glutathione, glutathione peroxidase and superoxide dismutase. Conversely, no change was noted in renal catalase activity. Moreover, the kidneys of CsA-treated rats showed interstitial inflammation and renal tubular atrophy. 4. Taurine markedly reduced elevated blood pressure, attenuated renal dysfunction and the reduction in serum NO levels and counteracted the deleterious effects of CsA on oxidative stress markers. Furthermore, taurine ameliorated CsA-induced morphological changes. 5. These data clearly indicate the protective potential of taurine against CsA-induced hypertension and nephrotoxicity and suggest a significant contribution of its anti-oxidant property to this beneficial effect.

Antioxidant supplementation enhances erythrocyte antioxidant status and attenuates cyclosporine-induced vascular dysfunction.

The aim of this study was to determine the effects of dietary antioxidant supplementation with alpha-tocopherol and alpha-lipoic acid on cyclosporine-induced alterations to erythrocyte and plasma redox balance, and cyclosporine-induced endothelial and smooth muscle dysfunction. Rats were randomly assigned to either control, antioxidant, cyclosporine or cyclosporine + antioxidant treatments. Cyclosporine A was administered for 10 days after an 8-week feeding period. Plasma was analyzed for alpha-tocopherol, total antioxidant capacity, malondialdehyde and creatinine. Erythrocytes were analyzed for glutathione, methemoglobin, superoxide dismutase, catalase, glutathione peroxidase, glucose-6-phosphate dehydrogenase, alpha-tocopherol and malondialdehye. Vascular endothelial and smooth muscle function was determined in vitro. Antioxidant supplementation resulted in significant increases in erythrocyte alpha-tocopherol concentration and glutathione peroxidase activity in both of the antioxidant-supplemented groups. Cyclosporine administration caused significant decreases in glutathione concentration, methemoglobin concentration and superoxide dismutase activity. Antioxidant supplementation attenuated the cyclosporine-induced decrease in superoxide dismutase activity. Cyclosporine therapy impaired both endothelium-independent and -dependent relaxation of the thoracic aorta, and this was attenuated by antioxidant supplementation. In summary, dietary supplementation with alpha-tocopherol and alpha-lipoic acid attenuated the cyclosporine-induced decrease in erythrocyte superoxide dismutase activity and attenuated cyclosporine-induced vascular dysfunction.

Curcumin, a diferuloylmethane, attenuates cyclosporine-induced renal dysfunction and oxidative stress in rat kidneys.

BACKGROUND: In India, Curcumin (CMN) is popularly known as "Haldi", and has been well studied due to its economic importance. Traditional Indian medicine claims the use of its powder against biliary disorders, anorexia, coryza, cough, diabetic wounds, hepatic disorder, rheumatism and sinusitis. This study was designed to examine the possible beneficial effect of CMN in preventing the acute renal failure and related oxidative stress caused by chronic administration of cyclosporine (CsA) in rats. CMN was administered concurrently with CsA (20 mg/kg/day s.c) for 21 days. Oxidative stress in kidney tissue homogenates was estimated using thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) content, superoxide dismutase (SOD), and Catalase (CAT). Nitrite levels were estimated in serum and tissue homogenates. RESULTS: CsA administration for 21 days produced elevated levels of TBARS and marked depletion of renal endogenous antioxidant enzymes and deteriorated the renal function as assessed by increased serum creatinine, Blood Urea Nitrogen (BUN) and decreased creatinine and urea clearance as compared to vehicle treated rats. CMN markedly reduced elevated levels of TBARS, significantly attenuated renal dysfunction increased the levels of antioxidant enzymes in CsA treated rats and normalized the altered renal morphology. CONCLUSION: In conclusion our study showed that CMN through its antioxidant activity effectively salvaged CsA nephrotoxicity.

Green tea extract attenuates cyclosporine A-induced oxidative stress in rats.

Cyclosporine A (CsA) nephrotoxicity underweighs the therapeutic benefits of such a powerful immunosuppressant. Whether oxidative stress plays a role in such toxicity is not well delineated. We investigated the potential of green tea extract (GTE) to attenuate CsA-induced renal dysfunction in rats. Three main groups of Sprague-Dawley rats were used: CsA, GTE, and GTE plus CsA-receiving animals. Corresponding control groups were also used. CsA was administered in a dose of 20mg kg(-1) day(-1), i.p., for 21 days. In the GTE/CsA groups, the rats received different concentrations of GTE (0.5, 1.0 and 1.5%), as their sole source of drinking water, 4 days before and 21 days concurrently with CsA. The GTE group was treated with 1.5% concentration of GTE only for 25 days. A concomitant administration of GTE, to CsA receiving rats, markedly prevented the generation of thiobarbituric acid-reacting substances (TBARS) and significantly attenuated CsA-induced renal dysfunction as assessed by estimating serum creatinine, blood urea nitrogen, uric acid and urinary excretion of glucose. A considerable improvement in terms of reduced glutathione content and activity of antioxidant enzymes in the kidney homogenate of the GTE/CsA-receiving rats was observed. The activity of lysosomal enzymes, N-acetyl-beta-glucosaminidase, beta-glucuronidase and acid phosphatase was significantly inhibited following GTE co-administration. Our data prove the role of oxidative stress in the pathogenesis of CsA-induced kidney dysfunction. Supplementation of GTE could be useful in reducing CsA nephrotoxicity in rats. However, clinical studies are warranted to investigate such an effect in human subjects.

Comparison of the effects of polysaccharides from wood-cultured and bag-cultured Ganoderma lucidum on murine spleen lymphocyte proliferation in vitro.

AIM: To compare the influences of wood-cultured Ganoderma lucidum polysaccharides (Gl-PS-WC) and bag-cultured Ganoderma lucidum polysaccharides (Gl-PS-BC) on the proliferation activities of murine spleen lymphocytes in vitro, and investigate whether Gl-PS-BC can be substituted for Gl-PS-WC. METHODS: Mixed lymphocyte culture (MLC) reaction, lymphocyte proliferation induced by concanavalin A (Con A, 1 mg.L-1) or lipopolysaccharide (LPS, 5 mg.L-1), MLC reactions inhibited by immunosuppressive drugs, cyclosporine A (CsA, 0.1 mg.L-1), mitomycin (Mit C, 0.1 mg.L-1), or antitumor drug, etoposide (VP-16, 0.1 mg.L-1), were detected in the presence or absence of Gl-PS-WC and Gl-PS-BC in the concentration range of 0.2-12.8 mg.L-1. RESULTS: Two kinds of polysaccharides were shown to promote MLC in the range of 0.2-12.8 mg.L-1, increase lymphocyte proliferation induced by Con A or LPS and antagonize the inhibitory effects of CsA, Mit C or VP-16 on MLC. No significant difference was observed between these two kinds of polysaccharides in selected concentrations. CONCLUSION: Gl-PS-WC and Gl-PS-BC showed similar effects on the proliferation activities of murine spleen lymphocytes in vitro.

Lacidipine protects against cyclosporine-induced nephrotoxicity in rats.

The effect of lacidipine (LA), a new calcium channel blocker with an antioxidant effect, has been studied on cyclosporine (CsA)-induced nephrotoxicity in male Wistar rats. Lacidipine (1 mg/kg BW) was administered orally 3 days before and 14 days concurrently with CsA (50 mg/kg BW orally). Urine volume, Na+, K+, Li+ and creatinine in urine, and blood urea, serum creatinine, lithium, plasma malondialdehyde (MDA) and CsA levels were estimated in blood after 14 days CsA treatment. Kidneys were examined using histological techniques. Blood urea and serum creatinine were increased by 305 and 211%, respectively, with CsA when compared to the saline-treated animals. Creatinine clearance (Ccr) and lithium clearance (Licr) were decreased and proximal tubule fractional reabsorption 1-(Licr/Ccr) was significantly increased with CsA. Lacidipine protected rats from CsA-induced nephrotoxicity. Changes in blood urea, serum creatinine, Ccr, Licr and proximal tubule fractional reabsorption induced by CsA were significantly prevented by LA. There was a 160% rise in MDA levels with CsA, which was significantly reduced equal to control with LA. Histomorphology showed microcalcification with CsA, while it was normal with LA. In rats treated with LA, CsA did not show any microcalcification. Our data suggest that supplementation of LA may be helpful to reduce CsA nephrotoxicity.

Cyclosporin A increases hypoxia and free radical production in rat kidneys: prevention by dietary glycine.

The major side effect of cyclosporin A is severe nephrotoxicity. It is likely that cyclosporin A causes vasoconstriction leading to hypoxia-reperfusion injury; therefore, these experiments were designed to attempt to obtain physical evidence for hypoxia and free radical production in kidney following cyclosporin A. Rats were treated daily with cyclosporin A (25 mg/kg ig) for 5 days, and pimonidazole, a hypoxia marker, was injected 2 h after the last dose of cyclosporin A. A dose of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (4-POBN) was injected 3 h after cyclosporin A to trap free radicals. Cyclosporin A doubled serum creatinine and decreased glomerular filtration rates by 65% as expected. Pimonidazole adduct binding in the kidney was increased nearly threefold by cyclosporin A, providing physical evidence for tissue hypoxia. Moreover, cyclosporin A increased 4-POBN/radical adducts nearly sixfold in the urine but did not alter levels in the serum. Glycine, which causes vasodilatation and prevents cyclosporin A toxicity, minimized hypoxia and blocked free radical production; however, it did not alter cyclosporin A blood levels. These results demonstrate for the first time that cyclosporin A causes hypoxia and increases production of a new free radical species exclusively in the kidney. Therefore, it is concluded that cyclosporin A causes renal injury by mechanisms involving hypoxia-reoxygenation, effects which can be prevented effectively by dietary glycine.

Investigation of a possible interaction between ciprofloxacin and cyclosporine in renal transplant patients.

BACKGROUND: Bacterial infection is a common complication during the first few months after renal transplantation. Ciprofloxacin, a fluoroquinolone broad-spectrum antibiotic, is used frequently in treating infections in the early posttransplant period. Evidence from in vitro studies has suggested that ciprofloxacin can antagonize the cyclosporine (CsA)-dependent inhibition of interleukin-2 production. Such an effect in renal transplant patients could antagonize the immunosuppressive activity of CsA and lead to rejection of the graft. METHODS: To investigate the possibility of a pharmacodynamic interaction between ciprofloxacin and CsA, we conducted a case-control study in 42 patients who had received a kidney transplant and who were prescribed ciprofloxacin in the first 1-6 months after transplantation and in their matched controls (two per case) who did not receive ciprofloxacin during the study period. RESULTS: There was a twofold greater incidence (P=0.008) of ciprofloxacin use at 1-3 months (65%) than was observed at 4-7 months (35%) after transplantation. The proportion of cases experiencing at least one episode of biopsy-proven rejection 1-3 months posttransplant (45%) was significantly greater (P=0.004) than that of controls (19%). Furthermore, there was a marked increase (P<0.001) in the incidence of rejection temporally associated with ciprofloxacin use among cases (29%) compared with that experienced by the controls (2%). CONCLUSIONS: The possibility that ciprofloxacin increases rejection rates in renal transplant patients may be of clinical importance and therefore warrants further investigation.

L-Arginine and allopurinol protect against cyclosporine nephrotoxicity.

The role of nitric oxide (NO) and oxygen free radicals in cyclosporine (CsA) nephrotoxicity was investigated using L-arginine, an NO substrate, and allopurinol, a xanthine oxidase inhibitor (involved in the formation of oxygen radicals) in an experimental model with Wistar rats. CsA, administered at 15 mg/kg/body weight (BW) subcutaneously for 10 days, caused a decrease in glomerular filtration rate, with inulin clearance of 0.33+/-0.04 vs. 1.11+/-0.06 ml/min/100 g BW (P<0.01 vs. control). L-Arginine, 1.5% in drinking water 5 days before and during CsA administration, partially protected the animals against this fall in glomerular filtration rate, with inulin clearance of 0.68+/-0.03 ml/min/100 g BW (P<0.01 vs. CsA). Allopurinol, at 10 mg/kg/BW by gavage, also had a protective action, with inulin clearance of 0.54+/-0.04 ml/min/100 g (P<0.01 vs. CsA). CsA caused an elevation in NO production, as assessed by urinary excretion of its metabolites, nitrite and nitrate (NO2 and NO3; 0.836+/-0.358 vs. 0.107+/-0.019 nmol/microg creatinine). NO production was as much as threefold higher in the L-arginine group (1.853+/-0.206 nmol/g creatinine). This CsA effect is probably related to its vasoconstrictive stimulus. Supplementation with L-arginine, which provides more substrate for NO formation, may enhance vasodilatation and consequently reduce the impairment of renal function. The protection provided by allopurinol may be related to the reduced formation of oxygen radicals, preventing the deleterious effects of lipid peroxidation.

Reduction of chronic ciclosporin nephrotoxicity by thromboxane synthase inhibition with OKY-046.

Ciclosporin A (CsA) is a potent immunosuppressive agent which is extremely effective in controlling allograft rejection and in the treatment of autoimmune disease and nephrotic syndrome. Unfortunately, its use is limited by chronic, irreversible nephrotoxicity. Administration of CsA induces renal vasoconstriction, causing a reduction in renal blood flow. An alteration of the prostaglandin-thromboxane cascade may be involved in the vasoconstriction. We studied the role of thromboxane A2 in CsA nephrotoxicity and the ability of a thromboxane synthase inhibitor, OKY-046, to reduce the CsA nephrotoxicity. Daily administration of CsA 25 mg/kg for 28 days to Sprague-Dawley rats resulted in increased excretion of urinary thomboxane B2 (47.9+/-11.5 vs. 27.2+/-9.7 ng/24 h; p<0.05) and decreased creatinine clearance (0.25+/-0.07 vs. 0.43+/-0.17ml/min/100 g; p<0.01) as compared with administration of vehicle only. Histologically, large numbers of lysosomes in the tubular epithelium were characteristic. Coadministration of OKY-046 prevented both the rise in urinary thromboxane B2 excretion (40.0+/-11.8 ng/24 h) and the reduction in the creatinine clearance (0.44+/-0.11 ml/min/100 g). The severity of the histological changes was significantly diminished. Selective inhibition of thromboxane production with OKY-046 may be valuable in the attenuation of CsA nephrotoxicity.

Lipid peroxidation accompanies cyclosporine nephrotoxicity: effects of vitamin E.

Cyclosporine A (CsA) has been demonstrated to induce renal microsomal lipid peroxidation in vitro. To examine whether CsA induces lipid peroxidation in vivo, uninephrectomized rats were gavaged with vehicle, CsA 12.5 or 25 mg/kg/day for four weeks. CsA-induced reduction in GFR and RBF was associated with a dose-related increase in renal cortical malondialdehyde (MDA) and conjugated diene, as well as a similar increase in arterial MDA. The latter was apparent within two hours of a single intraperitoneal injection of 25 mg/kg CsA and preceded the acute fall in GFR. To address whether lipid peroxidation contributed to CsA nephrotoxicity, rats were gavaged with vehicles, CsA 25 mg/kg/day or CsA plus vitamin E 25 mg/kg/day for eight weeks. Vitamin E, a lipid radical scavenger, inhibited MDA raise and reduced CsA-induced renal damage. Conversely, CsA administration to vitamin E and selenium deficient rats was accompanied by a greater increase in arterial MDA and fall in GFR. These novel findings, that CsA nephrotoxicity is associated with lipid peroxidation and that a chain-breaking antioxidant ameliorates whereas its deficiency exacerbates, indicate a role for lipid peroxidation, presumably free radical-mediated, in CsA toxicity.

Prevention of experimental cyclosporine nephrotoxicity by dietary supplementation with LSL 90202, a lysine salt of eicosapentaenoic acid. Role of thromboxane and prostacyclin in renal tissue.

Cyclosporine (CsA) nephrotoxicity is partially mediated by renal vasoconstriction due to an imbalance between vasodilator and vasoconstrictor eicosanoids. LSL 90202 is a purified lysine salt of eicosapentaenoic acid which is a known inhibitor of renal eicosanoid synthesis. The aim of the present work was to determine if chronic dietary supplementation with LSL 90202 prevented CsA nephrotoxicity and to establish the role of thromboxane and prostacyclin in renal tissue. Thirty-three male Sprague-Dawley rats were divided into 4 groups: group 1, CsA in olive oil (n = 10); group 2, isovolumetric olive oil (n = 7); group 3, CsA in olive oil plus LSL 90202 (n = 8); group 4, isovolumetric olive oil plus LSL 90202 (n = 8). CsA and LSL 90202 were given at 20 mg/kg/day. Weight and creatinine clearance (CrCl) were determined before and on days 14 and 30. On day 30 whole-blood CsA was determined and renal tissue processed for renal malondialdehyde, thromboxane B2 and 6-keto-PGF1 alpha measurement and for conventional histology. CrCl was severely reduced in the CsA in olive oil group compared to olive oil and LSL 90202 control groups. On day 30, CrCl in the CsA in olive oil plus LSL 90202 group showed a slight decrease, but the mean CrCl was significantly higher than in the CsA in olive oil group. Trough whole blood CsA levels were not significantly different in both groups given the drug. No morphological differences were found between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Alteration of cyclosporine (CsA)-induced nephrotoxicity by gamma linolenic acid (GLA) and eicosapentaenoic acid (EPA) in Wistar rats.

Administration of cyclosporine (CsA), 37.4 microM (45 mg)/Kg, per day for 7 days, to Wistar rats, induced decreased creatinine clearance (Ccr) and body weight loss (BWL), but it did not induce proteinuria. These changes were associated with enhanced urinary thromboxane B2 (TXB2) and diminished 6-keto-PGF1 alpha (6kPGF1 alpha) and prostaglandin E2 (PGE2) excretions. The augmentation in TXB2 and the decrease in PGs highly diminished the ratios of 6kPGF1 alpha/TXB2 and PGE2/TXB2. In microscopic sections all of the kidneys were affected to variable degrees. When CsA was administered to animals fed for 70 days, prior to the experiment, on standard chow (SC) containing evening primrose oil (EPO) or fish oil (FO), 1% and 10% respectively (EPO contained 9% gamma-linolenic acid (GLA) and FO 5.6% eicosapentaenoic acid (EPA)), the nephrotoxic effect of CsA was partially prevented. These changes were accompanied by increased ratios of urinary 6kPGF1 alpha/TXB2 and PGE2/TXB2 excretions. Light microscopic (LM) studies showed that rats' kidneys fed on SC containing EPO or FO were not always affected and the lesions were of minor importance. In conclusion, these results suggest that EPO (GLA) and FO (EPA) could play a beneficial role in the development or the modulation of the renal syndrome induced by CsA.