The restoration of ATP synthesis may explain the protective effect of calcium antagonists against cyclosporine a nephrotoxicity

Salducci, M. D.; Chauvet-Monges, Anne-Marie; Berland, Yvon; Dussol, B.; Elsen, R.; Crevat, A.

doi:10.1016/0024-3205(92)90571-6

Cited by 19 publications

(9 citation statements)

References 15 publications

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“…21,41 Moreover, Zhong et al 11 have shown that CsA administration results in excess local production of hydroxyl radical, leading to lipid peroxidation and nephrotoxicity. The production of ROS by CsA may be due to the action of CsA as an uncoupler and inhibitor of the mitochondrial electron transport system 44 and CsA metabolism by cytochrome P450 3A. 45 In addition, CsA causes increased renal vascular resistance and decreased renal blood flow.…”

Section: Discussionmentioning

confidence: 99%

Taurine Attenuates Hypertension and Renal Dysfunction Induced by Cyclosporine a in Rats

Hagar¹,

Etter²,

Arafa

2006

Clin Exp Pharma Physio

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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.

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Section: Discussionmentioning

confidence: 99%

Taurine Attenuates Hypertension and Renal Dysfunction Induced by Cyclosporine a in Rats

Hagar¹,

Etter²,

Arafa

2006

Clin Exp Pharma Physio

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“…It is well known that CsA can block the bpermeability transition poreQ [38], which involves accumulation of mitochondrial Ca 2+ [39] and alteration in mitochondrial electron transport chain [40]. These events cause the oxidative phosphorylation uncoupling [41] and the subsequent increase in ROS production. On the basis of these data, we can hypothesise that the induction of HSPs could be a defensive mechanism by which hepatic cells contrast these alterations.…”

Section: Discussionmentioning

confidence: 99%

Protective role of melatonin in cyclosporine A-induced oxidative stress in rat liver

Rezzani

Buffoli

Rodella

et al. 2005

International Immunopharmacology

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“…Cyclosporine increases free radical formation (Serino et al ., 1993; Wang & Salahudeen, 1994) leading among other effects to reduction of oxidative phosphorylation and to decreased mitochondrial ATP‐concentrations (Packer, 1998). The immunophilin FKBP‐12, the major intra‐cellular binding protein of rapamycin and SDZ‐RAD (Schuler et al ., 1997), is an important component in the regulation of ryanodine and inositol 1,4,5,‐triphosphate receptors, both major intracellular calcium channels (Salducci et al ., 1992; Schreiber, 1991; Shou et al ., 1998; Snyder et al ., 1998). It has been hypothesized that inhibition of FKBP‐12 by macrolide immunosuppressants results in calcium overload of mitochondria which inhibits oxidative phosphorylation (Salducci et al ., 1992).…”

Section: Discussionmentioning

confidence: 99%

“…The immunophilin FKBP‐12, the major intra‐cellular binding protein of rapamycin and SDZ‐RAD (Schuler et al ., 1997), is an important component in the regulation of ryanodine and inositol 1,4,5,‐triphosphate receptors, both major intracellular calcium channels (Salducci et al ., 1992; Schreiber, 1991; Shou et al ., 1998; Snyder et al ., 1998). It has been hypothesized that inhibition of FKBP‐12 by macrolide immunosuppressants results in calcium overload of mitochondria which inhibits oxidative phosphorylation (Salducci et al ., 1992). This hypothesis is not supported by the results of our study.…”

Section: Discussionmentioning

confidence: 99%

The novel immunosuppressant SDZ‐RAD protects rat brain slices from cyclosporine‐induced reduction of high‐energy phosphates

Serkova

Litt

Leibfritz

et al. 2000

British J Pharmacology

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1 SDZ-RAD, 40-O-(2-hydroxyethyl)-rapamycin, is a novel macrolide immunosuppressant. Because of its synergistic interaction, SDZ-RAD is under clinical investigation as immunosuppressant in combination with cyclosporine after organ transplantation. Neurotoxicity is a critical side-e ect of cyclosporine. 2 We studied the e ect of SDZ-RAD and its combination with cyclosporine on high-energy phosphates, phosphocreatine (PCr) and nucleoside triphosphates (NTP), in brain slices using 31 Pmagnetic resonance spectroscopy (MRS). 3 Cyclosporine signi®cantly reduced high-energy phosphates after 2 h in a dose-dependent manner (100 mg l 71 : 93+3% of control (NTP), 91+3% (PCr); 500 mg l 71 : 84+2% (NTP), 73+2 (PCr); 5000 mg l 71 : 68+3% (NTP), 55+5% (PCr); n=6; P50.02). 4 In contrast, after perfusion for 2 h, SDZ-RAD (500 mg l 71 and 5000 mg l 71 ) signi®cantly increased high-energy phosphate concentrations in the brain slices (P50.02). Even at the lowest concentration, SDZ-RAD protected brain energy metabolism against cyclosporine toxicity: 100 mg l 71 SDZ-RAD+5000 mg l 71 cyclosporine: 86+3% (NTP), 83+7% (PCr), n = 3, P50.03 compared to cyclosporine alone. 5 As evaluated using an algorithm based on Loewe isobolograms, the e ects of SDZ-RAD/ cyclosporine combinations on brain energy reduction were antagonistic. Both drugs were found in mitochondria using h.p.l.c-MS analysis. 6 We conclude that cyclosporine inhibits mitochondrial high-energy phosphate metabolism, which can be antagonized by SDZ-RAD.

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The restoration of ATP synthesis may explain the protective effect of calcium antagonists against cyclosporine a nephrotoxicity

Cited by 19 publications

References 15 publications

Taurine Attenuates Hypertension and Renal Dysfunction Induced by Cyclosporine a in Rats

Taurine Attenuates Hypertension and Renal Dysfunction Induced by Cyclosporine a in Rats

Protective role of melatonin in cyclosporine A-induced oxidative stress in rat liver

The novel immunosuppressant SDZ‐RAD protects rat brain slices from cyclosporine‐induced reduction of high‐energy phosphates

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