Protective Effect of L-Carnitine against Gentamicin-Induced Nephrotoxicity in Rats

Authors: Mohamed F. Ahmed, Mabruka S. Elashheb, Fatma M. Ben Rabha

Abstract:

This study aimed to determine the possible protective effects of L‐carnitine against gentamicin‐induced nephrotoxicity. Forty male albino rats were divided into 4 groups (10 rats each); Group 1: normal control, group 2: induced nephrotoxicity (gentamicin 50 mg/kg/day S.C; 8 days), group 3: treated with L‐ carnitine (40 mg/kg/d SC for 12 days) and group 4: treated with L‐ carnitine 4 days before and for 8 days in concomitant with gentamicin. Gentamicin‐induced nephrotoxicity (group 2): caused significant increase in serum urea, creatinine, urinary N‐acetyl‐B‐D‐ glucosaminidase (NAG), gamma glutamyl transpeptidase (GGT), urinary total protein and kidney tissue malondialdehyde (MDA) with significant decrease in serum superoxide dismutase (SOD), serum catalase and creatinine clearance and marked tubular necrosis in the proximal convoluted tubules with interruption in the basement membrane around the necrotic tubule compared to the normal control group. L‐carnitine 4 days before and for 8 days in concomitant with gentamicin (group 4) offered marked decrease in serum urea, serum creatinine, urinary NAG, urinary GGT, urinary proteins and kidney tissue MDA, with marked increase in serum SOD, serum catalase and creatinine clearance with marked improvement in the tubular damage compared to gentamicin‐induced nephrotoxicity group. L‐carnitine administered for 12 days produced no change in the parameters mentioned above as compared to the normal control group. In conclusion: L‐carnitine could reduce most of the biochemical parameters and also improve the histopathological features of kidney asscociated with gentamicin induced‐nephrotoxicity. 

Keywords: Gentamicin, kidney disease, L‐carnitine, nephrotoxicity.

Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1107423

References:

[1] Abdel-aleem S, Nada MA, Sayed-Ahmed M, Hendrickson SC, St Louis J, Walthall HP, Lowe JE. (1996): Regulation of fatty acid oxidation by acetyl-CoA generated from glucose utilization in isolated myocytes. J Mol Cell Cardiol. ; 28(5):825-33.
[2] Al-Shabanah OA, Aleisa AM, Al-Yahya AA, Al-Rejaie SS, Bakheet SA, Fatani AG, Sayed-Ahmed MM. (2010): Increased urinary losses of carnitine and decreased intramitochondrial coenzyme A in gentamicininduced acute renal failure in rats. Nephrol. Dial. Transplant..; 25(1):69- 76.
[3] Arduini A, Rossi M, Mancinelli O, et al. (1990): Effect of L-carnitine and acetyl L-carnitine on the human erythrocyte membrane stability and deformability. Life Sci; 47:2395–400.
[4] Bartels H., Boehmer M. (1971): Micro-determination of creatinine. Clin. Chim. Acta. ; 32:81–85.
[5] Begg EJ, Barclay ML, Kirkpatrick CM. (2001): The therapeutic monitoring of antimicrobial agents.Br J Clin Pharmacol. 52:35S–43S.
[6] Bennett WM, Mela-Riker LM, Houghton DC, Gilbert DN, Buss WC. (1988): Microsomal protein synthesis inhibition: an early manifestation of gentamicin nephrotoxicity. Am J Physiol.; 255: F265-9.
[7] Bremer J. (1983): Carnitine--metabolism and functions. Physiol Rev.; 63(4):1420-80.
[8] Clairborne, A. (2000): Catalase acivity. In: Greenwald, E.R. (Ed.). Handbook of Methods for Oxygen Radical Research, CRC Press, Florida, pp: 283-284.
[9] Cockcroft DW, Gault MH. (1976): Prediction of creatinine clearance from serum creatinine. Nephron. ; 16(1):31-41.
[10] De la Cruz Rodríguez, Carmen Rosa Araujo, Sara Emilia Posleman, María Rosario Rey (2010): Attenuation of gentamicin-induced nephrotoxicity: trimetazidine versus N-acetyl cysteine. J. Apple. Toxicol. 30(4):343-53.
[11] Erdem, A., Gundogan, N.U., Usubutun, A., Kilinc, K., Erdem, S.R., Kara, A., Bozkurt, A. (2000): The protective effect of taurine against gentamicin-induced acute tubular necrosis in rats. Nephrol. Dial.Transplant. 15, 1175–1182.
[12] Ergün O, Ulman C, Kiliçalp AS, Ulman I. (2001): Carnitine as a preventive agent in experimental renal ischemia-reperfusion injury. Urol Res.; 29(3):186-9.
[13] Fawcett JK and Scott JE (1960): A rapid and precise method for the determination of urea. Clin Pathol.; 13:156-9.
[14] Giovannini L, Migliori M, De Pietro S, Taccola D, Panichi V, Bertelli AA, Bertelli A. (1999): L-propionyl carnitine reduces toxicity correlated to cyclosporine-induced intracellular ATP concentrations. Drugs Exp Clin Res.; 25(4):173-7.
[15] Halliwell B, Chirico S. (1993): Lipid peroxidation: its mechanism, measurement and significance. Am J Clin Nutr. 57:715–25.
[16] Haywood, J.P.; Shaffer, R.A. and Fastenow, C. (1981): Regional blood flow measurment with plused Doppler flowmeter in conscious rats. Am. J. Physiol., 241: 273-78.
[17] Kaloyanides GJ, Ramsammy L S. (1991): Alterations of biophysical properties of liposomes predict aminoglycoside toxicity: inhibitory effect of polyaspartic acid. In: Bach PH, Delacrey L, Gregg NJ, Wilks MF, eds. Proceedings of the Fourth International Symposium on Nephrotoxicity. Marcel Dekker, New York; 117–126.
[18] Kaloyanides, G. J. (1984): Aminoglycoside-Induced Functional and Biochemical Defects in the Renal Cortex. Fundam. Appl. Toxicol. ; 930–943.
[19] Kirschbaum BB. (1984): Interactions between renal brush border membranes and polyamines. J Pharmacol Exp Ther ; 229(2):409-16.
[20] Klein G, Geibel E. (1990): Evaluation of a new photometric assay for the kinetic determination of N-acetyl-b-D-glucosaminidase in urine samples. Progr Med Lab; 4/5: 450.
[21] Kopple JD, Ding H, Letoha A, Ivanyi B,Qing DP, Dux L. (2002): lCarnitine ameliorates gentamicin-induced renal injury in rats. Nephrol Dial Transplant.17:2122–31.
[22] Longoni B, Giovannini L, Migliori M, Bertelli AA, Bertelli A. ( 1999): Cyclosporine-induced lipid peroxidation and propionyl carnitine protective effect. Int J Tissue React. ; 21(1):7-11.
[23] Misra, HP. (2000): Adrenochrome assay. In Greenwald, A.R. (Ed.). Hand books of Methods for Oxygen Radical Research. CRC Press, Florida, pp: 237-242.
[24] Moriyama T, Nakahama H, Fukuhara Y, Horio M, Yanase M, Orita Y, Kamada T, Kanashiro M, Miyake Y. (1989): Decrease in the fluidity of brush-border membrane vesicles induced by gentamicin. A spin labeling study. Biochem Pharmacol. ; 38(7):1169-74.
[25] Moudden M, Laurent G, Leclercq M, Tulkens P. (2000): Gentamicin induced apoptosis in renal cell lines and embryonic rat fibroblasts. Toxicol Sci. 56:229–39.
[26] Mouedden M., Laurent G. and Tulkens PM. (2010): Mechanism of Protective Effect of L-carnitine on Human Kidney Tubular Epithelial Cell Line Injury Induced by Oxidative Stress, Posted on May, 17, 2010 by China Papers.
[27] Orsonneau JL, Douet P, Massoubre C, Lustenberger P, Bernard S. (1989) :An improved Pyrogallol Red-Molybdate Method for Determining Total Urinary Protein. Clin Chem.; 35:2233-6.
[28] Packer L, Valenza M, Serbinova E, Starke-Reed P, Frost K, Kagan V. (1991): Free radical scavenging is involved in the protective effect of Lpropionyl-carnitine against ischemia-reperfusion injury of the heart. Arch Biochem Biophys. ; 288(2):533-7.
[29] Parlakpinar H, Tasdemir S, Polat A, Bay-Karabulut A, Vardi N, Ucar M. (2006): Protective effect of chelerythrine on gentamicin-induced nephrotoxicity. Cell Biochem Funct. 24(1):41–8.
[30] Parlakpinar, H., Ozer,M.K., Sahna, E., Vardi, N., Cigremis, Y., Acet, A. (2003): Amikacin-induced acute renal injury in rats: protective role of melatonin. J. Pineal. Res. 35, 85–90.
[31] Pedraza-Chaverrí J, Gonzalez-Orozcoa AE, Maldonado PD, Barrera D, Medina-Campos ON, Hernandez-Pando R. (2003): Diallyl disulfide ameliorates gentamicin induced oxidative stress and nephropathy in rats. Eur J Pharmacol. 473: 71–8.
[32] Pedraza-Chaverri, J., Maldonado, P.D., Mediana-Campos, O.N., Olivares-Corichi, I.M., Granados-Silvestre, M.A., Hernandez- Pando, R Ibarra-Rubio, M.E. (2000): Garlic ameliorates gentam icin nephrotoxicity: relation to antioxidant enzymes. Free Radic. Biol. Med. 29, 602–611.
[33] Prins JM, Weverling GJ, de Blok K, van Ketel RJ, Speelman P. (1996): Validation and nephrotoxicity of a simplified once-daily aminoglycoside dosing schedule and guidelines for monitoring therapy. Anti-microb Agents Chemother. 40: 2494–9.
[34] Ramsammy LS, Kaloyanides GJ. (1987): Effect of gentamicin on the transition temperature and permeability to glycerol of phosphatidylinositol-containing liposomes. Biochem Pharmacol; 36(7):1179-81.
[35] Reiter, R.J., Tan, D., Sainz, R.M., Mayo, J.C., Lopez, B.S. (2002): Melatonin reducing the toxicity and increasing the efficacy of drugs. J. Pharm. Pharmacol. 5, 1299–1321.
[36] Sandoval RM, Dunn KW, Molitoris BA. (2000): Gentamicin traffics rapidly and directly to the Golgi complex in LLC-PK (1) cells. Am J Physiol Renal Physiol.; 279(5):F884-90.
[37] Selby NM, Shaw SM, Woodier N, Fluck RJ, Kohle NV. (2009): Gentamicin-associated acute kidney injury. Q J Med.102:873–80.
[38] Shug AL. (1987): Protection from adriamycin-induced cardiomyopathy in rats. Z, Kardiol. ; 76 Suppl 5:46-52.
[39] Steiber A, Kerner J, Hoppel CL. (2004): Carnitine: a nutritional, biosynthetic, and functional perspective. Mol Aspects Med.; 25(5- 6):455-73.
[40] Sweileh WM. (2009): A prospective comparative study of gentamicinand amikacininduced nephrotoxicity in patients with normal baseline renal function. Fundam Clin Pharmacol. 23(4):515–20.
[41] Szasz, G. (1969): A kinetic photometric method for serum γglutamyl transpeptidase.Clin. Chem. 15: 124–136.
[42] Walker PD and Shah SV (1988): Evidence Suggesting a Role for Hydroxyl Radical in Gentamicin-induced acute renal failure in Rats. J. Clin. Invest. ; 81: 334-341.
[43] Walker PD, Barri Y, Shah SV. (1999): Oxidant mechanisms in gentamicin nephrotoxicity. Ren Fail.; 21(3-4):433-42.
[44] Weinberg JM, Humes HD (1980): Mechanisms of gentamicin-induced dysfunction of renal cortical mitochondria. I. Effects of mitochondrial respiration. Arch Biochem Biophys; 205:222–231.
[45] Williams PD, Holohan PD, and Ross CR (1981): Gentamicin nephrotoxicity. II. Plasma membrane changes. Toxicol, Appl. Pharmacol.61:243–251.