Original Articles

L-Carnitine Protect against Cyclophosphamide Induced Skeletal and Neural Tube Malformations in Rat Fetuses

Abstract

Cyclophosphamide (CP) is a mustard alkylating agent used in the treatment of a number of neoplastic diseases and as an immunosuppressant for the prevention of xenograft rejection. There are many reports that the teratogenic effects of cyclophosphamide can be prevented by application of antioxidant drugs and stimulation of the maternal immune system. Also, there is some evidence that L-carnitine is antioxidant. Therefore, in this study, the prophylactic effect of L-carnitine on teratogenic effects of CP was evaluated. This study was performed on 31 pregnant rats divided into 5 groups. Control group received normal saline and test groups received L-carnitine (500 mg/kg), CP (15 mg/kg), CP (15 mg/kg) plus L-carnitine (250 mg/kg) and CP (15 mg/kg) plus L-carnitine (500 mg/kg) intraperitoneally at 9th day of gestation. Fetuses were collected at 20th day of gestation and after determination of weight and length; they were stained by Alizarin red-Alcian blue method. Cleft palate, spina bifida, and exencephaly incidence were 55.55%, 33.34% and 27.77% in fetuses of mice that received only CP. Cleft palate, spina bifida, exencephaly incidence were 21.42%, 4.76% and 9.52% in the group which received CP plus L-carnitine (250 mg/kg), respectively. However, cleft palate, spina bifida, and exencephaly incidence were 8%, 0% and 8% range in the group received CP plus L-carnitine (500 mg/kg), respectively. In addition, skeletal anomalies incidence including limbs, vertebrae, and sternum defects were decreased by L-carnitine. The mean of weight and length of animals' fetuses received L-carnitine were significantly greater than those received only CP. In conclusion, L-carnitine significantly decreased teratogenicity induced by CP; but this subject needs more detailed evaluation.

Zincke H, Woods JE. Donor pretreatment in cadaver renal transplantation. Surg Gynecol Obstet 1977;145(2):183-8.

Wexler P, editor. Encyclopedia of toxicology. 1st ed. New York: Academic Press; 1998: p. 392-3.

Hardman JG, Limbird Lee E, editors. The Pharmacological Basis of Therapiutics.10th ed. New York: McGrow-Hill; 2001: p. 1477.

Moore KL, Persaud TVN, editors. The Developing Human Clinically Oriented Embryology. 8th ed. Philadelphia: Saunders Elsevier; 2008: p. 458.

Giavini E, Menegola E. Gene-teratogen chemically induced interactions in congenital malformations. Biol Neonate 2004;85(2):73-81.

Syska E, Schmidt R, Schubert J. The time of palatal fusion in mice: a factor of strain susceptibility to teratogens. J Craniomaxillofa Surg 2004;32(1):2-4.

Chahoud I, Kuriyama SN, Paumgartten FJR. Maternal protein-andenergy restriction reduces the developmental toxicity of cyclophosphamide and hydroxyuria in rats. Toxicology 2002;179(1-2):137-49.

Kang H-G, Lee C-H, Lee K-C, et al. Effects of butylated hydroxyanisole on glutathione S-transferases activity and cyclophosphamide-induced teratogenicity in rats. J Toxicol Pub Health 2003;19(3):181-7.

Kim H-J, Lee J-E, Choi E-K, et al. Effects of butylated hydroxyanisole on glutathione S-transferases activity and teratogenicity of cyclophosphamide in mice. Korean J Lab Anim Sci 2003;19(2):120-5.

Holladay SD, Sharova LV, Punareewattana K, et al. Maternal immune stimulation in mice decreases fetal malformations caused by teratogens. Int Immunopharmacol 2002;2(2-3):325-32.

Holladay SD, Sharova LV, Smith BJ, et al. Nonspecific stimulation of the maternal immune system. I. Effects on teratogen-induced fetal malformations. Teratology 2000;62(6):413-9.

Carp HJ, Toder V, Torchinsky A, et al. Allogeneic leukocyte immunization after five or more miscarriage immunotherapy trialists group. Huma Reprod 1997;12(2):250-5.

Toder V, Strassburger D, Irlin Y, et al. Nonspecific immunopotentiators and pregnancy loss: complete Freund adjuvant reverses high fetal resorption rate in CBA x DBA/2 mouse combination. Am J Repord Immunol 1990;24(3):63-6.

Ho HN, Chen SU, Yang YS, et al. Age, environment, and lymphocyte immunization influence the spontaneous resorption rate in the CBA/J x DBA/2J mouse model. Am J Repord Immunol 1994;31(1):47-51.

Nomura T, Hata S, Kusafuka T. Suppression of developmental anomalies by maternal macrophages in mice. J Exp Med 1990;172(5):1325-30.

Ivnitsky I, Torchinsky A, Gorivodsky M, et al. TNF-alpha expression in embryos exposed to a teratogen. Am J Reprod Immunol 1998;40(6):431-40.

Savion S, Brengauz-Breitmann, M, Torchinsky A, et al. A possible role for granulocyte macrophage-colony stimulating factor in modulating teratogen-induced effects. Teratog Carcinog Mutagen 1999;19(3):171-82.

Sinclair C, Gilchrist JM, Hennessey JV, et al. Muscle carnitine in hypo- and hyperthyroidism. Muscle Nerve 2005;32(3):357-9.

Ulvi H, Aygül R, Demir R. Effect of L-carnitine on diabetic neuropathy and ventricular dispersion in patients with diabetes mellitus. Turk J Med Sci 2010;40(2):169-75.

Al-Majed AA. Carnitine deficiency provokes cisplatininduced hepatotoxicity in rats. Basic Clin Pharmacol Toxicol 2007;100(3):145-50.

Aleisa AM, Al-Majed AA, Al-Yahya AA, et al. Reversal of cisplatininduced carnitine deficiency and energy starvation by propionyl- L-carnitine in rat kidney tissues. Clin Exp Pharmacol Physiol 2007;34(12):1252-9.

Cayir K, Karadeniz A, Yildirim A, et al. Protective effect of L-carnitine against isplatin-induced liver and kidney oxidant injury in rats. Cent Eur J Med 2009; 4(2):184-91.

Pehlivan M, Coşkun A, Zengin A, et al. Does L-carnitine increase serum TNF -α and IGF-1 during liver regeneration in the rat? Turk J Med Sci 2009;39(6):875-80.

Gulcin I. Antioxidant and antiradical activities of lcarnitine. Life Sci 2006;78(8):803-11.

Onem G, Aral E, Enli Y, et al. Neuroprotective effects of L-carnitine and vitamin E alone or in combination against ischemia-reperfusion injury in rats. Surg Res 2006;131(1):124-30.

Akin M, Kurukahvecioglu O, Gulbahar O, et al. Comparison of the effects of sodium nitroprusside and Lcarnitine in experimental ischemia-reperfusion injury in rats. Transplant Proc 2007;39(10):2997-3001.

Ramezani M, Bahadoran H, Abasi S. Effect of L-carnitine on Cadmium Induced Toxicity in Rat Embryo Hippocampus. International Conference on Environmental and Computer Science. IPCBEE 2011;6(19):147-50.

Berni A, Meschini R, Filippi S, et al. L-carnitine enhence resistance to oxidative stress by reducing DNA damage in ataxia telangiectasia cells. Mutat Res 2008;650(2):165-74.

Slott VL, Hales BF. Sodium 2-mercaptoethane sulfonate protection against cyclophosphamide-induced teratogenicity in rats. Toxicol Appl Pharmacol 1986;82(1):80-6.

Kimmel CA, Trammekl C. A rapid procedure for routine double staining of cartilage and bone in fetal and adult animals. Stain Tech 1981;56(5):271-3.

Ivnitsky I, Torchinsky A, Savion S, et al. TGFbeta2 in embryos with inborn anomalies: effect of maternal immunopotentiation. Am J Reprod Immunol 2001;45(1):41-51.

Winn LM, Wells PG. Maternal administration of superoxide dismutase and catalase in phenytoin teratogenicity. Free Radic Biol Medm 1999;26(3-4):266-74.

Sharova LV, Gogal RM, Sharov AA, et al. Stimulation in urethane- exposed pregnant mice increase expression level of spleen leukocyte genes for TGF beta 3 GM- CSF and other cytokines that may play a role reduced chemical - induced birth defects. Int Immunopharmacol 2002;2(10):1477-89.

Ujhazy E, Balonova T, Durisova M, et al. Teratogenicity of cyclophosphamide in New Zealand white rabbits. Neoplasma 1993;40(1):45-9.

Shah RM, Izadnegahdar MF, Henh BM, et al. In vivo/in vitro studies on the effects of cyclophosphamide on growth and differentiation of hamster palate. Anticancer Drugs 1996;7(2):204-212.

Gibson JE, Becker BA. The teratogenicity of cyclophosphamide in mice. Cancer Researsh1968;28(3):475-80.

Wells PG, Kim PM, Laposa RR, et al. Oxidative damage in chemical teratogenesis. Mutat Res 1997;396(1-2):65-78.

Cetinkaya A, Bulbuloglu E, Kantarceken B, et al. Effectsof L-carnitine on oxidant/antioxidant status in acetic acidinduced colitis. Dig Dis Sci 2006;51(3):488-94.

Yildirim S, Yildirim A, Dane S, et al. Dose-Dependent Protective Effect of L-Carnitine on Oxidative Stress in the Livers of Hyperthyroid Rats. EAJM 2013;45(1):1-6.

Derin N, Izgut-Uysal VN, Agac A, et al. L-carnitine protects gastric mucosa by decreasing ischemiareperfusion induced lipid peroxidation. J Physiol Pharmacol 2004;55(3):595-606.

Cha YS, Soh JR, Kim CK, et al. Effect of carnitine and, antioxidant supplementation on carnitine and lipid profiles in trained and non-trained humans. FASEB J 2003;17(Suppl 1):A733-44.

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IssueVol 53, No 11 (2015) QRcode
SectionOriginal Articles
Keywords
Cyclophosphamide Cleft palate Exencephaly L-carnitine Teratogenicity Rat

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How to Cite
1.
Khaksary Mahabady M, Najafzadeh Varzi H, Zareyan Jahromi S. L-Carnitine Protect against Cyclophosphamide Induced Skeletal and Neural Tube Malformations in Rat Fetuses. Acta Med Iran. 2015;53(11):703-710.