Effects of Topiramate Antiepileptic Drug on Development of Neural Tube and Skeletal of Fetus in NMRI Mouse

Authors
mahboobeh ebrahimi verkiani
abdolhossein shiravi
vida hojati
Islamic Azad University, Damghan Branch
Abstract
Introduction and Aim: Topiramate is a new generation of antiepileptic drugs, that there is incomplete information about the role of this drug in creating teratogenic effects on the fetus. This study was designed in order to determine teratogenic effects of topiramate on the development of neural tube and skeletal during the period of organogenesis of mouse fetus.

Materials and Methods: In this experimental study forty pregnant female mouse (NMRI type) were divided in to three experimental groups (Ι، Π ‚ III) and one control group. Three experimental groups Ι, Π and Ш received 50, 100 and 200 Milligrams per kilogram of body weight in day of topiramate with 0.2 milliliter injection volume intraperitoneally from the day 6 (GD6) to day 14 (GD14) of pregnancy and the control group received the same volume of normal saline instead. The mices were sacrifieed on the eighteen day of pregnancy and fetuses were studied in view point of skeletal malformations. Then fetuses were stained with Alizarin Rea S/ Alcian blue 8GX and fetuses were studied in view point of neural tube defects. Then data were analyzd by using SPSS statistical software and LSD test.

Results: In all three experimental groups Ι, Π and Ш were observed abnormalities for neural tube defects and skeletal malformations that showed a significant increase from the statistical point in comparison with the control group (P<0.05).

Conclusion: This study showed that the utilization of topiramate drug during organogenesis in mouse fetus can induce neural tube defects and skeletal malformations.
Keywords
topiramate
mouse fetuses
neural tube defects
skeletal malformations
Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, et al. Epileptic seizures and epilepsy: definitions proposed by the International League against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005;46(4):470-2.
Greco A, Rizzo MI, De Virgilio A, Conte M, Gallo A, Attanasio G, et al. Autoimmune epilepsy. Autoimmun Rev 2016;15(3):221-5.
Fadel RA, Sequeira RP, Abu-Hijleh MF, Obeidat M, Salem AH. Effect of prenatal administration of therapeutic doses of topiramate on ossification of ribs and vertebrae in rat fetuses. Rom J Morphol Embryol 2012;53(2):321-7.
Lyseng-Williamson KA, Yang LP. Topiramate: a review of its use in the treatment of epilepsy. Drugs. 2007;67(15):2231-56.
Katzung BG, Masters SB, Trevor AJ. Basic and clinical pharmacology. 12th ed‚ USA: Mc Grow Hill Medical; 2011.
Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 2000;41(suppl1):S3-9.
Pinto EC, Dolzan MD, Cabral LM, Armstrong DW, Sousa VP. Topiramate: A review of analytical approaches for the drug substance, its impurities and pharmaceutical formulations. J Chromatogr Sci 2016;54(2):280-90.
Ornoy A, Zvi N, Arnon J, Wajnberg R, Shechtman S, Diav-Citrin O. The outcome of pregnancy following topiramate treatment: a study on 52 pregnancies. Reprod Toxicol 2008;25(3):388-9.
Glier C, Dzietko M, Bittigau P, Jarosz B, Korobowicz E, Ikonomidou C. Therapeutic doses of topiramate are not toxic to the developing rat brain. Exp Neurol 2004;187(2):403-9.
Ramadan NM, Buchanan TM. New and future migraine therapy. Pharmacol Ther 2006;112(1):199-212.
Eadie MJ, Vajda FJ. Antiepileptic drugs and pregnancy. A guide for prescribers. Adis Switzerland: Springer; 2015.
Harden CL. Topiramate, Zonisamide and Small for Gestational Age: Maternal Factors, Timing of Exposure and Baby Fat. Epilepsy Curr 2014;14(4):199-200.
Zalewska-Kaszubska J, Bajer B, Gorska D, Andrzejczak D, Dyr W, Bieńkowski P. Effect of repeated treatment with topiramate on voluntary alcohol intake and beta-endorphin plasma level in Warsaw alcohol high-preferring rats. Psychopharmacology. 2013;225(2):275-81.
Walker MC, Sander JW. Topiramate: a new antiepileptic drug for refractory epilepsy. Seizure 1996;5(3):199-203.
Arnone D. Review of the use of topiramate for treatment of psychiatric disorders. Ann Gen Psychiatry 2005;4(1):5.
Öhman I, Vitols S, Luef G, Söderfeldt B, Tomson T. Topiramate kinetics during delivery, lactation, and in the neonate: preliminary observations. Epilepsia 2002;43(10):1157-60.
Wilson RD; SOGC GENETICS COMMITTEE; SOGC INFECTIOUS DISEASE COMMITTEE. Principles of Human Teratology: Drug Chemical and Infectious Exposure. J Obstet Gynaecol Can 2007;29(11):911-7.
Wilmer E, Chai S, Kroumpouzos G. Drug safety: Pregnancy rating classifications and controversies. Clinics in Dermatology 2016;34(3):401-9.
Hernández-Díaz S, Mittendorf R, Smith CR, Hauser WA, Yerby M, Holmes LB, et al. Association between topiramate and zonisamide use during pregnancy and low birth weight. Obstet Gynecol 2014;123(1):21-8
Mackenzie KM‚ Hour RM. Developmental toxicology. In: Derelanko MJ‚ editor. Handbook of Toxicology. 2002;497-521.
Kaufman MH, Bard J. The anatomical basis of mouse development. Academic Press; 1999.
Wallace H. Principles and Method of Toxicology. Philadelphia: taylor & francis.2001
Kimmel CA, Trammell C. A rapid procedure for routine double staining of cartilage and bone in fetal and adult animals. Stain Technol 1981;56(5):271-3.
Inouye M. Differential staining of cartilage and bone in fetal mouse skeleton by alcian blue and alizarin red. Congential Anomalies 1976;16:171-1.
Lindhout D. Pharmacogenetics and drug interactions. Neurology 1992;42(5):43-7.
Biale Y, Lewenthal H. Effect of folic acid supplementation on congenital malformations due to anticonvulsive drugs. Eur J Obstet Gynecol Reprod Biol 1984;18(4):211-6.
Dansky LV, Rosenblatt DS, Andermann E. Mechanisms of teratogenesis: Folic acid and antiepileptic therapy. Neurology 1992;42(4):32-42.
Nau H, Tzimas G, Mondry M, Plum C, Spohr HL. Antiepileptic drugs alter endogenous retinoid concentrations: a possible mechanism of teratogenesis of anticonvulsant therapy. Life Sci 1995;57(1):53-60.
Yerby MS. Teratogenicity and antiepileptic drugs: potential mechanisms. Int Rev Neurobiol 2008;83:181-204.
Briner W. The effect of GABA receptor ligands in experimental spina bifida occulta. BMC Pharmacol 2001;1(1):2.
Artama M, Ritvanen A, Gissler M, Isojärvi J, Auvinen A. Congenital structural anomalies in offspring of women with epilepsy—a population-based cohort study in Finland. Int J Epidemiol 2006;35(2):280-7.
Simko J, Fekete S, Gradosova I, Malakova J, Zivna H, Valis M, et al. The effect of topiramate and lamotrigine on rat bone mass, structure and metabolism. J Neurol Sci 2014;340(1-2):80-5.
Linnebank M, Moskau S, Semmler A, Widman G, Stoffel‐Wagner B, Weller M, et al. Antiepileptic drugs interact with folate and vitamin B12 serum levels. Ann Neurol 2011;69(2):352-9.
Belcastro V, Striano P, Gorgone G, Costa C, Ciampa C, Caccamo D, et al. Hyperhomocysteinemia in epileptic patients on new antiepileptic drugs. Epilepsia 2010;51(2):274-9.
Vacek TP, Kalani A, Voor MJ, Tyagi SC, Tyagi N. The role of homocysteine in bone remodeling. Clin Chem Lab Med 2013;51(3):579-90.
Voudris K, Moustaki M, Zeis PM, Dimou S, Vagiakou E, Tsagris B, et al. Alkaline phosphatase and its isoenzyme activity for the evaluation of bone metabolism in children receiving anticonvulsant monotherapy. Seizure 2002;11(6):377-80.