Main Article Content
Objective: Even if epileptic women can give birth to healthy babies, the rates of premature birth, low birth weight, fetal and neonatal death risk, congenital malformations and growth retardation in pregnant women who use the antiepileptic drugs (AEDs) are high compared to the population. The present study aimed to examine the effects of AED Lacosamide (LCM) during pregnancy on the fetus in terms of neuronal and embryonic development in 48-hour chick embryo model.
Material and Methods: 40SPF fertilized eggs divided into 4 equal numbers. At the 28th hour, LCM was applied in the sub-blastoderm, and the experiment was terminated at the 48th hour. Embryos were evaluated morphologically by neural tube position, somite number, and cranio-caudal length. Histopathologically, hematoxylin-eosin, Caspase-3 immunohistochemistry, and TUNEL staining were performed and and assessed for cell death.
Results: LCM adversely affected neural tube position in groups 3 and 4 compared to control. In addition, it regressed embryonic development by decreasing somite number and craniocaudal length in groups 3 and 4. When evaluated in terms of apoptotic cell death, LCM increased caspase-3 immunoreactivity and the number of TUNEL-positive cells in groups 3 and 4, respectively (p=0.002), (p≤0.001).
Conclusion: LCM was caused to regression of embryonic development and impaired neural tube position in early chick embryo model, dose-dependent manner. It increased cell death and showed teratogenic effects in the early embryo model. The usage of LCM for pregnant women should be considered carefully. It is obvious that more preclinic studies are needed to demonstrate LCM effects comprehensively.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Arfman IJ, Wammes-van der Heijden EA, ter Horst PGJ, Lambrechts DA, Wegner I, Touw DJ. Therapeutic Drug Monitoring of Antiepileptic Drugs in Women with Epilepsy Before, During, and After Pregnancy. Clinical Pharmacokinetics [Internet]. 2020 Apr 8;59(4):427–45. Available from: http://link.springer.com/10.1007/s40262-019-00845-2 DOI: https://doi.org/10.1007/s40262-019-00845-2
Meador KJ, Baker GA, Browning N, Cohen MJ, Bromley RL, Clayton-Smith J, et al. Effects of fetal antiepileptic drug exposure: Outcomes at age 4.5 years. Neurology [Internet]. 2012 Apr 17;78(16):1207–14. Available from: https://www.neurology.org/lookup/doi/10.1212/WNL.0b013e318250d824 DOI: https://doi.org/10.1212/WNL.0b013e318250d824
Harden CL, Pennell PB, Koppel BS, Hovinga CA, Gidal B, Meador KJ, et al. Practice Parameter update: Management issues for women with epilepsy--Focus on pregnancy (an evidence-based review): Vitamin K, folic acid, blood levels, and breastfeeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Asses. Neurology [Internet]. 2009 Jul 14;73(2):142–9. Available from: https://www.neurology.org/lookup/doi/10.1212/WNL.0b013e3181a6b325 DOI: https://doi.org/10.1212/WNL.0b013e3181a6b325
Voinescu PE, Park S, Chen LQ, Stowe ZN, Newport DJ, Ritchie JC, et al. Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy. Neurology [Internet]. 2018 Sep 25;91(13):e1228–36. Available from: https://www.neurology.org/lookup/doi/10.1212/WNL.0000000000006240 DOI: https://doi.org/10.1212/WNL.0000000000006240
Catherine J. Chu-Shore EAT. New Drugs for Pediatric Epilepsy. Seminars in Pediatric Neurology [Internet]. 2010;17(4):214–23. Available from: https://doi.org/10.1016/j.spen.2010.10.003 DOI: https://doi.org/10.1016/j.spen.2010.10.003
Gürses AA. Lacosamide add-on treatment in refractory focal epilepsy: experience of a single tertiary center. Journal of the Turkish Epilepsi Society [Internet]. 2020; Available from: http://archepilepsy.org/en/lacosamide-add-on-treatment-in-refractory-focal-epilepsy-the-experience-of-a-single-tertiary-center-1375 DOI: https://doi.org/10.14744/epilepsi.2020.04274
Beydoun A, D’Souza J, Hebert D, Doty P. Lacosamide: pharmacology, mechanisms of action and pooled efficacy and safety data in partial-onset seizures. Expert Review of Neurotherapeutics [Internet]. 2009 Jan 9;9(1):33–42. Available from: http://www.tandfonline.com/doi/full/10.1586/14737188.8.131.52 DOI: https://doi.org/10.1586/14737184.108.40.206
Majtnerová P, Roušar T. An overview of apoptosis assays detecting DNA fragmentation. Molecular Biology Reports [Internet]. 2018 Oct 18;45(5):1469–78. Available from: http://link.springer.com/10.1007/s11033-018-4258-9 DOI: https://doi.org/10.1007/s11033-018-4258-9
Hamburger V, Hamilton HL. A series of normal stages in the development of the chick embryo. Developmental Dynamics [Internet]. 1992 Dec;195(4):231–72. Available from: https://onlinelibrary.wiley.com/doi/10.1002/aja.1001950404 DOI: https://doi.org/10.1002/aja.1001950404
Ertekin T, Bilir A, Aslan E, Koca B, Turamanlar O, Ertekin A, et al. The effect of diclofenac sodium on neural tube development in the early stage of chick embryos. Folia Morphologica [Internet]. 2019 May 28;78(2):307–13. Available from: https://journals.viamedica.pl/folia_morphologica/article/view/58694 DOI: https://doi.org/10.5603/FM.a2018.0080
Gündüz K, Demireli P, Vatansever S, Inanir I. Examination of bcl-2 and p53 expressions and apoptotic index by TUNEL method in psoriasis. Journal of Cutaneous Pathology [Internet]. 2006 Dec;33(12):788–92. Available from: https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0560.2006.00564.x DOI: https://doi.org/10.1111/j.1600-0560.2006.00564.x
Tomson T, Landmark CJ, Battino D. Antiepileptic drug treatment in pregnancy: Changes in drug disposition and their clinical implications. Epilepsia [Internet]. 2013 Mar;54(3):405–14. Available from: https://onlinelibrary.wiley.com/doi/10.1111/epi.12109 DOI: https://doi.org/10.1111/epi.12109
Patel SI, Pennell PB. Management of epilepsy during pregnancy: an update. Therapeutic Advances in Neurological Disorders [Internet]. 2016 Mar 27;9(2):118–29. Available from: http://journals.sagepub.com/doi/10.1177/1756285615623934 DOI: https://doi.org/10.1177/1756285615623934
Mete M, Gurcu B, Collu F, Unsal UU, Duransoy YK, Tuglu MI, et al. Effects of lacosamide “a novel antiepileptic drug” in the early stages of chicken embryo development. Child’s Nervous System [Internet]. 2016 Sep 29;32(9):1715–9. Available from: http://link.springer.com/10.1007/s00381-016-3181-4 DOI: https://doi.org/10.1007/s00381-016-3181-4
Boeckman HJ, Trego KS, Turchi JJ. Cisplatin sensitizes cancer cells to ionizing radiation via inhibition of nonhomologous end joining. Molecular Cancer Research. 2005;3(5):277–85. DOI: https://doi.org/10.1158/1541-7786.MCR-04-0032
Ertekin A, Atay E, Bozkurt E, Aslan E. Effect of buscopan, a compound that alleviates cramps, on the developing nervous system of the chick embryo. Birth Defects Research [Internet]. 2021 Sep 29;113(15):1140–51. Available from: https://onlinelibrary.wiley.com/doi/10.1002/bdr2.1929 DOI: https://doi.org/10.1002/bdr2.1929
Lee SH, Kang JW, Lin T, Lee JE, Jin D Il. Teratogenic Potential of Antiepileptic Drugs in the Zebrafish Model. BioMed Research International [Internet]. 2013;2013:1–6. Available from: http://www.hindawi.com/journals/bmri/2013/726478/ DOI: https://doi.org/10.1155/2013/726478
Ylikotila P, Ketola RA, Timonen S, Malm H, Ruuskanen JO. Early pregnancy cerebral venous thrombosis and status epilepticus treated with levetiracetam and lacosamide throughout pregnancy. Reproductive Toxicology [Internet]. 2015 Nov;57:204–6. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0890623815300022 DOI: https://doi.org/10.1016/j.reprotox.2015.07.068
GÜRCÜ B, Oludağ Mete T, Çöllü F, Aydemir I, Tuğlu Mİ. The Effects of Lacosamide in the Early Stages of Neural Tube Development in Chick Embryos. Celal Bayar Üniversitesi Fen Bilimleri Dergisi [Internet]. 2018 Mar 30;14(1):51–5. Available from: https://dergipark.org.tr/en/doi/10.18466/cbayarfbe.342317 DOI: https://doi.org/10.18466/cbayarfbe.342317
Wilson SM, Xiong W, Wang Y, Ping X, Head JD, Brittain JM, et al. Prevention of posttraumatic axon sprouting by blocking collapsin response mediator protein 2-mediated neurite outgrowth and tubulin polymerization. Neuroscience [Internet]. 2012 May;210:451–66. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0306452212001819 DOI: https://doi.org/10.1016/j.neuroscience.2012.02.038
Khanna R, Wilson SM, Brittain JM, Weimer J, Sultana R, Butterfield A, et al. Opening Pandora’s jar: a primer on the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders. Future Neurology [Internet]. 2012 Nov;7(6):749–71. Available from: https://www.futuremedicine.com/doi/10.2217/fnl.12.68 DOI: https://doi.org/10.2217/fnl.12.68
Mete M, Alpay S, Aydemir I, Unsal UU, Collu F, Özel HF, et al. Therapeutic effects of Lacosamide in a rat model of traumatic brain injury: A histological, biochemical and electroencephalography monitoring study. Injury [Internet]. 2021 Apr;52(4):713–23. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0020138321001583 DOI: https://doi.org/10.1016/j.injury.2021.02.055