The effect of sodium valproate and citronellol on the concentration of estriol, placental gonadotropin and alpha phytoprotein in maternal and fetal serum and amniotic fluid in rats

Document Type : Original Article

Authors

1 Associate Professor, Department of Comparative Anatomy, Research Center for Non-Communicable Disease, Faculty of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran.

2 General Physician, Student Research Committee, Faculty of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran.

3 Assistant Professor, Department of Anatomical Sciences, Faculty of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran.

4 Assistant Professor, Department of Comparative Histology, Research Center for Non-Communicable Disease, Faculty of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran.

Abstract

Introduction: Taking many antiepileptic drugs such as sodium valproate during pregnancy has harmful and teratogenic effects. Therefore, the present study was performed with aim to compare the effect of sodium valproate and the less dangerous drug citronellol on the level of three variables for the diagnosis of nervous system abnormalities in mother and fetus.
Methods: In this experimental study, which was performed in 2019, eighteen adult female Wistar rats (200-220 g, 10 to 12 weeks) were divided into 3 groups of 6 including control, experimental 1 (receiving sodium valproate, 400 mg/kg) and experimental 2 (receiving citronellol, 400 mg/kg). Female rats were mated with male rats. After confirming pregnancy (vaginal plaque and vaginal smear), they intraperitoneally received sodium valproate and citronellol intraperitoneally on days 7, 8, 9 and 10 of pregnancy. On the 18th day of pregnancy, maternal serum, fetal serum, and amniotic fluid were sampled and free estriol, chorionic gonadotropin, and alpha phytoprotein were measured by ELISA method. Data analysis was done using SPSS statistical software (version 21) and ANOVA and Duncan's test. A p value of less than 0.05 was considered significant.
Results: The mean concentration of estriol, chorionic gonadotropin and alpha phytoprotein in maternal serum, fetal serum and amniotic fluid in citronellol group did not show any significant difference compared to the control group (p>0.05). However, in sodium valproate group, a significant decrease in the level of estriol and placental gonadotropin and a significant increase in alpha phytoprotein in maternal serum, fetal serum, and amniotic fluid were observed compared to the control and experimental groups 2 (p<0.05).
Conclusion: Citronellol as an antiepileptic drug with less side effects and greater safety can be used during pregnancy.

Keywords


  1. Avagliano L, Massa V, George TM, Qureshy S, Bulfamante GP, Finnell RH. Overview on neural tube defects: From development to physical characteristics. Birth defects research 2019; 111(19):1455-67.
  2. Olafsson E, Hallgrimsson JT, Hauser WA, Ludvigsson P, Gudmundsson G. Pregnancies of women with epilepsy: a population‐based study in Iceland. Epilepsia 1998; 39(8):887-92.
  3. Aneja S, Sharma S. Newer anti-epileptic drugs. Indian Pediatrics 2013; 50:1033-40.
  4. Heikkinen J, Mäentausta O, Ylöstalo P, Jänne O. Serum bile acid levels in intrahepatic cholestasis of pregnancy during treatment with phenobarbital or cholestyramine. European Journal of Obstetrics & Gynecology and Reproductive Biology 1982; 14(3):153-62.
  5. Idänpään-Heikkilä JE, Jouppila PI, Puolakka JO, Vorne MS. Placental transfer and fetal metabolism of diazepam in early human pregnancy. American Journal of Obstetrics and Gynecology 1971; 109(7):1011-6.
  6. Brewer JM, Waltman PA. Epilepsy and pregnancy: maternal and fetal effects of phenytoin. Critical care nurse 2003; 23(2):93-8.
  7. Mawer G, Clayton-Smith J, Coyle H, Kini U. Outcome of pregnancy in women attending an outpatient epilepsy clinic: adverse features associated with higher doses of sodium valproate. Seizure 2002; 11(8):512-8.
  8. Viswanatha GL, Venkataranganna MV, Prasad NB, Ashok G. Evaluation of anti-epileptic activity of leaf extracts of Punica granatum on experimental models of epilepsy in mice. Journal of Intercultural Ethnopharmacology 2016; 5(4):415.
  9. Mehrzadi S, Sadr S, Hosseinzadeh A, Gholamine B, Shahbazi A, FallahHuseini H, et al. Anticonvulsant activity of the ethanolic extract of Punica granatum L. seed. Neurological research 2015; 37(6):470-5.
  10. Malami S, Kyari H, Danjuma NM, Ya’u J, Hussaini IM. Anticonvulsant properties of methanol leaf extract of Laggera aurita Linn. F.(Asteraceae) in laboratory animals. Journal of Ethnopharmacology 2016; 191:301-6.
  11. Lawless J. The illustrated encyclopedia of essential oils: the complete illustrated guide to the use of oils in aromatherapy and herbalism. Shaftesbury, Dorset, UK: Element. 1995.
  12. Revay EE, Kline DL, Xue RD, Qualls WA, Bernier UR, Kravchenko VD, et al. Reduction of mosquito biting-pressure: spatial repellents or mosquito traps? A field comparison of seven commercially available products in Israel. Acta Tropica 2013; 127(1):63-8.
  13. de Sousa DP, Gonçalves JC, Quintans-Júnior L, Cruz JS, Araújo DA, de Almeida RN. Study of anticonvulsant effect of citronellol, a monoterpene alcohol, in rodents. Neuroscience letters 2006; 401(3):231-5.
  14. Melo MS, Sena LC, Barreto FJ, Bonjardim LR, Almeida JR, Lima JT, et al. Antinociceptive effect of citronellal in mice. Pharmaceutical Biology 2010; 48(4):411-6.
  15. Couto AC, Ferreira JD, Rosa AC, Pombo-de-Oliveira MS, Koifman S, Brazilian Collaborative Study Group of Infant Acute Leukemia. Pregnancy, maternal exposure to hair dyes and hair straightening cosmetics, and early age leukemia. Chemico-biological interactions 2013; 205(1):46-52.
  16. Williams W. Pre-Conception Care and Aromatherapy in Pregnancy. J. Clin. Aromather 2005; 2:15-9.
  17. Kunder SK, Bairy LK, Arivazhahan A. Effect of sodium valproate and docosahexaenoic acid on pain in rats. Journal of Clinical and Diagnostic Research: JCDR 2017; 11(3):FF05.
  18. Deora H, Srinivas D, Shukla D, Devi BI, Mishra A, Beniwal M, et al. Multiple-site neural tube defects: embryogenesis with complete review of existing literature. Neurosurgical Focus 2019; 47(4):E18.
  19. Menegola E, Broccia ML, Nau H, Prati M, Ricolfi R, Giavini E. Teratogenic effects of sodium valproate in mice and rats at midgestation and at term. Teratogenesis, carcinogenesis, and mutagenesis 1996; 16(2):97-108.
  20. Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. Jama 2013; 309(16):1696-703.
  21. Voinescu PE, Pennell PB. Delivery of a personalized treatment approach to women with epilepsy. InSeminars in neurology 2017; 37(06):611-623.
  22. Błaszczyk B, Miziak B, Pluta R, Czuczwar SJ. Epilepsy in pregnancy—management principles and focus on valproate. International journal of molecular sciences 2022; 23(3):1369.
  23. Pennell PB. Use of antiepileptic drugs during pregnancy: evolving concepts. Neurotherapeutics 2016; 13:811-20.
  24. Tung EW, Winn LM. Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: a role for oxidative stress in valproic acid-induced neural tube defects. Molecular pharmacology 2011; 80(6):979-87.
  25. Etemad L, Moshiri M, Moallem SA. Epilepsy drugs and effects on fetal development: Potential mechanisms. Journal of research in medical sciences: the official journal of Isfahan University of Medical Sciences 2012; 17(9):876.
  26. Defoort EN, Kim PM, Winn LM. Valproic acid increases conservative homologous recombination frequency and reactive oxygen species formation: a potential mechanism for valproic acid-induced neural tube defects. Molecular pharmacology 2006; 69(4):1304-10.
  27. Kawai Y, Arinze IJ. Valproic acid–induced gene expression through production of reactive oxygen species. Cancer research 2006; 66(13):6563-9.
  28. Fiorentino DG, Hughes F. Fetal Screening for Chromosomal Abnormalities. NeoReviews 2021; 22(12):e805-18.
  29. Taubøll E, Gregoraszczuk EL, Wojtowicz AK, Milewicz T. Effects of levetiracetam and valproate on reproductive endocrine function studied in human ovarian follicular cells. Epilepsia 2009; 50(8):1868-74.
  30. Ryniec J, Esfandiari N. Early Serum hCG in IVF: Are We Trending in the Right Direction?. Reproductive Sciences 2021; 28:1827-38.
  31. Dabiri A, Rafiee S, Motamed N, Jalilvand A, Keshavarz Afshar M, Bayat F. The sensitivity, specificity, and accuracy of Creatinine test and human chorionic gonadotropin (HCG) test of cervical mucus discharge to diagnose preterm premature rupture of membranes (PPROM). Iran J Obstet Gynecol Infertil 2021; 24(5):31-9.
  32. Yang M, Lei ZM, Rao CV. The central role of human chorionic gonadotropin in the formation of human placental syncytium. Endocrinology 2003; 144(3):1108-20.
  33. Cole LA. New discoveries on the biology and detection of human chorionic gonadotropin. Reproductive Biology and Endocrinology 2009; 7(1):1-37.
  34. Rubinchik‐Stern M, Shmuel M, Bar J, Kovo M, Eyal S. Adverse placental effects of valproic acid: studies in perfused human placentas. Epilepsia 2018; 59(5):993-1003.
  35. Kwiecińska P, Wiśniewska J, Gregoraszczuk E. Effects of valproic acid (VPA) and levetiracetam (LEV) on proliferation, apoptosis and hormone secretion of the human choriocarcinoma BeWo cell line. Pharmacological Reports 2011; 63(5):1195-202.
  36. Aboughalia H, Bastawrous S, Revzin MV, Delaney SS, Katz DS, Moshiri M. Imaging findings in association with altered maternal alpha-fetoprotein levels during pregnancy. Abdominal Radiology 2020; 45:3239-57.
  37. Cuckle H, Wald N, Lindenbaum R. Maternal serum alpha-fetoprotein measurement: a screening test for Down syndrome. The Lancet 1984; 323(8383):926-9.
  38. Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, et al. First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial). American journal of obstetrics and gynecology 2004; 191(4):1446-1451.
  39. Lakshmi S, Sunanda K. Effect of anti-epileptic drugs in pregnancy and teratogenesis. Indian Journal of Clinical Biochemistry 2008; 23:267-71.
  40. Besimoglu B, Öcal FD, Sinaci S, Atalay A, Tanaçan A, Şahin D. Effect of antiepileptic drugs on serum biochemical marker levels of first and second trimester screening tests. Journal of Obstetrics and Gynaecology Research 2022; 48(7):1607-12.
  41. Jayaraj RL, Azimullah S, Parekh KA, Ojha SK, Beiram R. Effect of citronellol on oxidative stress, neuroinflammation and autophagy pathways in an in vivo model of Parkinson's disease. Heliyon 2022; 8(11).
  42. Brito RG, Guimarães AG, Quintans JS, Santos MR, De Sousa DP, Badaue-Passos D, et a. Citronellol, a monoterpene alcohol, reduces nociceptive and inflammatory activities in rodents. Journal of natural medicines 2012; 66:637-44.