Asia Pacific Journal of Medical Toxicology

Evaluating the Supplementary Effects of Vitamin C on Carbamazepine and Pentylenetetrazol-Induced Seizures and Preimplantation Loss in Pregnant Wistar Rats: Implications for Human Pregnancy

Document Type : Original Article

Authors

Ganiu Jimoh Akorede 1
Suleiman Folorunsho Ambali 1
Olatunbosun Agunbiade 1
Aisha Omobolanle Olatunji 1
Abdulfatai Aremu 1
Muftau Shittu 2
Afisu Basiru 3
Saliu Akanni Ameen 4
Yusuf Kolawole Suleiman 3
Lukman Oladimeji Raji 5

1 Department of Veterinary Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Ilorin, Nigeria

2 Department of Veterinary Pharmacology and Toxicology, Faculty of Veterinary Medicine, Ahmadu Bello University, Zaria, Nigeria

3 Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ilorin, Nigeria

4 Department of Veterinary Medicine, Faculty of Veterinary Medicine, University of Ilorin, Nigeria

5 Department of Theriogenology and Production, Faculty of Veterinary Medicine, University of Ilorin, Nigeria

https://doi.org/10.22038/apjmt.2024.79911.1456
Abstract
Background: Epilepsy is a complex neurological disorder affecting millions worldwide and is the most common major neurological complication during pregnancy. Carbamazepine, a widely used antiepileptic drug, has been associated with oxidative damage. Vitamin C, a powerful antioxidant has shown potential in controlling seizures and improving fertility. This study aimed to evaluate the protective effects of vitamin C against carbamazepine and pentylenegtetrazole-induced seizures on pre-implantation loss in pregnant Wistar rats.
Methods: We randomly assigned Thirty pregnant rats into six groups of five animals each. Group received distilled water (2 ml/kg), Group 2 was administered pentylenetetrazol (PTZ) at a dose of 60 mg/kg, Group 3 received vitamin C (100mg/kg) along with PTZ (60 mg/kg), Group 4 was given carbamazepine (20 mg/kg),  Group 5 received both carbamazepine (20 mg/kg) and PZT (60 mg/kg), and Group 6 was pretreated with vitamin C, carbamazepine and PZT at doses of 100 mg/kg, 20 mg/kg and 60mg/kg, respectively. Treatments were administered via gavage once daily for 11 consecutive days, while PTZ was administered intraperitoneally ones. Oxidative stress parameters were assessed in the pituitary, ovary and uterine tissues alongside hematological parameters and sex hormones concentrations. We also evaluated preimplantation loss.  
Results: The results demonstrated that vitamin C effectively mitigated the adverse effects of oxidative stress, hormonal disruptions, preimplantation loss, and hematological changes induced by seizure and carbamazepine.
Conclusion: The study concludes that antioxidant properties of vitamin C at gestation contribute to its protective effects against seizures and carbamazepine-induced alterations in reproductive parameters. The findings may have implications for human exposure to antiepileptics during pregnancy.

Keywords

Seizure
Oxidative stress
Pentylenetetrazol
Carbamazepine
Preimplantation loss
Vitamin C
Subjects
  1. Lu H, Chang W, Huang ACW, Shyu BC. Detection of pentylenetetrazol-induced seizure activity in the 19-21 Hz beta range using a magnetic coil induction method. Front Biosci (Landmark Ed). 2022;27(3):1-12.
  2. Beghi E. The epidemiology of epilepsy. Neuroepidemiology. 2020;54(2):185-91.
  3. Farghaly WMA, Hamdy NE, Tarek AR, Eman MM, Nabil AM, Ghaydaa AS, et al. Epidemiology of uncontrolled epilepsy in the Al-Kharga District, New Valley, Egypt. Seizure. 2013;22(9):611-6.
  4. Chen Y, Chiou H, Lin H, Lin H. Effect of seizures during gestation on pregnancy outcomes in women with epilepsy. Arch Neurol. 2009;66(8):979-84.
  5. Wang Y, Wei P, Yan F, Luo Y, Zhao G. Animal models of epilepsy: a phenotype-oriented review. Aging Dis. 2022;13(1):215-31.
  6. Shimada T, Yamagata K. Pentylenetetrazole-induced kindling mouse model. J Vis Exp. 2018;(136):1-10.
  7. Szabo CA. Patient page. Risk of fetal death and malformation related to seizure medications. Neurology. 2006;67:6-7.
  8. Bhatti SFM, De-Risio L, Muñana K, Penderis J, Stein VM, Tipold A. International veterinary epilepsy task force consensus proposal: medical treatment of canine epilepsy in Europe. BMC Vet Res. 2015;11(1):176.
  9. Maan JS, Duong TH, Saadabadi A. Carbamazepine. StatPearls. 2023 [cited 2023 Nov 25]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482455/
  10. Mittag N, Meister S, Berg AM, Walther UI. A case report of a carbamazepine overdose with focus on pharmacokinetic aspects. Pharmacopsychiatry. 2016;49(2):76-8.
  11. Akorede GJ, Ambali SF, Olatunji AO, Aremu A, Ahmed AO, Basiru A, et al. Vitamin C protects against blood and thyroid toxicities induced by the chronic use of carbamazepine in rats. Iran J Toxicol. 2023;17(2):147-56.
  12. Al-Bishri WM, Abdel-Reheim ES, Zaki AR. Purslane protects against the reproductive toxicity of carbamazepine treatment in pilocarpine-induced epilepsy model. Asian Pac J Trop Biomed. 2017;7(4):339-46.
  13. Yan S, Wang M, Zha L, Li W, Luo Q, Sun J, et al. Environmentally relevant concentrations of carbamazepine caused endocrine-disrupting effects on non-target organisms, Chinese rare minnows (Gobiocypris rarus). Environ Sci Technol. 2018;52(2):886-94.
  14. Akorede GJ, Ambali SF, Hudu MG, Olatunji AO, Shittu M, Aremu A, et al. Protective effect of vitamin C on chronic carbamazepine-induced reproductive toxicity in male Wistar rats. Toxicol Rep. 2020;7:269-76.
  15. Artama M, Auvinen A, Raudaskoski T, Isojärvi I, Isojärvi J. Antiepileptic drug use of women with epilepsy and congenital malformations in offspring. Neurology. 2005;64(11):1874-8.
  16. Bech BH, Kjaersgaard MI, Pedersen HS, Howards PP, Sørensen MJ, Olsen J, et al. Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth: population-based cohort study. BMJ. 2014;349:5159.
  17. Ibitoroko GM, Adebayo AO, Confidence W. Effect of vitamins C and E on hematological parameters in Albino rats treated with gasoline. Glob Vet. 2011;7(4):347-52.
  18. Wasan GA. Vitamin C supplementation in relation to subfertility and ovarian function. Karbala J Med. 2014;7(1):1-8.
  19. Rajesh KR, Surenda R, Thangam J. Effect of valproic acid and carbamazepine on learning and memory in rats. Indian J Pharmacol. 1991;23(3):185-9.
  20. Damasceno DC, Volpato GT, Sartori TCF, Rodrigues PF, Perin EA, Calderon IMP, et al. Effects of Annona squamosa extract on early pregnancy in rats. Phytomedicine. 2002;9(7):667-72.
  21. Draper HH, Hardley M. Malondialdehyde deformation as an index of lipid peroxidation. Methods Enzymol. 1990;186:421-31.
  22. Martin JP, Dailey M, Sugarman E. Negative and positive assays of superoxide dismutase based on haematoxylin autooxidation. Arch Biochem Biophys. 1987;225:329-36.
  23. Paglia DE, Valentine WN. Studies on quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967;70:158-69.
  24. Features D. Pentylenetetrazol models of chemically-induced acute seizures. Funct MRI Epilepsy. 2006;14:127-52.
  25. Pylvänen V, Pakarinen A, Knip M, Isojärvi JI, Lönnqvist J. Carbamazepine affects weight but not leptin secretion in epileptic patients. Pharmacol Toxicol. 2002;90(2):71-4.
  26. Sener U, Uygur R, Aktas C, Uygur E, Erbaş O. Oxidative stress in carbamazepine use: a meta-analysis. Seizure. 2003;12(7):497-502.
  27. Kadar-Ali SH, Raja WA. The effect of antioxidants in acute amitriptyline poisoning. Toxicol Rep. 2019;6:380-8.
  28. Nasr NA, Abd El Aal MF, El-Sokkary GH. Carbamazepine-induced oxidative stress in epileptic children: the role of SOD1 and GPx1 gene polymorphisms. Eur J Paediatr Neurol. 2013;17(6):594-600.
  29. Fridorich I. Superoxide radicals and superoxide dismutases. Annu Rev Biochem. 1992;64:97-112.
  30. Aprioku JS. Pharmacology of free radicals and the impact of reactive oxygen species on the testis. J Reprod Infertil. 2013;14(4):158-72.
  31. Li ZH, Li P, Randak T. Effect of a human pharmaceutical carbamazepine on antioxidant responses in brain of a model teleost in vitro: an efficient approach to biomonitoring. J Appl Toxicol. 2010;30:644-8.
  32. Pisoschi AM, Pop A. The role of antioxidants in the chemistry of oxidative stress: a review. Eur J Med Chem. 2015;97:55-74.
  33. Tahbet F, Touyz RM. Reactive oxygen species, oxidative stress and vascular biology in hypertension. Compr Hypertens. 2007;3:337-47.
  34. Afshar M, Moallem MSA, Mohammadpour AH, Shiravi A, Jalalian SM, Golalipour MJ. Teratogenic effects of carbamazepine on embryonic eye development in pregnant mice. Cutan Ocul Toxicol. 2010;29(1):10-5.
  35. Akunne TC, Okafor SN, Igweze Z, Njoku CN, Ojapinwa OO. Toxicological profile of carbamazepine and levetiracetam on some biochemical and hematological parameters in rats. Pharma Biosci J. 2017;5(4):30-7.
  36. Aliyu H, Ayo JO, Ambali SF, Zezi AU. Effects of administration of carbamazepine and/or phenytoin on serum biochemical parameters in Wistar rats. Afr J Pharm Pharmacol. 2013;7(23):1585-91.
  37. Gowthami V, Sudha P, Suresh T, Mounika P, Dhivya K. Prospective study on the effect of monotherapy antiepileptics on haematological parameters and various biochemical parameters in epilepsy patients. J Chem Pharm Res. 2017;9(5):277-81.
  38. Ambili TR, Saravanan M, Ramesh M, Abhijith DB, Poopal RK. Toxicological effects of the antibiotic oxytetracycline to an Indian major carp Cirrhinus mrigala under tropical conditions. Chemosphere. 2013;91(2):206-16.
  39. Rivera-Rodriguez KM, Rodríguez-Rivera AV, Roman-Julia R, Morales-Borges R. Effectiveness of vitamin C in the treatment of anemia in patients with chronic diseases: A case study. Res Rev Pharm Pharm Sci. 2016;5(4):31-5.
  40. Kavitha C, Malarvizhi A, Senthil-Kumaran S, Ramesh M. Toxicological effects of arsenate exposure on hematological, biochemical, and liver transaminases activity in an Indian major carp, Catla catla. Food Chem Toxicol. 2010;48(10):2848-54.
  41. Çağ I, Altun Y, Altunışık E. Do antiepileptic drugs have any effect on neutrophil/lymphocyte and platelet/lymphocyte ratio? Med Sci Discov. 2019;6(4):76-81.
  42. Osuntokun OS, Olayiwola G, Oladele A, Ola I, Ayoka AO. Chronic administration of gabapentin and a gabapentin-carbamazepine combination reversibly suppresses testicular function in male Wistar rats (Rattus norvegicus). Pathophysiology. 2017;24:63-9.
  43. Deng W, Sun R, Du J, Wu X, Ma L, Wang M, Lv Q. Prediction of miscarriage in first trimester by serum estradiol, progesterone, and β-human chorionic gonadotropin within 9 weeks of gestation. BMC Pregnancy Childbirth. 2022;22(112):23-32.
  44. Verma P, Verma R, Nair RR, Budhwar S, Khanna A, Agrawal NR, Sinha R, Birendra R, Rajender S, Singh K. Altered crosstalk of estradiol and progesterone with myeloid-derived suppressor cells and Th1/Th2 cytokines in early miscarriage is associated with early breakdown of maternal-fetal tolerance. Am J Reprod Immunol. 2019;81(2)
  45. Zhang W, Tian Y, Xie D, Miao Y, Liu J, Wang X. The impact of peak estradiol during controlled ovarian stimulation on the cumulative live birth rate of IVF/ICSI in non-PCOS patients. J Assist Reprod Genet. 2019;36(11):2333-44.
  46. Gao Q, Wang M, Rong T. Serum estradiol level in pregnant women of four to eight weeks and its relationship with threatened abortion. J Shandong Univ. 2008;46(9):884-6.
  47. Di-Renzo GC, Giardina I, Clerici G, Brillo E, Gerli S. Progesterone in normal and pathological pregnancy. Horm Mol Biol Clin Investig. 2016;27(1):35-48.
  48. Sane N, Goudarzi F. Seizure in patients with antiepileptic drug overdose: study on patients admitted to Shoushtari Hospital in Shiraz. Asia Pac J Med Toxicol. 2013;2:101-4.
  49. Ajam M, Reyhani T, Roshanravan V, Zare Z. Increased miscarriage rate in female farmers working in saffron fields: a possible effect of saffron toxicity. Asia Pac J Med Toxicol. 2014;3:73-5.
Asia Pacific Journal of Medical Toxicology
Volume 13, Issue 2
Spring 2024
Pages 56-64

Home

Guide for Authors

Submit Manuscript

Reviewers

Contact Us