Cent Eur J Public Health 2004, 12(Supplement):S83-S86

Effect of Melatonin and Strobadine on Maternal and Embryofoetal Toxicity in Rats Due to Intrauterine Hypoxia Induced by Phenytoin Administration

Ujházy E.1, Mach M.1, Dubovický M.1, Navarová J.1, Šoltés L.1, Juránek I.1, Brucknerová I.2, Zeman M.3
1 Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava
2 1st Children's Hospital School of Medicine, Comenius University, Bratislava
3 Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic

The aim of the present study was to test the hypothesis that the natural antioxidant melatonin (MEL) and the synthetic antioxidant stobadine (STO) could reduce the incidence of maternal and embryofoetal toxicity in rats due to intrauterine hypoxia. Chronic hypoxia was induced pharmacologically by the administration of the anticonvulsant phenytoin (PHT) during the entire period of pregnancy. PHT disturbed the normal course of pregnancy, affected reproductive parameters and increased the incidence of skeletal anomalies. MEL did not protect the PHT-induced development toxicity in rat. On the other hand, STO partially prevented PHT-induced reduction of foetal and placental weights. Administration of STO also decreased the frequency of pre- and post-implantation loss and resorptions in the PHT group. We concluded that pretreatment of pregnant rats with STO prevented to a certain extent reproductive and foetal development alterations caused by chronic intrauterine hypoxia.

Keywords: intrauterine hypoxia, phenytoin, developmental toxicity, rat, melatonin, stobadine

Published: March 1, 2004  Show citation

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Ujházy E, Mach M, Dubovický M, Navarová J, Šoltés L, Juránek I, et al.. Effect of Melatonin and Strobadine on Maternal and Embryofoetal Toxicity in Rats Due to Intrauterine Hypoxia Induced by Phenytoin Administration. Cent Eur J Public Health. 2004;12(Supplement):S83-86. PubMed PMID: 15141990.
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References

  1. Sastre J, Asensi M, Rodrigo F, Pallardo FV, Vento M, Vina J: Antioxidant administration to the mother prevents oxidative stress associated with birth in the neonatal rat. Life Sci 1994; 54(26): 2055-2059. Go to original source...
  2. Allen RG, BalinAK: Oxidative influence on development and differentiation: an overview of a free radical theory of development. Free Radic Biol Med 1989; 6: 631-661. Go to original source...
  3. Fantel AG: Reactive oxygen species in developmental toxicity : review and hypothesis. Teratology 1996; 53: 196-217. Go to original source... Go to PubMed...
  4. Danielsson BR, Azarbayjani F, Skold AC, Webster WS: Initiation of phenytoin teratogenesis: pharmacologically induced embryonic bradycardia and arrhythmia resulting in hypoxia and possible free radical damage at reoxygenation. Teratology 1997; 56: 271-281. Go to original source... Go to PubMed...
  5. Azarbayjani F, Danielsson BR: Pharmacologically induced embryonic dysrhythmia and episodes of hypoxia followed by reoxygenation: a common teratogenic mechanism for antiepileptic drugs? Teratology 1998; 57: 117-126. Go to original source... Go to PubMed...
  6. Harbison RD, Becker BA: Diphenylhydantoin teratogenicity in rats. Toxicol Appl Pharmacol 1972; 22: 193-200. Go to original source...
  7. Ujházy E, Dubovický M, Mach M, Juránek I, Navarová J, Sadloňová I, Gajdošík A: Effect of phenytoin on prenatal and postnatal development of rats. Biologia 2000; Suppl. 8: 125-130.
  8. Huether G: The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates. Experiencia 1993; 49: 665-670. Go to original source...
  9. Jahnke G, Marr M, Myers C, Wilson R, Travlost G, Price C: Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats. Tox Sci 1999; 50: 271-279. Go to original source...
  10. Horáková L, Štolc S: Antioxidant and pharmacodynamic effects of pyridoindole stobadine: A review. Gen Pharmac 1998; 30: 789-799. Go to original source...
  11. Balonová T, Zeljenková D, Ďurišová M, Nosál R, Jakubovský J, Líška J, Štolc S: Reproductive toxicity studies with cis(-)-2,3,4,4a,5,9-b-hexahydro-2,8-dimethyl-1H-pyrido-(4,3-b)indole dipalmitate in rats. Arzneim-Forsch 1991; 41(1): 1-5.
  12. Ujházy E, Dubovický M, Balonová T, Janšák J: Teratological study of the antoxidant stobadine in rats. Gen Physiol Biophys Focus Issue 1999; 18: 171-176.
  13. Štolc S, Bauer V, Beneš L, Tichý M: Medicine with antiarrhythmic and antihypoxic activity and its methods of preparation. 1983, Patent ČS. 229067, SWED. 8204693-9, BELG. 894148, SWISS 651 754, BRD. P-323 1088, SPAIN 553 017, JAP. 151 4040.
  14. Pizzi WJ, Jersey RM: Effects of prenatal diphenylhydantoin treatment on reproductive outcome, development, and behavior in rats. Neurotoxicol Teratol 1992; 14: 111-117. Go to original source...
  15. Mach M, Ujházy E, Dubovický M, Navarová J, Blažíček P, Šoltés L: Structural and functional changes in rat offspring induced by prenatal phenytoin administration. Med Mil Lett LXX: 2001; 79-82.
  16. Gitto E, Reiter RJ, Karbownik M, Tan DX, Gitto P, Barberi S, Barberi I: Causes of oxidative stress in the pre- and perinatal period. Biol Neonate 2002; 81: 14-57. Go to original source... Go to PubMed...
  17. Penn, JS, Talmon BL, Bullard LE: Effect of a water-soluble vitamin analog of retinopathy of prematurity. Free Rad Biol Med 1997; 22: 977984. Go to original source...
  18. Cedeberg J, Siman CM, Eriksson UJ: Combined treatment with vitamin E and vitamin C decreases oxidative stress and improves fetal outcome in experimental diabetic pregnancy. Pediatr Res 2001; 49: 755-762. Go to original source... Go to PubMed...
  19. Finnel RH, Kerr BM, van Waes M, Rebecca LS, René HL: Protection from phenytoin-induced congenital malformations by coadministration of the antiepileptic drug stiripentol in a mouse model. Epilepsia 1994; 35: 141-148. Go to original source...
  20. Harbison RD, Becker BA: Effects of phenobarbital or SKF525A pretreatment on diphenylhydantoin teratogenicity in mice. J Pharmacol Exp Ther 1970; 175: 283-288. Go to PubMed...
  21. Palmer AK: Incidence of sporadic malformations, anomalies and variations in random bred laboratory animals. In: Neubert D, Mecker H-J, Kwasigroch TE, eds. Methods in Prenatal Toxicology, Stuttgart, Georg Thieme Publishers 1977: 52-71.
  22. Muchova S: Biochemical indicators of cell and tissue activity induced by phenytoin. PhD thesis. STU Bratislava, 2000, 1-79. (In Slovak.)