Ebru ELİBOL, Süleyman KAPLAN, Gamze ALTUN, Abdurrahman AKSOY, Berrin Zuhal ALTUNKAYNAK

The effects of different doses of diclofenac sodium on newborn rat hippocampus exposed during the third trimester

The main aim of the present study was to examine the neurotoxic effects of prenatal exposure to varying doses of diclofenac sodium DS on the rat hippocampus. Twenty-eight Wistar albino adult female rats weighing 280-300 g were initially used for pregnancy. When vaginal plaques were seen in female rats, it was accepted as the 0th day of pregnancy. Female rats were divided into five main groups; pure control, saline, low dose DS 3.6 mg/kg , moderate dose DS 9 mg/kg , and high dose DS 18 mg/kg . They were exposed to these treatments during their gestation. After birth, all newborn male rats were euthanized by overdose anesthesia on the 7th postnatal day. Histological and stereological techniques were used for analyzing tissue samples. The stereological analyses in this study showed that the number of neurons in the hippocampus may be reduced due to the use of DS. Histological investigation of the drug-treated groups showed significant cell loss compared to the control. Darkly stained nuclei of the neurons in the high dose group compared to the other groups were also obvious. When the results are evaluated, it can be concluded that the use of diclofenac sodium during pregnancy may have teratogenic effects on the development of the nervous system.

Keywords:

Diclofenac sodium, hippocampus, prenatal, stereology, rat,

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1. Nettis E, Colanardi MC, Ferrannini A, Tursi A. Update on sensitivity to nonsteroidal antiinflammatory drugs. Current Drug Targets - Immune, Endocrine & Metabolic Disorders 2001; 1: 233-240. doi: 10.2174/1568008013341235
2. Odacı E, Cihan OF, Aslan H, Rağbetli MÇ, Kaplan S. Prenatal diclofenac sodium administration increases the number of Purkinje cells in female rats: a stereological study. International Journal of Developmental Neuroscience 2009; 28: 145-151. doi: 10.1016/j.ijdevneu.2009.12.004
3. Gökçimen A, Rağbetli MC, Baş O, Tunc AT, Aslan H et al. Effect of prenatal exposure to an anti-inflammatory drug on neuron number in cornu ammonis and dentate gyrus of the rat hippocampus: a stereological study. Brain Research 2007; 1127:185-192. doi: 10.1016/j.brainres.2006.10.026
4. Cassina M, De Santis M, Cesari E, Eijkeren M, Berkovitch M et al. First trimester diclofenac exposure and pregnancy outcome. Reproductive Toxicology 2010; 30: 401-404. doi: 10.1016/j. reprotox.2010.04.010
5. Smith SR, Deshpande BR, Collins JE, Katz JN, Losina E. Comparative pain reduction of oral non-steroidal antiinflammatory drugs and opioids for knee osteoarthritis: systematic analytic review. Osteoarthritis and Cartilage 2016; 24: 962-972. doi: 10.1016/j.joca.2016.01.135
6. Beck A, Krischak G, Sorg T, Augat P, Farker K et al. Influence of diclofenac (group of nonsteroidal antiinflammatory drugs) on fracture healing. Archives of Orthopaedic and Trauma Surgery 2003; 123: 327-332. doi: 10.1007/s00402-003-0537-5
7. Siu KL, Lee WH. Maternal diclofenac sodium ingestion and severe neonatal pulmonary hypertension. Journal of Paediatric and Child Health 2004; 40: 152-153. doi: 10.1111/j.1440- 1754.2004.00319
8. Aygün D, Kaplan S, Odaci E, Onger ME, Altunkaynak ME. Toxicity of non-steroidal anti-inflammatory drugs: a review of melatonin and diclofenac sodium association. Histology and Histopathology 2012; 27: 417-436. doi: 10.14670/HH-27.417
9. Nielsen GL, Sørensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. British Medical Journal 2001; 322: 266- 270. doi: 10.1136/bmj.322.7281.266
10. Persaud TVN, Moore KL. Inhibitors of prostaglandin synthesis and fetal development. Lancet 1974; 1: 93. doi: 10.1016/s0140- 6736(74)92312-5
11. Harris WH. The effects of repeated doses of indomethacin on fetal rabbit mortality and on the patency of the ductus arteriosus. Canadian Journal of Physiology and Pharmacology 1980; 58: 212-216. doi: 10.1139/y80-034
. Rudolf AM. The effect of nonsteroidal antiinflammatory compounds on fetal circulation and pulmonary function. Obstetrics & Gynecology 1981; 58: 63-67. doi: 10.1002/uog.1038
13. Shastri AT, Abdulkarim D, Clarke P. Maternal diclofenac medication in pregnancy causing in utero closure of the fetal ductus arteriosus and hydrops. Pediatric Cardiology 2013; 34: 1925-1927. doi: 10.1007/s00246-012-0461-y
14. Sabry SA, Sakr SM, Shahin MA. Histological and ultrastructural studies on the effect of diclofenac sodium on the renal cortex of fetuses of albino mice. Global Journal of Pharmacology 2014; 8: 369-377. doi: 10.5829/idosi.gjp.2014.8.3.83264
15. El-Mashad AER, El-Mahdy H, El Amrousy D, Elgendy M. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. European Journal of Pediatrics 2016; 2016: 1-8. doi: 10.1007/s00431-016-2830-7
16. Gupta R. Pain Management. Berlin, Germany: Springer; 2014.
17. Goldin E, Harel S, Tomer A, Yavin E. Arachidonic acid oxidation by brain and placenta preparations from normal and placental insufficient fetal rabbit. Journal of Neurochemistry 1987; 48: 695- 701. doi: 10.1111/j.1471-4159.1987.tb05572.x
18. Kudo C, Kori M, Matsuzaki K, Yamai K, Nakajima A et al. Diclofenac inhibits proliferation and differentiation of neural stem cells. Biochemical Pharmacology 2003; 66: 289-295. doi: 10.1016/S0006-2952(03)00235-1
19. Chang JK, Wang GJ, Tsai ST, Ho ML. Non-steroidal antiinflammatory drug effects on osteoblastic cell cycle, cytotoxicity, and cell death. Connective Tissue Research 2005; 46: 200-210. doi: 10.1080/03008200500344025
20. Zenker M, Klinge J, Krüger C, Singer H, Scharf J. Severe pulmonary hypertension in a neonate cause by premature closure of ductus arteriosus following maternal treatment with diclofenac: a case report. Journal of Perinatal Medicine 1998; 26: 231-234.
21. Ostensen ME, Skomsvoll JF. Anti-inflammatory pharmacotherapy during pregnancy. Expert Opinion on Pharmacotherapy 2004; 5: 571-580. doi: 10.1517/eoph.5.3.571.27370
22. Rein AJ, Nadjari M, Elchalal U, Nir A. Contraction of the fetal ductus arteriosus induced by diclofenac. Fetal Diagnosis and Therapy 1999; 14: 24-25. doi: 10.1159/000020882
23. Siu SS, Yeung JH, Lau TK. A study on placental transfer of diclofenac in first trimester of human pregnancy. Human Reproduction 2000; 15: 2423-2425. doi: 10.1093/humrep/15.11.2423
24. Mogilner BM, Ashkenazy M, Borenstein R, Lancet M. Hydrops fetalis caused by maternal indomethacin treatment. Acta Obstetricia et Gynecologica Scandinavica 1982; 61: 183-185. doi: 10.3109/00016348209156552
25. Arad I, Bar-Oz B, Amit Y. Neonatal limb ischaemia following maternal indomethacin treatment in twin pregnancies. Journal of Perinatal Medicine 1995; 23: 487-491. doi: 10.1515/ jpme.1995.23.6.487
26. Takahashi Y, Harada K, Ishida A, Tanaka T, Tsuda A et al. Doppler echocardiographic finding of indomethacin induced occlusion of the fetal ductus arteriosus. American Journal of Perinatology 1996; 13: 15-18. doi: 10.1055/s-2007-994195
27. Pratt L, DiGiosia J, Swenson J, Trampe B, Martin CB. Reversible fetal hydrops associated with indomethacin use. Obstetrics and Gynecology 1997; 90: 676-678. doi: 10.1016/S0029- 7844(97)00392-X
28. Hickey EJ, Raje RR, Reid VE, Gross SM, Ray SD. Diclofenac induced in vivo nephrotoxicity may involve oxidative stressmediated massive genomic DNA fragmentation and apoptotic cell death. Free Radical Biology and Medicine 2001; 31: 139-152. doi: 10.1016/S0891-5849(01)00560-3
29. Kaplan S, Esrefoglu M, Aktas A, Gul M, Onger ME et al. The effect of prenatal exposure of a non-steroidal anti-inflammatory drug on the optic nerve of female rats: a stereological, histological, and electron microscopic study. Journal of Maternal-Fetal and Neonatal Medicine 2013; 26: 1860-1864. doi: 10.3109/14767058.2013.811227