Özden KAMIŞLI, , Handan SOYSAL, Zümrüt DOĞAN, Nihat EKİNCİ, Yusuf TÜRKÖZ

Lamotrigin kullanan epileptik ratların yeni doğan yavrularının karaciğerlerinde oksidatif hasarın incelenmesi

Bu çalışmada amacımız epilepsi tedavisinde sıkça kullanılan antiepileptik ilaçlardan lamotirijinin yalnız veya folik asit ile birlikte gebelikte kullanımının yeni doğan yavruların karaciğerlerinde oksidatif stres parametreleri üzerine etkilerini araştırmaktır. Çalışmamız 170-250 gr ağırlığında 10 adet erişkin dişi Wistaralbino türü rat ve bunlardan doğan 20 yavru rat ile yapıldı. Ratlar; Gebe ratlar kontrol grubu, deneysel epilepsi grubu, lamotrijin grubu, lamotrijin+deneysel epilepsi grubu ve lamotrijin epilepsi+folik asit olarak beş gruba ayrıldı. Gebeliğin 13. Gününde gebe ratlara deneysel penisilin akut epilepsi modeli oluşturuldu. Lamotrijin grubuna gebeliğin ilk gününden itibaren her gün intraperitoneal enjeksiyon ile 25mg/gün dozunda lamotrijin verildi. Lamotrijin+folik asit grubuna her gün intraperitoneal enjeksiyon ile 25mg/gün dozunda lamotrijin ve 400µg/kg folik asit verildi. Daha sonra gebe ratların doğum yapmaları beklendi. Doğumdan hemen sonra yeni doğan ratların karaciğerlerinde glutatyon, malondialdehit, glutatyon peroksidaz ve superoksid dismutaz seviyeleri spektrofotometrik olarak ölçüldü. Lamotrijin ve lamotrijin+epilepsi gruplarına ait biyokimyasal değerler incelendiğinde, karaciğer malondialdehit anlamlı bir şekilde yükseldiği, glutatyon peroksidaz enzim aktivasyonlarının kontrol grubuna göre istatistiksel olarak anlamlı azalmış olduğu görüldü. Folik asit ile birlikte lamotrijin verilen grupta, karaciğer doku örneklerine ait malondialdehit düzeylerinin anlamlı azaldığı, glutatyon ve glutatyon peroksidaz düzeyinin arttığı tespit edildi. Gebe ratlar üzerinde gerçekleştirmiş olduğumuz bu çalışmada, lamotrijin kullanımının yeni doğan yavruların karaciğerlerinde erken dönemde bir oksidatif hasar meydana getirebileceği ancak meydana gelen oksidatif doku hasarının folik asit kullanıldığında engellendiği biyokimyasal olarak ortaya kondu

Anahtar Kelimeler:

Lamotrijin, epilepsi, gebelik, karaciğer, oksidatif stres

Pages 10-14

The present study was performed to evaluate the effects of lamotrigine, which is a widely used antiepileptic drug for epilepsy treatment, on oxidative stress parameters in the liver of neonates. Ten adult Wistar-albino rats and twenty newborn of these rats were used in this study. Adult rats weighing 170–250 g were divided into five groups: the pregnant control group, experimental epilepsy group, lamotigine group, lamotrigine + experimental epilepsy group and lamotrigine + epilepsy + folic acid group. An experimental penicillin acute epilepsy model was created in pregnant rats on day 13 of pregnancy. The lamotrigine group was administered lamotrigine at 25 mg/day by intraperitoneal injection starting from the first day of pregnancy. The lamotrigine + folic acid group was administered 400 microgram/kg folic acid and 25 mg/day lamotrigine by intraperitoneal injection. We then waited for the rats to give birth. Immediately after birth, the glutathione, malondialdehyde, glutathione peroxidase and superoxide dismutase levels in the newborn rat liver were measured by spectrophotometry. The lamotrigine and lamotrigine + epilepsy groups showed significantly elevated liver malondialdehide levels, while glutathione peroxidase enzyme activation was significantly decreased compared to the control group. In the group administered folic acid together with lamotrigine, the liver tissue sample for malondialdehide levels showed a significant decrease, while glutathion and glutathion peroxidase levels increased. This study on pregnant rats demonstrated that lamotrigine use can lead to hepatic oxidative damage in newborn rats, and this oxidative tissue damage was prevented by folic acid use.

Keywords:

Lamotrigine, epilepsy, pregnancy, liver, oxidative stress,

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1. Yerby MS. Pregnancy and epilepsy. Epilepsia. 1991; 32: 51-9.
2. Dansky LV, Andermann E, Andermann F. Marriage and fertility in epileptic patients. Epilepsia 1980; 21(3): 261-71.
3. Crawford P. Epilepsy and pregnancy.Seizure. 2002; 11: 212-9.
4. Katz JM, Pacia SV, Devinsky O. Current Management of Epilepsy and Pregnancy: Fetal Outcome, Congenital Malformations, and Developmental Delay.Epilepsy Behav. 2001; 2(2): 119-23.
5. Maertens P, Dyken P, Graf W, Pippenger C, Chronister R, Shah A. Free radicals, anticonvulsants and the neuronal ceroid lipofuscinoses.Am J Med Genet. 1995; 7: 225-8.
6. Martinez BC, Pita CE, Sanchez GY, Rodriguez LCM, Agil A. Lipid peroxidation in adult epileptic patients treated with valproic acid. Rev Neurol. 2004; 38: 101-6.
7. Stanton PK, Moskal JR. Diphenylhydantoin protects against hypoxia induced impairment of hippocampal synaptic transmission. Brain Res. 1991; 546: 351-4
8. Arora T, Mehta AK, Sharma KK, Mediratta PK. Effect of carbamazepine and lamotrigine on cognitive function and oxidative stress in brain during chemical epileptogenesis in rats. Basic Clin Pharmacol Toxicol. 2010; 106(5): 372-7.
9. Shor S, Koren G, Nulman I. Teratogenicity of lamotrigine. Can Fam Physician. 2007; 53(6): 1007-9.
10. Ornoy A.Neuroteratogens in man: an overview with special emphasis on the teratogenicity of antiepileptic drugs in pregnancy. Reprod Toxicol. 2006; 22(2): 214-26.
11. Bakare A, Shao L, Cui J, Young LT, Wang JF. Mood stabilizing drugs lamotrigine and olanzapine increase expression and activity of glutathione S-transferase in primary cultured rat cerebral cortical cells. Neurosci Lett. 2009; 455(1): 70-3.
12. Eren I, Naziroğlu M, Demirdaş A.Protective effects of lamotrigine, aripiprazole and escitalopram on depression-induced oxidative stress in rat brain. Neurochem Res. 2007; 32(7): 1188-95.
13. Agarwal NB, Agarwal NK, Mediratta PK, Sharma KK. Effect of lamotrigine, oxcarbazepine and topiramate on cognitive functions and oxidative stress in PTZ-kindled mice. Seizure. 2011; 20(3): 257-62
14. Fayad M, Choueiri R, Mikati M. Potential hepatotoxicity of lamotrigine. Pediatr Neurol. 2000; 22: 49-52.
15. Dubnov-Raz G, Shapiro R, Merlob P. Maternal lamotrigine treatment and elevated neonatal gamma-glutamyl transpeptidase. Pediatr Neurol 2006; 35: 220–222.
16. Paxinos G, Watson C. The rat brain in sterotaxic coordinates. San Diego, CA, Academic Press, 1982, Plate 25.
17. Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem. 1978; 86: 271–8.
18. Ellman GL. Tissue sulphhydryl groups. Arch Biochem Biophys. 1959; 82: 70–7. 19. Paglia DE, Valentine WN. Studies on the qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967; 70: 158–63.
20. Spielberg SP, Gordon GB, Blake DA, Mellits ED, Bross, DS. Anticonvulsant toxicity in vitro: possible role of arene oxides. Journal of Pharmacology and Experimental Therapeutics. 1981; 217: 386–89.
21. Hussaini, SH, Farrington EA. Idiosyncratic druginduced liver injury: an overview. Expert Opinion on Drug Safety. 2007; 6: 673–84.
22. Boelsterli UA, Lim PL. Mitochondrial abnormalities–a link to idiosyncraticdrug hepatotoxicity? Toxicology and Applied Pharmacology. 2007; 220: 92–107.
23. Neuman MG, Malkiewicz IM, Shear NH. A novel lymphocyte toxicity assay to assess drug hypersensitivity syndromes. Clinical Biochemistry. 2000; 33: 517–24.
24. Nitti M, Pronzato MA, Marinari UM, Domenicotti C. PKC signaling in oxidative hepatic damage. Molecular Aspects of Medicine. 2008; 29: 36–42.
25. Chang TKH, Abbott FS. Oxidative stress as a mechanism of valproic acid associated hepatotoxicity. Drug Metabolism Reviews. 2006; 38: 627–39.
26. Duncan JS, Thompson PJ. The cognitive consequences of epilepsy. Ann Neurol 2003; 54: 421–2.
27. Sudha K, Rao AV, Rao A. Oxidative stress and anti-oxidants in epilepsy. Clin Chim Acta. 2001; 303: 19–24.
28. Gupta YK, Kumar MHV, Srivastava AK. Effect of Centella asiatica on pentylenetetrazoleinduced kindling, cognition and oxidative stress in rats. Pharmacol Biochem Behav 2003; 74: 579- 85.
29. Aycicek A, Iscan A. The effects of carbamazepine, valproic acid and phenobarbital on the oxidative and antioxidative balance in epileptic children. European Neurology. 2007; 57: 65–9.
30. Santos NA, Medina WS, Martins NM, Rodrigues MA, Curti C, Santos AC. Involvement of oxidative stress in the hepatotoxicity induced by aromatic antiepileptic drugs.Toxicol In Vitro. 2008; 22(8): 1820-4.