PENTİLENTETRAZOL-İNDÜKLÜ NÖBETLERDE ERİTROPOİETİN ÖN TEDAVİSİNİN KARACİĞER, BÖBREK, KALP DOKUSU ÜZERİNE ETKİLERİ; OKSIDATİF MARKIRLAR, PROLİDAZ VE SİALİK ASİT AÇISINDAN DEĞERLENDİRME

Öz

Amaç: Antiepileptik ajan olarak sıklıkla çalışılan eritropoietinin (EPO)’nun periferik dokular üzerindeki etkileri araştırılmamıştır. Bu çalışmada pentilentetrazol (PTZ) ile indüklenen nöbetlerde EPO ön tedavisinin kalp, böbrek ve karaciğer dokularında malondialdehit (MDA), ileri protein oksidasyon ürünleri (AOPP), superoksid dismutaz (SOD), prolidaz ve sialik asit (SA) seviyelerine etkisi araştırıldı. Gereç ve Yöntem: Otuz üç erişkin erkek sıçan üç gruba ayrıldı. Salin enjekte edilmiş kontrol grubu, nöbetleri indüklemek için 60 mg/kg PTZ enjekte edilmiş grup, nöbetlerden 24 saat önce 3000 IU/kg EPO enjekte edilmiş grup. Nöbet şiddeti ve nöbet gecikmesi puanlandıktan sonra, sıçanlar sakrifiye edildi, dokular biyokimyasal analizler için hemen çıkarıldı. Bulgular: Pentilentetrazol ile indüklenen nöbetler, böbrekte MDA (p<0,01) ve karaciğerde AOPP’yi arttırdı (p<0,05), ancak kalp dokusunda bu markırları değiştirmedi. Her üç dokuda da SOD nöbetler nedeniyle değişmedi. Kalpte SA arttı (p<0,001), böbrekte azaldı (p<0,001), karaciğerde değişmedi. Prolidaz sadece böbrekte arttı (p<0,05), diğer dokularda değişmedi. EPO ön tedavisi nöbet şiddetini azalttı ve nöbet latansını artırdı. EPO böbrekte MDA artışını engelledi (p<0,01), ancak AOPP’yi artırdı (p<0,05) ve SOD’u azalttı (p<0,01) ve prolidazı nöbetlerin arttırdığından daha fazla artırdı (p<0,01). EPO ön tedavisi, karaciğerde AOPP artışını önledi (p<0,05), ancak kalp ve böbrekte PTZ’nin neden olduğu SA değişikliklerinde etkisizdi. Sonuç: Nöbetlerde kalp dokusundaki SA artışının nöbet-ilişkili kardiak aritmiler bağlamında araştırmayı hak eden orijinal bulgu olduğunu düşünüyoruz. Ayrıca EPO ön tedavisinin nöbet engelleyici etkisine rağmen özellikle böbrek dokusunda artmış protein oksidasyonu ve prolidaz da ileri araştırmayı gerektiren diğer önemli bulgudur.

Anahtar Kelimeler

• Eritropoietin
• PTZ-indüklü nöbetler
• oksidatif stres belirteçleri
• sialik asit
• prolidaz
• periferik dokular

EFFECTS OF ERYTHROPOIETIN PRETREATMENT ON LIVER, KIDNEY, HEART TISSUE IN PENTYLENTETRAZOL-INDUCED SEIZURES; EVALUATION IN TERMS OF OXIDATIVE MARKERS, PROLIDASE AND SIALIC ACID

Öz

Objective: The effects of erythropoietin (EPO) which has been frequently studied as an anti-epileptic agent, on peripheral tissues have not been investigated. This study investigated the effects on malondialdehyde (MDA), advanced protein oxidation products (AOPP), superoxide dismutase (SOD), prolidase and sialic acid (SA) levels in the heart, kidney and liver tissues of EPO pretreatment in pentylenetetrazole (PTZ)-induced seizures. Material and Method: Thirty three male adult rats were divided into three groups. A saline-injected control group, a 60 mg/kg PTZ-injected group to induce seizures and a 3000 IU/kg EPO-injected group 24 hours before seizures. After seizure severity and seizure latency were scored, the rats sacrificed, the tissues were immediately removed for biochemical analyses. Results: The PTZ-induced seizures increased MDA in kidney (p<0.01) and AOPP in liver (p<0.05) but didn’t alter these markers in heart tissue. In all three tissues, SOD didn’t change due to seizures. The SA levels increased in the heart (p<0.001), decreased in the kidney (p<0.001), and were unchanged in liver. Prolidase increased (p<0.05) only in kidney, and was unchanged in other tissues. EPO-pretreatment decreased seizure severity and increased seizure latency. It prevented the increase in MDA in the kidney (p<0.01) but increased AOPP (p<0.05) and decreased SOD (p<0.01) and further increased prolidase more than the seizures increased (p<0.01). EPO-pretreatment prevented the increase in AOPP in the liver (p<0.05) but was ineffective in PTZ-induced SA changes in the heart and kidney. Conclusion: We think that the increase in the heart SA level in seizures is an original finding and deserves investigation in the context of seizure-related cardiac arrhytmias. Also, despite the EPO’s anti-seizure effect, increased protein oxidaiton and prolidase, especially in the kidney, is an other important finding that needs further research.

Anahtar Kelimeler

• Erythropoietin
• PTZ-induced seizures
• oxidative stress markers
• sialic acid
• prolidase
• peripheral tissues

Kaynakça

1. 1. Hamed SA. The effect of antiepileptic drugs on the kidney function and structure. Expert Rev Clin Pharmacol 2017;10(9):993-1006. [CrossRef]
2. 2. Dillioglugil MO, Kir HM, Demir C, Ilbay G, Sahin D, Dillioglugil O, et al. Effect of pentylenetetrazole and sound stimulation induced single and repeated convulsive seizures on the MDA, GSH and NO levels, and SOD activities in rat liver and kidney tissues. Brain Res Bull 2010;83(6):356-9. [CrossRef]
3. 3. Willmore LJ, Wilder BJ, Bruni J, Villarreal HJ. Effect of valproic acid on hepatic function. Neurology 1978;28(9 Pt 1):961-4. [CrossRef]
4. 4. Arcasoy MO. Non-erythroid effects of erythropoietin. Haematologica 2010;95(11):1803-5. [CrossRef]
5. 5. Chu K, Jung KH, Lee ST, Kim JH, Kang KM, Kim HK, et al. Erythropoietin reduces epileptogenic processes following status epilepticus. Epilepsia 2008;49(10):1723-32. [CrossRef]
6. 6. Üzüm G, Sarper Diler A, Bahçekapılı N, Ziya Ziylan Y. Erythropoietin prevents the increase in blood-brain barrier permeability during pentylentetrazol induced seizures. Life Sci 2006;78(22):2571-6. [CrossRef]
7. 7. Bahçekapılı N, Akgün-Dar K, Albeniz I, Kapucu A, Kandil A, Yağız O, et al. Erythropoietin pretreatment suppresses seizures and prevents the increase in inflammatory mediators during pentylenetetrazole-induced generalized seizures. Int J Neurosci 2014;124(10):762-70. [CrossRef]
8. 8. Abdelrahman M, Sharples EJ, McDonald MC, Collin M, Patel NS, Yaqoob MM, et al. Erythropoietin attenuates the tissue injury associated with hemorrhagic shock and myocardial ischemia. Shock 2004;22(1):63-9. [CrossRef]

9. 9. Patel NS, Sharples EJ, Cuzzocrea S, Chatterjee PK, Britti D, Yaqoob MM, et al. Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo. Kidney Int 2004;66:983-9. [CrossRef]
10. 10. Akbas SH, Yegin A, Ozben T. Effect of pentylenetetrazolinduced epileptic seizure on the antioxidant enzyme activities, glutathione and lipid peroxidation levels in rat erythrocytes and liver tissues. Clin Biochem 2005;38(11):1009-14. [CrossRef]
11. 11. Tigaran S, Molgaard H, McC lelland R, Dam M, Jaffe AS. Evidence of cardiac ischemia during seizures in drug refractory epilepsy patients. Neurology 2003;60(3):492-5. [CrossRef]
12. 12. Surges R, Sander JW. Sudden unexpected death in epilepsy: mechanisms, prevalence, and prevention. Curr Opin Neurol 2012;25(2):201-7. [CrossRef]
13. 13. Zimmer T, Haufe V, Blechschmidt S. Voltage-gated sodium channels in the mammalian heart. Glob Cardiol Sci Pract 2014;(4):449-63. [CrossRef]
14. 14. Bennett E, Urcan MS, Tinkle SS, Koszowski AG, Levinson SR. Contribution of sialic acid to the voltage dependence of sodium channel gating. A possible electrostatic mechanism. J Gen Physiol 1997;109(3):327-43. [CrossRef]
15. 15. Liu G, Nakayama K, Awata S, Tang S, Kitaoka N, Manabe M, et al. Prolidase isoenzymes in the rat: their organ distribution, developmental change and specific inhibitors. Pediatr Res 2007;62(1):54-9. [CrossRef]
16. 16. Surazynski A, Miltyk W, Palka J, Phang JM. Prolidasedependent regulation of collagen biosynthesis. Amino Acids 2008;35(4):731-8. [CrossRef]
17. 17. Duygu F, Koruk ST, Karsen H, Aksoy N, Taskin A, Hamidanoglu M. Prolidase and oxidative stress in chronic hepatitis C. J Clin Lab Anal 2012;26(4):232-7. [CrossRef]
18. 18. Karacan N, Çalik M, Kazanasmaz H, Ethemoğlu Ö, Güzelçiçek A, Yaşin S, et al. The serum prolidase enzyme activity as a biomarker for evaluation of the subclinical vascular damage in children with epilepsy. Ann Indian Acad Neurol 2020;23(6):787-91.
19. 19. Kapucu A, Üzüm G, Kaptan Z, Akgün-Dar K. Effects of erythropoietin pretreatment on single dose pentylentetrazole-induced seizures in rats. Biotech Histochem 2020;95(6):418-27. [CrossRef]
20. 20. Lüttjohann A, Fabene PF, van Luijtelaar GA. Revised Racine’s scale for PTZ-induced seizures in rats. Physiol Behav 2009;98(5):579-86. [CrossRef]
21. 21. Lowry OH, Rosebrough NJ, Farr AL, Randall J. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193(1):265-75. [CrossRef]
22. 22. Hanasand M, Omdal R, Norheim KB, Gøransson LG, Brede C, Jonsson G. Improved detection of advanced oxidation protein products in plasma. Clin Chim Acta 2012;413(9- 10):901-6. [CrossRef]
23. 23. Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol 1978;52:302-10. [CrossRef]
24. 24. Tram TH, Brand Miller JC, McNeil Y, McVeagh P. Sialic acid content of infant saliva: comparison of breast fed with formula fed infants. Arch Dis Child 1997;77(4):315-8. [CrossRef]
25. 25. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem 1988;34(3):497-500. [CrossRef]
26. 26. Ozcan O, Gultepe M, Ipcioglu O, Bolat B, Kayadibi H. Optimization of the photometric enzyme activity assay for evaluating real activity of prolidase. Turk J Biochem 2007;32(1):12-6.
27. 27. Uma Devi P, Pillai KK, Vohora D. Modulation of pentylenetetrazole-induced seizures and oxidative stress parameters by sodium valproate in the absence and presence of N-acetylcysteine. Fundam Clin Pharmacol 2006;20(3):247-53. [CrossRef]
28. 28. Maes M, Supasitthumrong T, Limotai C, Michelin AP, Matsumoto AK, de Oliveira Semão L, et al. Increased oxidative stress toxicity and lowered antioxidant defenses in temporal lobe epilepsy and mesial temporal sclerosis: associations with psychiatric comorbidities. Mol Neurobiol 2020;57(8):3334-48. [CrossRef]
29. 29. Ercegovac M, Jovic N, Simic T, Beslac-Bumbasirevic L, Sokic D, Djukic T, et al. Byproducts of protein, lipid and DNA oxidative damage and antioxidant enzyme activities in seizure. Seizure 2010;19(4):205-10. [CrossRef]
30. 30. Gill SS, Pulido OM. Glutamate receptors in peripheral tissues: current knowledge, future research, and implications for toxicology. Toxicol Pathol 2001;29(2):208-23. [CrossRef]
31. 31. Sharma A. Monosodium glutamate-induced oxidative kidney damage and possible mechanisms: a mini-review. J Biomed Sci 2015;22:93. [CrossRef]
32. 32. Lindberg G, Eklund GA, Gullberg B, Råstam L. Serum sialic acid concentration and cardiovascular mortality. BMJ 1991;302(6769):143-6. [CrossRef]
33. 33. Crook M, Haq M, Haq S, Tutt P. Plasma sialic acid and acute-phase proteins in patients with myocardial infarction. Angiology 1994;45(8):709-15. [CrossRef]
34. 34. Babal P, Slugen I, Danis D, Zaviacic M, Gardner WA Jr. Sialic acid expression in normal and diseased human kidney. Acta Histochem 1996;98(1):71-7. [CrossRef]
35. 35. Purves D, Augustine GJ, Fitzpatrick D, Katz LC, LaMantia A-S, McNamara JO, Williams SM, editors. Neuroscience 2nd edition. Glutamate Receptors in Chapter 7. Oxford Unıversity Press, Oxford, Sinauer Associates; 2001.
36. 36. Pasaoglu H, Ofluoglu Demir FE, Yılmaz Demirtas C, Hussein A, Pasaoglu OT. The effect of caffeine on oxidative stress in liver and heart tissues of rats. Turkish J of Med Sci 2011;41:665-71.
37. 37. Myara I, Myara A, Mangeot M, Fabre M, Charpentier C, Lemonnier A. Plasma prolidase activity: a possible index of collagen catabolism in chronic liver disease. Clin Chem 1984;30(2):211-5. [CrossRef]
38. 38. Gu L, Xu H, Wang F, Xu G, Sinha D, Wang J, et al. Erythropoietin exerts a neuroprotective function against glutamate neurotoxicity in experimental diabetic retina. Invest Ophthalmol Vis Sci 20114;55(12):8208-22. [CrossRef]