Sibel Çiğdem TUNCER, Cihan GÜR, Nurhan AKARAS, Fatih Mehmet KANDEMİR

SIÇANLARDA SODYUM VALPROAT KAYNAKLI MİDE HASARI ÜZERİNE RUTİN’İN OKSİDATİF STRES, İNFLAMASYON VE APOPTOZ ÜZERİNDEKİ KORUYUCU ETKİLERİNİN ARAŞTIRILMASI

Amaç Sodyum valproat, antiepileptik ilaçlardan en yaygın kullanılanlardan birisi olup uzun süreli maruziyet sonucunda toksik etkilidir. Uzun süreli sodyum valproat maruziyeti dokularda özellikle oksidatif stres ve inflamasyon artışına neden olmaktadır. Rutin, birçok bitkide doğal olarak bulunan antioksidan, antiinflamatuvar ve antiapoptotik etkilere sahip bir flavanoiddir. Bu çalışmada, sodyum valproat kaynaklı mide doku hasarı üzerine doğal bir antioksidan olan rutinin kullanımı ve muhtemel etkilerinin araştırılması amaçlanmıştır. Gereç ve Yöntem 35 adet Wistar albino cinsi sıçan kontrol, rutin, sodyum valproat, sodyum valproat+rutin-50mg ve sodyum valproat+rutin-100mg grupları olmak üzere 5 gruba ayrıldı. 14 gün boyunca 500 mg/kg dozda sodyum valproat uygulamasıyla birlikte 50 veya 100 mg/ kg rutin uygulaması oral gavaj yolla yapıldı. 15. günde sıçanlar dekapite edilerek mide dokuları alındı. SOD, KAT, GPx aktiviteleri ile MDA, GSH seviyeleri ile oksidatif stres hasarı spektrofotormetrik yöntem ile analiz edildi. NF-κB, TNF-α, COX-2 ve MMP-9 transkripsiyon düzeyleri ile inflamasyon hasarı ve Bax, Bcl-2, Kaspaz-3 mRNA transkripsiyon düzeyleri ile apoptotik hasar analizi RT-PCR yöntemi ile analiz edildi. Ayrıca konjesyon, hemoraji, mukoza hasarı, hücre infiltrasyonu ve bez dilatasyonu açısından skorlama için hematoksilen-eozin boyama ile histolojik analizler yapıldı. Bulgular Mide dokularında kontrol grubuna göre sodyum valproat grubunda MDA düzeyi ile NF-κB, TNF-α, MMP-9, COX-2, Bax ve Kaspaz-3 mRNA transkripsiyon düzeyleri artmış (p<0.05), KAT, SOD, GPX aktiviteleri ile GSH düzeyi ve Bcl-2 mRNA transkripsiyon düzeyi azalmıştır (p<0.05). Rutin uygulamasıyla birlikte sodyum valproata bağlı tüm bu değişikliklerde tersi yönde aktivite meydana gelmiştir (p<0.05). Sonuç Mide dokularında sodyum valproat maruziyetinin neden olduğu toksik etkiye karşı rutinin potansiyel koruyucu özelliklere sahip olduğu sonucuna varıldı.

Anahtar Kelimeler:

Apoptoz, İnflamasyon, Mide Toksisitesi, Oksidatif stres, Rutin, Valproat

PROTECTIVE EFFECT OF RUTIN ON OXIDATIVE STRESS, INFLAMMATION AND APOPTOSIS IN VALPROAT-INDUCED GASTRIC TOXICITY

Objective Sodium valproate is one of the most commonly used antiepileptic drugs and is toxic after long-term exposure. Long-term exposure to sodium valproate causes an increase in oxidative stress and inflammation in tissues. Rutin is a flavonoid naturally found in many plants with antioxidant, anti-inflammatory, and antiapoptotic effects. This study aimed to investigate the use and possible outcomes of rutin, a natural antioxidant, on gastric tissue damage caused by sodium valproate. Material and Method 35 Wistar albino rats were divided into 5 groups: control, rutin, sodium valproate, sodium valproate+rutin-50mg, and sodium valproate+rutin-100mg. For 14 days, a 500 mg/kg dose of sodium valproate and 50 or 100 mg/kg of rutin were administered by oral gavage. On the 15th day, rats were decapitated and gastric tissues were removed. SOD, CAT, GPx activities, MDA, GSH levels, and oxidative stress damage were analyzed by spectrophotometric method. Inflammation damage by NF-κB, TNF-α, COX-2, and MMP-9 transcription levels and apoptotic damage by Bax, Bcl-2, and Caspase-3 mRNA transcription levels were analyzed by RT-PCR method. Histologic analysis with hematoxylin-eosin staining was also performed to score for congestion, hemorrhage, mucosal damage, cell infiltration and gland dilatation. Results In gastric tissues, MDA level and NF-κB, TNF-α, COX- 2, MMP-9, Bax and Caspase-3 mRNA transcription levels increased (p<0.05), CAT, SOD, GPX activities, GSH level and Bcl-2 mRNA transcription level decreased (p<0.05) in sodium valproate group compared to control group. Rutin administration resulted in a reversal of all these changes due to sodium valproate (p<0.05). Conclusion It was concluded that rutin has potential protective properties against the toxic effect of sodium valproate exposure in gastric tissues.

Keywords:

Valproate, Oxidative stress, Inflammation, Apoptosis, Gastric Toxicity, Rutin,

PDF

___

1. Ola OS, Adewole KE. Anticlastogenic and Hepatoprotective Effects of Kolaviron on Sodium Valproate-Induced Oxidative Toxicity in Wistar Rats. Egyptian Journal of Basic and Applied Sciences 2021;8(1):167-179
2. Adewole KE, Attah AF, Osawe SO. Exploring phytotherapeutic approach in the management of valproic acid-induced toxicity. Advances in Traditional Medicine. 2021:1-21. Doi: 10.1007/ s13596-021-00575-6
3. Kandemir FM, Ileriturk M, Gur C. Rutin Protects Rat Liver and Kidney From Sodium Valproate-İnduce Damage by Attenuating Oxidative Stress, ER Stress, Inflammation, Apoptosis And Autophagy. Mol Biol Rep 2022;49(7):6063-6074
4. Patel AR, Nagalli S. Valproate Toxicity. [Updated 2022 Nov 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih. gov/books/NBK560898/
5. Mei X, Wu HC, Ruan M, Cai LR. Acute Liver Failure With Thrombotic Microangiopathy Due To Sodium Valproate Toxicity: A Case Report. World J Clin Cases 2021;9(17):4310-4317
6. Sharma A, Sinha S, Narang A, Chouhan DK, Gupta S. Waddling Gait: A Complication of Valproate Therapy and a Thought Beyond Vitamin D Deficiency. Sultan Qaboos Univ Med J 2020;20(1):e104-e108
7. Caglayan C, Kandemir FM, Darendelioğlu E, Yıldırım S, Kucukler S, Dortbudak MB. Rutin Ameliorates Mercuric Chloride- Induced Hepatotoxicity in Rats via İnterfering with Oxidative Stress, Inflammation And Apoptosis. J Trace Elem Med Biol 2019;56:60-68
8. Kandemir FM, Caglayan C, Aksu EH, et al. Protective Effect of Rutin on Mercuric Chloride-Induced Reproductive Damage in Male Rats. Andrologia 2020;52(3):e13524
9. Caglayan C, Kandemir FM, Yildirim S, Kucukler S, Eser G. Rutin Protects Mercuric Chloride-Induced Nephrotoxicity via Targeting of Aquaporin 1 Level, Oxidative Stress, Apoptosis and İnflammation in Rats. J Trace Elem Med Biol. 2019;54:69-78
10. Çelik H, Kandemir FM, Caglayan C, et al. Neuroprotective Effect Of Rutin Against Colistin-Induced Oxidative Stress, Inflammation and Apoptosis in Rat Brain Associated with the CREB/ BDNF Expressions. Mol Biol Rep 2020;47(3):2023-2034
11. Placer ZA, Cushman LL, Johnson BC. Estimation of Product of Lipid Peroxidation (Malonyl Dialdehyde) in Biochemical Systems. Anal Biochem 1966;16(2):359–364
12. Sun Y, Oberley LW, Li Y. A Simple Method for Clinical Assay of Superoxide Dismutase. Clin Chem 1988;34(3):497–500
13. Aebi H. Catalase in Vitro. Methods Enzymol 1984;105:121–126
14. Lawrence RA, Burk RF. Glutathione Peroxidase Activity in Selenium-Deficient Rat Liver. Biochem Biophys Res Commun 1976;71(4)952–958
15. Sedlak J, & Lindsay RH. Estimation of Total, Protein-Bound, and Nonprotein Sulfhydryl Groups in Tissue with Ellman's Reagent. Anal Biochem 1968;25(1),192–205
16. Lowry OH, Rosebrough NJ, Farr AL, et al. Protein Measurement with the Folin Phenol Reagent. J Biol Chem 1951;193(1):265– 275
17. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods 2001;25(4):402-8
18. Soliman SS, Sedik GA, Elghobashy MR, Zaazaa HE, Saad AS. Greenness Assessment Profile of a Qbd Screen-Printed Sensor for Real-Time Monitoring of Sodium Valproate. Microchem J 2022;182:107859
19. Khani S, Hejazi SA, Yaghoubi M, Sharifipour E. Comparative Study of Magnesium, Sodium Valproate, and Concurrent Magnesium-Sodium Valproate Therapy in the Prevention of Migraine Headaches: A Randomized Controlled Double-Blind Trial. J Headache Pain 2021;22(1):21
20. Badria FA, Fayed HA, Ibraheem AK, State AF, Mazyed EA. Formulation of Sodium Valproate Nanospanlastics as a Promising Approach for Drug Repurposing in the Treatment of Androgenic Alopecia. Pharmaceutics. 2020;12(9):866. doi:10.3390/pharmaceutics12090866
21. Gur C, Kandemir FM. Molecular and Biochemical Investigation of the Protective Effects of Rutin Against Liver and Kidney Toxicity Caused by Malathion Administration in a Rat Model. Environ Toxicol 2022;10.1002/tox.23700
22. Aksu EH, Kandemir FM, Özkaraca M, et al. Rutin Ameliorates Cisplatin-Induced Reproductive Damage via Suppression of Oxidative Stress and Apoptosis in Adult Male Rats. Andrologia 2017;49(1),10.1111/and.12593
23. Çelik H, Kucukler S, Çomaklı S, et al. Morin Attenuates Ifosfamide-Induced Neurotoxicity in Rats via Suppression of Oxidative Stress, Neuroinflammation and Neuronal Apoptosis. Neurotoxicology 2020;76:126-137
24. Gur C, Kandemir O, Kandemir FM. Investigation of the Effects of Hesperidin Administration on Abamectin‐Induced Testicular Toxicity in Rats Through Oxidative Stress, Endoplasmic Reticulum Stress, Inflammation, Apoptosis, Autophagy, and JAK2/ STAT3 Pathways. Environ Toxicol 2022;37(3):401-412
25. Alev-Tüzüner, B., Tunalı, S., Üstündağ, Ü.V., İpekçi, H., Emekli- Alturfan, E.,Tunalı-Akbay, T., Yanardağ, R., Yarat, A. (2023). Chard extract increased gastric sialic acid and ameliorated oxidative stress in valproic acid-administered rats. Food and Health, 9(2), 139-147. https://doi.org/10.3153/FH23013
26. Kandemir FM, Yıldırım S, Kucukler S, et al. Protective Effects of Morin Against Acrylamide-Induced Hepatotoxicity and Nephrotoxicity: a Multi-Biomarker Approach. Food Chem Toxicol 2020;138:111190
27. Öz M, Şimşek H. The Antinociceptive Effect Of Adalimumab, a TNF-Alpha Inhibitor, in a Mice Model of Inflammatory Pain. Türk Doğa ve Fen Dergisi 2020;11(3):89-93
28. Elshawi OE, Nabeel AI. Modulatory Effect of a New Benzopyran Derivative via COX-2 Blocking and Down Regulation of NF-Κb Against T-Radiation Induced-Intestinal Inflammation. J Photochem Photobiol B 2019;192:90-96
29. Silva NJ, Nagashima M, Li J, et al. Inflammation and Matrix Metalloproteinase 9 (Mmp-9) Regulate Photoreceptor Regeneration in Adult Zebrafish. Glia 2020;68(7):1445-1465
30. Ekinci-Akdemir FN, Bingöl Ç, Yıldırım S, et al. The Investigation of the Effect of Fraxin on Hepatotoxicity Induced by Cisplatin in Rats. Iran J Basic Med Sci 2020;23(11):1382
31. Simsek H, Akaras N. Acacetin ameliorates acetylsalicylic acid-induced gastric ulcer in rats by interfering with oxidative stress, inflammation, and apoptosis. International Journal of Medical Biochemistry, 2023;6(2), 96-103.
32. Akcılar R, Akcılar A, Koçak C, et al. Effects of Ukrain on Intestinal Apoptosis Caused by Ischemia-Reperfusion Injury in Rats. Int J Clin Exp Med 2015;8(12):22158–22166
33. Şimşek H, Demiryürek Ş, Demir T, et al. Assessment of Expressions of Bcl-Xl, B-FGF, Bmp-2, Caspase-3, PDGFR-Α, Smad1 and TGF-Β1 Genes in a Rat Model of Lung Ischemia/Reperfusion. Iran J Basic Med Sci 2016;19(2):209
34. Kuzu M, Kandemir FM, Yildirim S, et al. Morin Attenuates Doxorubicin-Induced Heart and Brain Damage by Reducing Oxidative Stress, Inflammation and Apoptosis. Biomedicine & Pharmacotherapy 2018;106:443-453
35. Çelik H, Kandemir FM, Caglayan C, et al. Neuroprotective effect of rutin against colistin-induced oxidative stress, inflammation and apoptosis in rat brain associated with the CREB/BDNF expressions. Molecular biology reports, 2020;47:2023-2034