The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury
Yıl: 2023 Cilt: 39 Sayı: 2 Sayfa Aralığı: 84 - 91 Metin Dili: İngilizce DOI: 10.30733/std.2023.01643 İndeks Tarihi: 04-07-2023
The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury
Öz: Aim: The present study aimed to investigate the effects of topiramate on pancreatic islets of Langerhans cells in Methotrexate-related pancreatic injury. Materials and Methods: The study was conducted between 04 July - 24 July 2022 in the Animal Research Unit of Recep Tayyip Erdogan University. Male Spraque-Dawley rats were divided into 3 groups with 8 animals in each group. Control group (C) (Only 0.9% saline was administered). A single dose of 20mg/ kg Methotrexate was administered to the MTX group (MTX). The TPM group (TPM) was administered 100 mg/kg/day Topiramate by oral gavage for a total of 14 days, 7 days before and after Methotrexate administration. All subjects were euthanized by anesthesia 16 hours after the last Topiramate dose. Results: We observed widespread edematous areas and necrotic cells in the islets of Langerhans in the MTX. We found that necrotic cells and edematous areas were decreased in the TPM compared to the MTX. We found fewer β cells showing insulin positivity in the MTX compared to the controls (p<0.05). We observed an increase in insulin-positive β-cells in the TPM compared to the MTX (p<0.05). We observed a significant decrease in the number of cells showing glucagon positivity in the MTX compared to the controls (p<0.05). We observed an increased number of α cells showing glucagon positivity in the TPM compared to the MTX (p<0.05). We found that the HDS increased from 0(0-1) in the control group to 6(6-8) in the MTX (p<0.05). It was found as 2(2-3) in the TPM (p<0.05). Conclusion: Our study shows that topiramate has a protective effect on pancreatic islet cells.
Anahtar Kelime: Topiramatın Metotreksat İlişkili Pankreas Hasarı Üzerine Etkisi
Öz: Amaç: Bu çalışmada metotreksat ilişkili pankreas hasarında topiramatın pankreasın Langerhans adacık hücreleri üzerine olan etkisinin araştırılması amaçlandı. Gereçler ve Yöntem: Çalışma 04 Temmuz- 24 Temmuz 2022 tarihinde Recep Tayyip Erdoğan Üniversitesi Hayvan Deneyleri ünitesinde gerçekleştirilmiştir. Çalışmada Spraque-Dawley erkek sıçanlar her grupta 8 hayvan olacak şekilde 3 gruba ayrıldı. Kontrol grubuna ait sıçanlara sadece %0.9’luk serum fizyolojik intraperiteonal (i.p.) olarak uygulandı. Metotreksat (MTX) grubuna tek doz 20mg/kg MTX uygulandı. Topiramat (TPM) tedavi grubuna MTX uygulamasından 7 gün önce ve 7 gün sonra olmak üzere toplam 14 gün süreyle günde tek doz TPM 100 mg/kg/gün oral gavaj yoluyla uygulandı. TPM uygulamasından 7 gün, son dozdan 16 saat sonra tüm denekler 50 mg/kg ketamin HCL ve 20 mg/kg ksilazin i.p. uygulanarak uyutuldu. Bulgular: MTX grubunda Langerhans adacıklarında yaygın ödematöz alanlar ve nekrotik hücreler gözlemledik. TPM grubunda MTX grubuna kıyasla nekrotik hücrelerin ve ödematöz alanların azaldığını saptadık. MTX grubunda insulin pozitivitesi gösteren β hücrelerinin kontrol grubuna kıyasla azalmış olduğunu saptadık (p<0.05). TPM grubundaki pankreas dokusuna ait kesitlerde MTX grubuna kıyasla insülin pozitivitesi gösteren β hücrelerinde anlamlı düzeyde artış olduğunu gözlemledik (p<0.05). MTX grubunda kontrol grubuna kıyasla glukagon pozitivitesi gösteren hücrelerin sayısında anlamlı olarak azalma olduğunu izledik (p<0.05). TPM grubunda MTX grubuna kıyasla glukagon pozitivitesini gösteren α hücrelerinin sayısının artmış olduğunu gözlemledik (p<0.05). Histopatolojik Hasar Skoru kontrol grubunda 0(0-1), MTX grubunda 6(6-8)’ya yükseldiğini saptadık (p<0.05). TPM grubunda HHS 2(2-3) olarak gözlemlendi (p<0.05). Sonuç: Çalışmamız topiramatın pankreas adacık hücreleri üzerinde koruyucu bir etkiye sahip olduğunu göstermektedir.
Anahtar Kelime: Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık
- 1. Nasr KY, Al Rabiah KA, Al SS, et al. Profiles of Drug Substances, Excipients and Related Methodology. In: Brittain HG, ed. Topiramate: Comprehensive profile. London: Elsevier (Inc.), 2020:333-77.
- 2. Cerine CH, Ljung H, Brodtkorb H, et al. Mechanisms underlying aggressive behavior induced by antiepileptic drugs: Focus on topiramate, levetiracetam, and perampanel. Behav Neurol 2018;2018:1-18.
- 3. Kheng GK, Chen CH, Lu ML. Topiramate mitigates weight gain in antipsychotic-treated patients with schizophrenia: Meta-analysis of randomised controlled trials. Int J Psychiatry Clin Pract 2019;23(1):14-32.
- 4. Frédéric P, Deshaies Y, Lalonde J, et al. Topiramate reduces energy and fat gains in lean (Fa/?) and obese (fa/fa) Zucker rats. Obes Res 2000;8:656-63.
- 5. Jason WJ, Nelson E, Osborne M, et al. Topiramate is an insulin-sensitizing compound in vivo with direct effects on adipocytes in female ZDF rats. Am J Physiol Endocrinol Metab 2005;288:617-25.
- 6. Eliasson, B, Gudbjörnsdottir S, Cederholm J, et al. Weight loss and metabolic effects of topiramate in overweight and obese type 2 diabetic patients: Randomized double-blind placebo-controlled trial. Int J Obes 2007;31:1140-47.
- 7. Chengappa R, Levine KNJ, Rathore D, et al. Long-term effects of topiramate on bipolar mood instability, weight change and glycemic control: A case-series. Eur Psychiatry 2001;16:186-90.
- 8. Francesca F, Chaffard G, Berwaer M, et al. The antiepileptic drug topiramate preserves metabolism-secretion coupling in insulin secreting cells chronically exposed to the fatty acid oleate. Biochem Pharmacol 2006;72:965-73.
- 9. Yin L, Chen X, Osborne M, et al. Topiramate ameliorates hyperglycaemia and improves glucose-stimulated insulin release in ZDF rats and db/db mice. Diabetes Obes Metab 2005;7:360-9.
- 10. Kim R, Boergesen M, Rubi B, et al. Peroxisome proliferatoractivated receptor α (PPARα) potentiates, whereas PPARγ attenuates, glucose-stimulated insulin secretion in pancreatic β-cells. Endocrinology 2005;146:3266-76.
- 11. Kudin AP, Debska-Vielhaber G, Vielhaber S, et al. The mechanism of neuroprotection by topiramate in an animal model of epilepsy. Epilepsia 2004;45:1478-87.
- 12. Celik K. Effects of antiepileptic drugs on experimental acute necrotizing pancreastitis in rats. Doctoral Thesis, Karadeniz Technical University, 2010.
- 13. Nabil SA. Effects of topiramate on diabetes mellitus induced by streptozotocin in rats. Eur J Pharmacol 2012;684:161-7.
- 14. Schafranski MD, Merlini AB, Chaves de Araújo EA, et al. Methotrexate: Update on pharmacology, clinical applications and warnings. New York: Nova Science Publishers (Inc.), 2012;13-23.
- 15. Rondon F, Mendez O, Spinel N, et al. Methotrexateinduced pulmonary toxicity in psoriatic arthritis (PsA): Case presentation and literature review. Clin Rheumatol 2011;30:1379-84.
- 16. Jared CM, Bateman E, Stephenson MD, et al. Methotrexateinduced toxicity pharmacogenetics: An umbrella review of systematic reviews and metaanalyses. Cancer Chemother Pharmacol 2016;78(1):27-39.
- 17. Freeman-Narrod M, Narrod SA. Chronic toxicity of methotrexate in mice. J Natl Cancer Inst1977;58:735-41.
- 18. Wang W, Zhou H, Liu L. Side effects of methotrexate therapy for rheumatoid arthritis: A systematic review. Eur J Med Chem 2018;158:502-16.
- 19. Mehrzadi S, Fatemi I, Esmaeilizadeh M, et al. Hepatoprotective effect of berberine against methotrexate induced liver toxicity in rats. Biomed Pharmacothe 2018;97:233-9.
- 20. Celle G, Dodero M, Pannacciulli I, et al. Methotrexate effects on enteric mucosa liver and pancreas of normal and bled rats. Eur J Cancer 1975;11:317-20.
- 21. Mercantepe T, Kalkan Y, Tumkaya L, et al. Protective effects of tumor necrosis factor alpha inhibitors on methotrexateinduced pancreatic toxicity. Adv Clin Exp Med 2018;27(6):715-20.
- 22. Jaykaran C, Kantharia N. How to calculate sample size in animal studies? J Pharmacol Pharmacother 2013;4:303-6.
- 23. Baruch JD, Donovan A, Webster PM, et al. Methotrexateinduced pulmonary toxicity. Can Respir J 2013;20:153-5.
- 24. Cure, E, Cure MC, Tumkaya L, et al. Topiramate ameliorates abdominal aorta cross-clamping induced liver injury in rats. Saudi J Gastroenterol 2014;20:297-303.
- 25. Kurt A, Kalkan Y, Turut H, et al. Topiramate reduces aortic cross-clamping-induced lung injury in male rats. Acta medica (Hradec Kralove) 2018;61:144-9.
- 26. Schmidt J, Rattner DW, Lewandrowski K, et al. A better model of acute pancreatitis for evaluating therapy. Ann Surg 1992;215:44-56.
- 27. Krymchantowski A, Tavares C. Weight variations in patients receiving topiramate migraine prophylaxis in a tertiary care setting. MedGenMed 2004;6:48.
- 28. Bailey SJ, Magalie AR, Rutter GA. Glucose-dependent regulation of γ-aminobutyric acid (GABA A) receptor expression in mouse pancreatic islet α-cells. Diabetes 2007;56:320-7.
- 29. Brice, NL, Varadi AS, Ashcroft JH, et al. Metabotropic glutamate and GABAB receptors contribute to the modulation of glucose-stimulated insulin secretion in pancreatic beta cells. Diabetologia 2002;45:242-52.
- 30. Park HJ, Kim HJ, Park HJ, et al. Protective effect of topiramate on kainic acid-induced cell death in mice hippocampus. Epilepsia 2008;49:163-7.
- 31. Masini E, Carta F, Scozzafava A, et al. Antiglaucoma carbonic anhydrase inhibitors: A patent review. Expert Opin Ther Pat 2013;23:705-16.
- 32. Niebauer M, Gruenthal M. Topiramate reduces neuronal injury after experimental status epilepticus. Brain Res 1999;837:263-9.
- 33. Kurul SH, Yi U, Kumral A, et al. Protective effects of topiramate against hyperoxic brain injury in the developing brain. Neuropediatrics 2009;40:22-7.
| APA | Mercantepe F, Tumkaya L (2023). The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury. , 84 - 91. 10.30733/std.2023.01643 |
| Chicago | Mercantepe Filiz,Tumkaya Levent The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury. (2023): 84 - 91. 10.30733/std.2023.01643 |
| MLA | Mercantepe Filiz,Tumkaya Levent The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury. , 2023, ss.84 - 91. 10.30733/std.2023.01643 |
| AMA | Mercantepe F,Tumkaya L The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury. . 2023; 84 - 91. 10.30733/std.2023.01643 |
| Vancouver | Mercantepe F,Tumkaya L The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury. . 2023; 84 - 91. 10.30733/std.2023.01643 |
| IEEE | Mercantepe F,Tumkaya L "The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury." , ss.84 - 91, 2023. 10.30733/std.2023.01643 |
| ISNAD | Mercantepe, Filiz - Tumkaya, Levent. "The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury". (2023), 84-91. https://doi.org/10.30733/std.2023.01643 |
| APA | Mercantepe F, Tumkaya L (2023). The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury. Selçuk Tıp Dergisi, 39(2), 84 - 91. 10.30733/std.2023.01643 |
| Chicago | Mercantepe Filiz,Tumkaya Levent The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury. Selçuk Tıp Dergisi 39, no.2 (2023): 84 - 91. 10.30733/std.2023.01643 |
| MLA | Mercantepe Filiz,Tumkaya Levent The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury. Selçuk Tıp Dergisi, vol.39, no.2, 2023, ss.84 - 91. 10.30733/std.2023.01643 |
| AMA | Mercantepe F,Tumkaya L The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury. Selçuk Tıp Dergisi. 2023; 39(2): 84 - 91. 10.30733/std.2023.01643 |
| Vancouver | Mercantepe F,Tumkaya L The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury. Selçuk Tıp Dergisi. 2023; 39(2): 84 - 91. 10.30733/std.2023.01643 |
| IEEE | Mercantepe F,Tumkaya L "The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury." Selçuk Tıp Dergisi, 39, ss.84 - 91, 2023. 10.30733/std.2023.01643 |
| ISNAD | Mercantepe, Filiz - Tumkaya, Levent. "The Effects of Topiramate on Methotrexate- Induced Pancreatic Injury". Selçuk Tıp Dergisi 39/2 (2023), 84-91. https://doi.org/10.30733/std.2023.01643 |
