Metotreksat kaynaklı beyin hasarına karşı bromelainin potansiyel faydalı etkilerinin araştırılması

Yıl 2021, Cilt: 14 Sayı: 4, 846 - 853, 01.10.2021

Kürşat Kaya Ali Gürel Volkan İpek

https://doi.org/10.31362/patd.912469

Cited By: 1

Öz

Amaç: Metotreksat, bazı kanser türleri ve romatoid artrit başta olmak üzere çeşitli hastalıkların tedavisinde kullanılan bir folik asit antagonistidir. Ancak, metotreksat kullanımıyla birlikte görülen ve nörotoksisiteyi de içeren birçok yan etki önemli bir klinik problemdir. Ananas bitkisinden elde edilen bromelain, radikal süpürücü ve lipit peroksidasyonu önleyici etkileri olan enzimatik bir karışımdır.

Gereç ve Yöntem: 28 adet rat rastgele 4 gruba bölündü (n=7). Birinci grup kontrol grubu olarak tutuldu. İkinci grup bromelain grubu olarak belirlendi ve bu gruptaki ratlara 14 gün boyunca 200 mg/kg/gün bromelain verildi. Üçüncü grup metotreksat grubu olarak belirlendi ve bu gruptaki ratlara üçüncü gün tek doz 20 mg/kg metotreksat verildi. Dördüncü grup metotreksat+bromelain grubu olarak belirlendi ve gruptaki ratlara metotreksat ve bromelain eşdeğer dozlarda birlikte verildi.

Bulgular: Metotreksat uygulaması gruplar arasında tiyobarbitürik asit reaktif substans seviyeleri açısından herhangi bir değişikliğe neden olmadı ancak redükte glutatyon seviyesinde ve süperoksit dismutaz, glutatyon peroksidaz ve katalaz aktivitelerinde kontrol grubu ile karşılaştırıldığında istatistiksel olarak anlamlı bir azalmaya neden oldu. Metotreksat ile birlikte bromelain uygulanması redükte glutatyon seviyesini ve süperoksit dismutaz aktivitesini metotreksat grubu ile karşılaştırıldığında anlamlı şekilde arttırdı ancak glutatyon peroksidaz ve katalaz aktivitelerindeki artış istatistiki olarak anlamlı değildi. Beyin dokusu histolojik açıdan da değerlendirildi. metotreksat uygulamasının beyinde histopatolojik olarak belirgin bir lezyon oluşumuna yol açmadığı görüldü.
Sonuç: Bulgularımız bromelain kullanımının nörolojik hasara karşı metotreksat ile tedavi edilen hastalarda fayda sağlayabileceğini desteklemektedir.

Anahtar Kelimeler

metotreksat,, bromelain, beyin hasarı, oksidatif stres

Investigation of potential beneficial effects of bromelain against methotrexate-induced brain injury

Öz

Abstract
Purpose: Methotrexate is a folic acid antagonist used in the treatment of various diseases, especially some types of cancer and rheumatoid arthritis. However, many side effects associated with methotrexate use, including neurotoxicity, are an important clinical problem. Bromelain obtained from the pineapple plant is an enzymatic mixture with radical scavenging and anti-lipid peroxidation effects.

Materials and methods: 28 rats were randomly divided into 4 groups (n=7). The first group was kept as the control group. The second group was determined as the bromelain group and 200 mg/kg/day bromelain was given to the rats in this group for 14 days. The third group was determined as methotrexate group and a single dose of 20 mg/kg methotrexate was given to the rats in this group on the third day. The fourth group was determined as methotrexate + bromelain group, and the rats in the group were given methotrexate and bromelain in equivalent doses together.

Results: Methotrexate administration did not cause any change in thiobarbituric acid reactive substance levels among groups, but caused a statistically significant decrease in reduced glutathione level and superoxide dismutase, glutathione peroxidase and catalase activities compared to the control group. The administration of bromelain with methotrexate significantly increased the reduced glutathione level and superoxide dismutase activity compared to the methotrexate group, but the increase in glutathione peroxidase and catalase activities was not statistically significant. Brain tissue was also evaluated histologically. It was observed that methotrexate administration did not cause a significant lesion formation in the brain histopathologically.

Conclusion: Our findings support that the use of bromelain may benefit patients treated with methotrexate against neurological damage.
Keywords: Methotrexate, bromelain, brain injury, oxidative stress.

Anahtar Kelimeler

Methotrexate, bromelain, brain injury, oxidative stress

Kaynakça

• 1. Hafez HM, Ibrahim MA, Ibrahim SA, Amin EF, Goma W, Abdelrahman AM. Potential protective effect of etanercept and aminoguanidine in methotrexate-induced hepatotoxicity and nephrotoxicity in rats. Eur J Pharmacol 2015;768:1-12. http://dx.doi.org/10.1016/j.ejphar.2015.08.047
• 2. Sun J, Sugiyama A, Inoue S, Takeuchi T, Furukawa S. Effect of methotrexate on neuroepithelium in the rat fetal brain. J Vet Med Sci 2014;76:347-354.
• 3. Howard SC, McCormick J, Pui C, Buddington RK, Harvey RD. Preventing and managing toxicities of high‐dose methotrexate. Oncologist 2016;21:1471-1482.
• 4. Campbell JM, Bateman E, Peters MDJ, Bowen JM, Keefe DM, Stephenson MD. Fluoropyrimidine and platinum toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Pharmacogenomics 2016;17:435–451.
• 5. Bernsen EC, Hagleitner MM, Kouwenberg TW, Hanff LM. Pharmacogenomics as a tool to limit acute and long-term adverse effects of chemotherapeutics: an update in pediatric oncology. Front Pharmacol 2020;11:1-19.
• 6. Leite RA, Vosgrau JS, Cortez Neto L, et al. Brainstem auditory pathway of children with acute lymphoid leukemia on chemotherapy with methotrexate. Arq Neuropsiquiatr 2020;78:63-69.
• 7. El-Demerdash FM, Baghdadi HH, Ghanem NF, Mhanna ABA. Nephroprotective role of bromelain against oxidative injury induced by aluminium in rats. Environ Toxicol Pharmacol 2020;80:103509. https://doi.org/10.1016/j.etap.2020.103509
• 8. Pavan R, Jain S, Shraddha, Kumar A. Properties and therapeutic application of bromelain: a review. Biotechnol Res Int 2012;2012:1-6.
• 9. White RR, Crawley FEH, Vellini M, Rovati LA. Bioavailability of 125I bromelain after oral administration to rats. Biopharm Drug Dispos 1988;9:397-403.
• 10. Castell J V., Friedrich G, Kuhn CS, Poppe GE. Intestinal absorption of undegraded proteins in men: presence of bromelain in plasma after oral intake. Am J Physiol - Gastrointest Liver Physiol 1997;273(1 36-1).
• 11. Ataide JA, De Carvalho NM, Rebelo MDA, et al. Bacterial nanocellulose loaded with bromelain: assessment of antimicrobial, antioxidant and physical-chemical properties. Sci Rep 2017;7:2-10.
• 12. Jebur AB, El-Demerdash FM, Kang W. Bromelain from Ananas comosus stem attenuates oxidative toxicity and testicular dysfunction caused by aluminum in rats. J Trace Elem Med Biol 2020;62:126631. https://doi.org/10.1016/j.jtemb.2020.126631 13. Yagi K. Simple assay for the level of total lipid peroxides in serum or plasma. Methods Mol Biol 1998;108:101-106.
• 14. Ighodaro OM, Akinloye OA. First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): their fundamental role in the entire antioxidant defence grid. Alexandria J Med 2018;54:287-93. https://doi.org/10.1016/j.ajme.2017.09.001
• 15. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem 1988;34:497–500.
• 16. Aebi H. Catalase. Methods Enzym Anal 1974;673-684.
• 17. Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 1967;70:158-169.
• 18. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 1968;25:192-205.
• 19. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. The folin by oliver. Readings 1951;193:265-275.
• 20. Wang W, Zhou H, Liu L. Side effects of methotrexate therapy for rheumatoid arthritis: a systematic review. Eur J Med Chem 2018;158:502-516. https://doi.org/10.1016/j.ejmech.2018.09.027
• 21. Şener G, Ekşioğlu-Demiralp E, Çetiner M, Ercan F, Yeğen B. β-glucan ameliorates methotrexate-induced oxidative organ injury via its antioxidant and immunomodulatory effects. Eur J Pharmacol 2006;542:170-178. https://doi: 10.1016/j.ejphar.2006.02.056
• 22. Abdel-Daim MM, Khalifa HA, Abushouk AI, Dkhil MA, Al-Quraishy SA. Diosmin attenuates methotrexate-ınduced hepatic, renal, and cardiac ınjury: a biochemical and histopathological study in mice. Oxid Med Cell Longev 2017;2017:3281670. https://doi: 10.1155/2017/3281670
• 23. Pınar N, Çakırca G, Özgür T, Kaplan M. The protective effects of alpha lipoic acid on methotrexate induced testis injury in rats. Biomed Pharmacother 2018;97:1486-1492.
• 24. Yang M, Kim JS, Kim J, et al. Acute treatment with methotrexate induces hippocampal dysfunction in a mouse model of breast cancer. Brain Res Bull 2012;89:50–56. http://dx.doi.org/10.1016/j.brainresbull.2012.07.003
• 25. Rollins N, Winick N, Bash R, Booth T. Acute methotrexate neurotoxicity: findings on diffusion-weighted imaging and correlation with clinical outcome. Am J Neuroradiol 2004;25:1688-1695.
• 26. Bhojwani D, Sabin ND, Pei D, et al. Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol 2014;32:949-959.
• 27. Pınar N, Kaplan M, Özgür T, Özcan O. Ameliorating effects of tempol on methotrexate-induced liver injury in rats. Biomed Pharmacother 2018;102:758-764.
• 28. Uzar E, Koyuncuoglu HR, Uz E, et al. The activities of antioxidant enzymes and the level of malondialdehyde in cerebellum of rats subjected to methotrexate: protective effect of caffeic acid phenethyl ester. Mol Cell Biochem 2006;291:63-68.
• 29. Sirichoat A, Krutsri S, Suwannakot K, et al. Melatonin protects against methotrexate-induced memory deficit and hippocampal neurogenesis impairment in a rat model. Biochem Pharmacol 2019;163:225-233. https://doi.org/10.1016/j.bcp.2019.02.010
• 30. Kumar GP, Khanum F. Neuroprotective potential of phytochemicals. Pharmacognosy Reviews 2012;6:81-90. https://doi: 10.4103/0973-7847.99898
• 31. Fikry EM, Hassan WA, Gad AM. Bone marrow and adipose mesenchymal stem cells attenuate cardiac fibrosis induced by methotrexate in rats. J Biochem Mol Toxicol 2017;31:11. https://doi: 10.1002/jbt.21970
• 32. Vardi N, Parlakpinar H, Ates B. Beneficial effects of chlorogenic acid on methotrexate-induced cerebellar Purkinje cell damage in rats. J Chem Neuroanat 2012;43:43–47. http://dx.doi.org/10.1016/j.jchemneu.2011.09.003
• 33. Kushwaha S, Tripathi DN, Vikram A, Ramarao P, Jena GB. Evaluation of multi-organ DNA damage by comet assay from 28 days repeated dose oral toxicity test in mice: a practical approach for test integration in regulatory toxicity testing. Regul Toxicol Pharmacol 2010;58:145-154. http://dx.doi.org/10.1016/j.yrtph.2010.05.004
• 34. Asci H, Ozmen O, Ellidag HY, Aydin B, Bas E, Yilmaz N. The impact of gallic acid on the methotrexate-induced kidney damage in rats. J Food Drug Anal 2017;25:890–897. https://doi.org/10.1016/j.jfda.2017.05.001
• 35. Agarwal S, Chaudhary B, Bist R. Bacoside A and bromelain relieve dichlorvos induced changes in oxidative responses in mice serum. Chem Biol Interact 2016;254:173–178. http://dx.doi.org/10.1016/j.cbi.2016.05.017
• 36. Sugiyama A, Sun J, Ueda K, Furukawa S, Takeuchi T. Effect of methotrexate on cerebellar development in infant rats. J Vet Med Sci 2015;77:789–797.
• 37. Hirako A, Furukawa S, Takeuchi T, Sugiyama A. Effect of methotrexate exposure at late gestation on development of telencephalon in rat fetal brain. J Vet Med Sci 2016;78:213-220.
• 38. Elens I, Dekeyster E, Moons L, D’Hooge R. Methotrexate affects cerebrospinal fluid folate and tau levels and ınduces late cognitive deficits in mice. Neuroscience 2019;404:62–70. https://doi.org/10.1016/j.neuroscience.2019.01.024