Yüksek doz gentamisin verilen sıçanlarda rosmarinik asidin koruyucu etkisinin araştırılması

Amaç: Gentamisin, mikroorganizmaların neden olduğu enfeksiyonları tedavi etmek için kullanılan bir antibiyotiktir. İlaçların neden olduğu toksik etkilere karşı antioksidan koruyucular kullanılarak endojen antioksidanlar güçlendirilir. Rosmarinik asit antioksidan, antienflamatuar, antiapoptotik ve antitümör etkilere sahiptir. Çalışmamızda rosmarinik asidin sıçanlarda gentamisin ile indüklenen nefrotoksisiteye karşı koruyucu etkisini, immünohistokimyasal değişiklikleri, oksidatif belirteçleri, histopatolojik değişiklikleri ve enflamasyona bağlı Ifi44 ekspresyonunu araştırmayı amaçladık. Gereç ve yöntem: Çalışmamızda 32 rat rastgele 4 gruba ayrıldı. Bu gruplar kontrol grubu, gentamisin grubu 100 mg/kg/gün gentamisin verildi, gentamisin + rosmarinik asit grubu gentamisin 100 mg/kg/gün ve rosmarinik asit 50 mg/kg/gün verildi, rosmarinik asit grubu rosmarinik asit 50 mg/kg/gün verildi. Çalışma sonunda böbrek dokularındaki histopatolojik, immünohistokimyasal ve biyokimyasal değişiklikler değerlendirildi. Bulgular: Rosmarinik asit, kan serumunda kreatin, üre, kan üre nitrojeni ve toplam oksidatif stresi azaltmıştır. Gentamisinin toksik etkisi böbreklerde ciddi histopatolojik değişikliklere neden olmuştur. Gentamisin + rosmarinik asit grubunda histopatolojik değişikliklerde hafif bir azalma gözlendi. Antiproliferatif Ifi44 ekspresyonu gentamisin grubunda ve gentamisin + rosmarinik asit grubunda daha yüksekti. Sonuç: Rosmarinik asit uygulaması sonucunda oksijen radikallerinde azalma ve antioksidan düzeylerinde artış gözlendi. Gentamisin ve rosmarinik asit birlikte kullanıldığında rosmarinik asidin koruyucu etkisi kısmen gözlenmiştir ancak tam koruma sağlayamamıştır.

Anahtar Kelimeler:

Gentamisin, rosmarinik asit, Ifi44, sıçan

Investigation of the protective effect of rosmarinic acid in rats given high dose gentamicin

Purpose: Gentamicin is an antibiotic, used to treat infections caused by microorganisms. Endogenous antioxidants are strengthened by using antioxidant protectors against the toxic effects caused by drugs. Rosmarinic acid has antioxidative, anti-inflammatory, antiapoptotic, and antitumoral effects. In our study, we aimed to investigate the protective effect, immunohistochemical changes, oxidative markers, histopathological changes and inflammation related Ifi44 expression of rosmarinic acid against gentamicin induced nephrotoxicity in rats. Materials and methods: In our study, 32 rats randomly divided into four groups. These groups are consisted of control group, gentamicin group received gentamicin 100 mg/kg/day, gentamicin + rosmarinic group acid received gentamicin 100 mg/kg/day and rosmarinic acid 50 mg/kg/day, and rosmarinic acid group received rosmarinic acid 50 mg/kg/day. At the end of the study, histopathological, immunohistochemical, and biochemical changes in kidney tissues evaluated. Results: Rosmarinic acid reduced creatine, urea, blood urea nitrogen, and total oxidative stress in blood serum. The toxic effect of gentamicin caused severe histopathological changes in the kidneys. A slight decrease in histopathological changes observed in the gentamicin + rosmarinic acid group. Antiproliferative Ifi44 expression was higher in the gentamicin group and gentamicin + rosmarinic acid group. Conclusion: As a result of the application of rosmarinic acid, a decrease in oxygen radicals and an increase in antioxidant levels observed. When used in combination with gentamicin and rosmarinic acid, the protective effect of rosmarinic acid was partially observed, but it could not provide full protection.

Keywords:

Gentamicin, rosmarinic acid, Ifi44, rat,

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1. Ali BH, AI Za’abi M, Blunden G, Nemmar A. Experimental gentamicin nephrotoxicity and agents that modify it: a mini-review of recent research. Basic Clin Pharmacol Toxicol 2011;109:225-232. https://doi. org/10.1111/j.1742-7843.2011.00728.x
2. Lenoir M, Marot M, Uziel A. Comparative ototoxicity of four aminoglycosidic antibiotics during the critical period of cochlear development in the rat. A functional and structural study. Acta Otolaryngol Suppl 1983;405:1- 16. https://doi.org/ 10.3109/00016488309105593
3. Vera Roman J, Krishnakantha TP, Cuppage FE. Gentamicin nephrotoxicitiy in rats. I. Acute biochemical and ultrastructural effects. Lab İnvest 1975;33:412- 417.
4. Geleilete TJ, Melo GC, Costa RS, Volpini RA, Soares TJ, Coimbra TM. Role of myofibroblasts, macrophages, transforming growth factor-beta endothelin, angiotensin-ll, and fibronectin in the progression of tubulointerstitial nephritis induced by gentamicin. J Nephrol 2002;15:633-642.
5. Yaman O, Balikci E. Protective effects of nigella sativa against gentamicin-induced nephrotoxicitiy in rats. ExpToxicol Pathol 2009;62:183-90. https://doi. org/10.1016/j.etp.2009.03.006
6. Lee KE, Kim EY, Kim CS, et al. Macrophage stimulating protein attenuates gentamicin-induced iniammation and apoptosis in human renal proximal tubular epithelial cells. Biochem Biophys Res Commun 2013;434:527- 533. https://doi.org/10.1016/j.bbrc.2013.03.108
7. Monteiro HS, Silva JA, Vieira PC, et al. Gingerol fraction from Zingiber officinale protects against gentamicin-induced nephrotoxicity. Antimicrob Agents Chemother 2014;58:1872-1878. http://doi.org/10.1128/ AAC.02431-13
8. Brewer MS. Natural antioxidants: sources, compounds, mechanisms of action, and potential applications. Compr Rev Food Sci Food Saf 2011;10:221-247. https://doi.org/10.1111/j.1541-4337.2011.00156.x
9. Bakirel T, Bakirel U, Keles OU, Ulgen SG, Yardibi H. In vivo assessment of antidiabetic and antioxidant activities of rosemary (Rosmarinus officinalis) in alloxandiabetic rabbits. J Ethnopharmacol 2008;116:64-73. https://doi.org/10.1016/j.jep.2007.10.039
10. Lee HJ, Cho HS, Seung EP, et al. Rosmarinic acid protects human Gannergic neuronal cells against hydrogen peroxide-induced apoptosis. Toxicology. 2008; 250:109-115. https://doi.org/10.1016/j. tox.2008.06.010
11. Venkatachalam K, Gunasekaran S, Jesudoss VA, Namasivayam N. The effect of rosmarinic acid on 1,2-dimethylhydrazine induced colon carcinogenesis. Exp Toxicol Pathol 2013;65:409-418. https://doi. org/10.1016/j.etp.2011.12.005
12. Amoah SK, Sandjo LP, Kratz JM, Biavatti MW. Rosmarinic acid-pharmaceutical and clinical aspects. Planta Med 2016;82:388-406. https://doi. org/10.1055/s-0035-1568274
13. Alagawany M, Abd El Hack ME, Farag MR, et al. Rosmarinic acid: modes of action, medicinal values and health benefits. Anim Health Res Rev 2017;18:167- 176. https://doi.org/10.1017/S1466252317000081
14. Nunes S, Madureira AR, Campos D, et al. Therapeutic and nutraceutical potential of rosmarinic acidcytoprotective properties and pharmacokinetic profile. Crit Rev Food Sci Nutr 2017;57:1799-1806. https://doi. org/10.1080/10408398.2015.1006768
15. Bekut M, Brkic S, Kladar N, DragovicG, Gavaric N, Bozin B. Potential of selected Lamiaceae plants in anti(retro) viral therapy. Pharmacol Res 2018;133:301- 314. https://doi.org/10.1016/j.phrs.2017.12.016
16. Elufioye TO, Habtemariam S. Hepatoprotective effects of rosmarinic acid: insight into its mechanisms of action. Biomed Pharmacother 2019;112:108600. https://doi. org/10.1016/j.biopha.2019.108600
17. Nadeem M, Imran M, Gondal TA, et al. Therapeutic potential of rosmarinic acid: a comprehensive review. Appl Sci 2019;9:3139. https://doi.org/10.3390/ app9153139
18. Rauch I, Müller M, Decker T. The regulation of inflammation by interferons and their STATs. JAKSTAT 2013;2:23820. https://doi.org/10.4161/jkst.23820
19. Hallen LC, Burki Y, Ebeling M, et al. Antiproliferative activity of the human IFN-alpha-inducible protein IF144. J Interferon Cytokine Res 2007;27:675-680. https://doi.org/10.1089/jir.2007.0021
20. Mahoney JM, Taroni J, Martyanov V, et al. Systems level analysis of systemic sclerosis shows a network of immune and profibrotic pathways connected with genetic polymorphisms. PloS Comput Biol 2015;11:1004005. https://doi.org/10.1371/journal. pcbi.1004005
21. Hu JG, Fu Y, Xu JJ, Ding XP, Xie HQ, Li Ling J. Altered gene expression profile in a rat model of gentamicin-induced ototoxicity and nephrotoxicity, and the potential role of upregulated Ifi44 expression. Mol Med Rep 2017;16:4650-4658. https://doi.org/10.3892/ mmr.2017.7150
22. Karahan I, Atessahin A, Yilmaz S, Ceribası AO, Sakin F. Protective effect of lycopene in gentamicin-induced oxidative stress and nephrotoxicity in rats. Toxicology 2005;215:198-204. https://doi.org/10.1016/j. tox.2005.07.007
23. Bayomy NA, Elbakary RH, Ibrahim MAA, Abdelaziz EZ. Effect of lycopene and rosmarinic acid on gentamicin induced renal cortical oxidative stress, apoptosis, Effects of rosmarinic acid on gentamicin induced nephrotoxicity and autophagy in adult male albino rat. Anat Rec 2017;300:1137-1149. https://doi.org/10.1002/ar.23525
24. Makino T, Ono T, Liu N, Nakamura T, Muso E, Honda G. Suppressive effects of rosmarinic acid on mesangioproliferative glomerulonephritis in rats. Nephron 2002;92:898-904. https://doi. org/10.1159/000065457
25. Al Shabanah OA, Aleisa AM, AI Yahya AA, et al. Increased urinary losses of carnitine and decreased intramitochondrial coenzyme a in gentamicin-induced acute renal failure in rats. Nephrol Dial Transplant 2010;25:69-76. https://doi.org/10.1093/ndt/gfp457
26. Kader C, Sunbul M, Das YK, et al. Telbivudine attenuates gentamicin-induced kidney injury in rats. Int J Antimicrob Agents 2017;49:595-602. https://doi. org/10.1016/j.ijantimicag.2017.01.015
27. Erdem A, Gundogan NU, Usubutun A, et al. The protective effect of taurine against gentamicininduced acute tubular necrosis in rats. Nephrol Dial Transpl 2000;15:1175-82. https://doi.org/10.1093/ ndt/15.8.1175
28. Al Majed AA, Mostafa AM, Al Rikabi AC, Al Shabanah OA. Protective effects of oral arabic gum administration on gentamicin-induced nephrotoxicity in rats. Pharmacol Res 2002;46:445-51. https://doi. org/10.1016/s1043661802001251
29. Cuzzocrea S, Mazzon E, Dugo L, et al. A role for superoxide in gentamicin-mediated nephropathy in rats. Eur J Pharmacol 2002;450:67-76. https://doi. org/10.1016/s0014-2999(02)01749-1
30. Smetana S, Khalef S, Nitsan Z, et al. Enhanced urinary trypsin inhibitory activity in gentamicin-induced nephrotoxicity in rats. Clin Chim Acta 1988;176:333-42. https://doi.org/10.1016/0009-8981(88)90191-x
31. Kuatsienu LE, Charles Ansah C, Adinortey MB. Toxicological evaluation and protective effect ethanolic leaf extract of Launaea taraxacifolia on gentamicin induced rat kidney injury. Asian Pac J Trop Biomed 2017;7:640-646. https://doi.org/10.1016/j. apjtb.2017.06.011
32. Félix L, Oliveira MM, Videira R, et al. Carvedilol exacerbate gentamicin-induced kidney mitochondrial alterations in adult rat. Exp Toxicol Pathol 2017;69:83- 92. https://doi.org/10.1016/j.etp.2016.11.006
33. Tavafi M, Ahmadvand H. Effect of rosmarinic acid on inhibition of gentamicin induced nephrotoxicity in rats. Tissue Cell 2011;43:392-397. https://doi.org/10.1016/j. tice.2011.09.001
34. Azab AE, Fetouh FA, Albasha MO. Nephroprotective effects of curcumin, rosemary and propolis against gentamicin induced toxicity in guinea pigs: morphological and biochemical study. Am J Clin Exp Med 2014;2:28-35. https://doi.org/10.11648/j. ajcem.20140202.14
35. Morales Al, Detaille D, Prieto M, et al. Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway. Kidney Int 2010;77:861-869. https://doi.org/10.1038/ ki.2010.11
36. Buyuklu M, Kandemir FM, Ozkaraca M, et al. Benefical effects of lycopene against contrast medium-induced oxidative stress, inflammation, autophagy, and apoptosis in rat kidney. Hum Exp Toxicol 2014;1:1-10. https://doi.org/10.1177/0960327114542964
37. Huerta Madroñal M, Caro León J, Espinosa Cano E, Aguilar MR, Vázquez Lasa B. Chitosan-Rosmarinic acid conjugates with antioxidant, anti-inflammatory and photoprotective properties. Carbohydrate Polymers 2021;273:118619. https://doi.org/10.1016/. carbpol.2021.118619
38. Rodrigues FA, Prata MM, Oliveira IC, et al. Gingerol fraction from Zingiber officinale protects against gentamicin-induced nephrotoxicity. Antimicrob Agents Chemother 2014;58:1872-1878. https://doi. org/10.1128/AAC.02431-13