Sıçanlarda Azitromisin ile Oluşturulan Kalp Hasarına Karşı Krisin’in Etkilerinin Araştırılması

Yıl 2025, Cilt: 20 Sayı: 2, 71 - 77, 27.08.2025

Serpil Aygörmez , Elif Dalkılınç , Nurhan Akaras , Şaban Maraşlı

Öz

Azitromisin (AZM), üst ve alt solunum yolu enfeksiyonlarının tedavisinde kullanılan bir makrolid antibiyotiktir. Terapötik etkilerinin yanında kardiyak ve oksidatif hasar gibi olumsuz etkilere sahiptir. Propoliste ve çeşitli bitkilerde bulunan Krisin (CHR), antioksidan özelliğiyle bilinen doğal bir flavonoiddir. Bu çalışmada, geniş spektrumlu bir antibiyotik olan AZM’nin neden olduğu kalp hasarına karşı CHR’nin koruyucu etkisi araştırıldı. Bu amaçla, yirmi sekiz dişi sıçan Kontrol, CHR, AZM, AZM+CHR olmak üzere dört gruba ayrıldı. AZM (200 mg/kg) ve CHR (50 mg/kg) yedi gün boyunca günde bir kez oral yoldan uygulandı. Kalp dokusunda hasarı belirlemek için kardiyak belirteçler ve oksidatif stres parametreleri analiz edildi. Doku hasarını ve yapısal değişiklikleri tespit etmek için histopatolojik analizler yapıldı. Bu analizler sonucunda elde edilen verilere göre AZM, kalp dokusunda laktat dehidrogenaz (LDH), kreatin kinaz-miyokardiyal bant (CK-MB) aktiviteleri ve kardiyak troponin-I (cTn-I) seviyesini artırdı. AZM toksikasyonu, süperoksit dismutaz (SOD), glutatyon peroksidaz (GPx), katalaz (CAT) aktiviteleri ve glutatyon (GSH) seviyeleri gibi antioksidan enzimlerin aktivitelerini azaltırken, malondialdehit (MDA) seviyelerini önemli ölçüde artırmıştır. AZM+CHR tedavisinin kalp dokusu kardiyak belirteçlerinde (LDH, CK-MB, cTn-I) azalma gösterdiği tespit edildi. Ayrıca, CHR tedavisinin AZM ile birlikte uygulanması MDA düzeyini düşürmüş ve GSH düzeyini ve GPx, SOD ve CAT aktivitelerini artırmıştır. Elde edilen bulgular birlikte değerlendirildiğinde, AZM’nin kardiyak belirteçleri ve oksidatif stresi artırarak kalp hasarına neden olduğu, CHR destekleyici tedavisinin ise bu parametreleri normale yakınlaştırarak hasarı azalttığı tespit edildi.

Anahtar Kelimeler

Azitromisin , Chrysin , Kalp , Oksidatif stres , Rat

Investigation of the Effects of Chrysin Against Azithromycin-Induced Heart Damage in Rats

Öz

Azithromycin (AZM) is macrolide antibiotic used to treat infections of the upper and lower respiratory tract. In addition to its therapeutic effects, it has adverse effects such as cardiac and oxidative damage. Chrysin (CHR), which is found in propolis and various plants, is a natural flavonoid known for its antioxidant properties. In this study, we investigated the protective effect of CHR against cardiac damage caused by AZM, a broad-spectrum antibiotic. For this purpose, twenty-eight female rats were divided into four groups: Control, CHR, AZM, AZM+CHR. AZM (200 mg/kg) and CHR (50 mg/kg) were administered orally once daily for seven days. Cardiac markers and oxidative stress parameters were analyzed to determine heart tissue damage. Histopathological analyses were performed to detect tissue damage and structural changes. According to the data obtained from these analyses, AZM increased lactate dehydrogenase (LDH) and creatine kinase-myocardial band (CK-MB) activities and cardiac troponin-I (cTn-I) levels in the heart tissue. AZM toxication significantly increased malondialdehyde (MDA) levels while reducing the activities of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) activities and glutathione (GSH) levels. AZM+CHR treatment decreased cardiac tissue cardiac markers (LDH, CK-MB, and cTn-I). In addition, CHR treatment together with AZM decreased MDA levels and increased GSH levels and GPx, SOD, and CAT activities. When the findings were evaluated together, it was determined that AZM caused heart damage by increasing cardiac markers and oxidative stress, while CHR supplementation reduced the damage by bringing these parameters closer to normal.

Anahtar Kelimeler

Azithromycin , Chrysin , Heart , Oxidative stress , Rat

Kaynakça

• 1. El-Shitany NA, El-Desoky K. Protective effects of carvedilol and vitamin C against azithromycin-Induced cardiotoxicity in rats via decreasing ROS, IL1-β, and TNF-α production and inhibiting NF-κB and caspase-3 expression. Oxid Med Cell Longev. 2016;1874762.
• 2. Mansour BS, Salem NA, Kader GA, et al. Protective effect of Rosuvastatin on Azithromycin induced cardiotoxicity in a rat model. Life Sci. 2021;15:119099.
• 3. Hamza RZ, Alaryani FS, Omara F, et al. Ascorbic acid ameliorates cardiac and hepatic toxicity induced by azithromycin-etoricoxib drug interaction. Curr Issues Mol Biol. 2022;44(6):2529-2541.
• 4. Li X, Xiong Y, Ailikaiti A, et al. Toxic effects of prenatal azithromycin exposure on fetal adrenal gland in mice: The role of stage, dose and course of treatment. Toxicol Appl Pharmacol. 2025;496:117244.
• 5. Salimi A, Eybagi S, Seydi E, et al. Toxicity of macrolide antibiotics on isolated heart mitochondria: a justification for their cardiotoxic adverse effect. Xenobiotica. 2016;46(1):82-93.
• 6. Wei L, Wang T, Luo M, et al. A "toxic window" study on the hippocampal development of mice offspring exposed to azithromycin at different doses, courses, and time during pregnancy. Chem Biol Interact. 2024;387:110814.
• 7. Atli O, Ilgin OS, Altuntas H, et al. Evaluation of azithromycin induced cardiotoxicity in rats. IJCEM. 2015;8(3):3681-3690
• 8. Ali MAM, Matouk AI, Hamza AA, et al. Gehan Hussein Heeba: Gallic and glycyrrhetinic acids prevent azithromycin-induced liver damage in rats by mitigating oxidative stress and inflammation. Sci Rep. 2025;15:9566.
• 9. Hanafy SM, Zakaria SS. The protective role of folic acid in biochemical and histopathological changes induced by azithromycin in the livers of pregnant albino rats. Medicina (Kaunas). 2025;61(3):415.
• 10. Karaca O, Akaras N, Şimşek H, et al. Therapeutic potential of rosmarinic acid in tramadol-induced hepatorenal toxicity: Modulation of oxidative stress, inflammation, RAGE/NLRP3, ER stress, apoptosis, and tissue functions parameters. Food Chem Toxicol. 2025;197:115275.
• 11. Ileriturk M, Benzer F, Aksu EH, et al. Chrysin protects against testicular toxicity caused by lead acetate in rats with its antioxidant, anti-inflammatory, and antiapoptotic properties. J Food Biochem. 2021;45(2):e13593.
• 12. Kankılıç NA, Şimşek H, Akaras N, et al. The ameliorative effects of chrysin on bortezomib-induced nephrotoxicity in rats: Reduces oxidative stress, endoplasmic reticulum stress, inflammation damage, apoptotic and autophagic death. Food Chem Toxicol. 2024a;190:114791.
• 13. Temel Y, Kucukler S, Yıldırım S, et al. Protective effect of chrysin on cyclophosphamide-induced hepatotoxicity and nephrotoxicity via the inhibition of oxidative stress, inflammation, and apoptosis. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(3):325-337.
• 14. Kucukler S, Benzer F, Yildirim S, et al. Protective effects of chrysin against oxidative stress and inflammation induced by lead acetate in rat kidneys: a biochemical and histopathological approach. Biol Trace Elem Res. 2021;199(4):1501-1514.
• 15. Tuncer SÇ, Küçükler S, Gür C, et al. Effects of chrysin in cadmium-induced testicular toxicity in the rat; role of multi-pathway regulation. Mol Biol Rep, 2023;50(10):8305-8318.
• 16. Akaras N, Ileriturk M, Gur C, et al. The protective effects of chrysin on cadmium-induced pulmonary toxicity; a multi-biomarker approach. Environ Sci Pollut Res Int. 2023a;30(38): 89479-89494.
• 17. Şimşek H, Akaras N, Gür C, et al. Beneficial effects of Chrysin on Cadmium-induced nephrotoxicity in rats: Modulating the levels of Nrf2/HO-1, RAGE/NLRP3, and Caspase-3/Bax/Bcl-2 signaling pathways. Gene. 2023;875:147502.
• 18. Varışlı B, Caglayan C, Kandemir FM, et al. Chrysin mitigates diclofenac-induced hepatotoxicity by modulating oxidative stress, apoptosis, autophagy and endoplasmic reticulum stress in rats. Mol Biol Rep. 2023;50(1):433-442.
• 19. Singh H, Prakash A, Kalia AN, et al. Synergistic hepatoprotective potential of ethanolic extract of Solanum xanthocarpum and Juniperus communis against paracetamol and azithromycin induced liver injury in rats. J Tradit Complement Med. 2015;6(4):370-376.
• 20. Placer ZA, Cushman LL, Johnson BC. Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem. 1966;16(2):359-364.
• 21. Aebi H, Catalase in vitro. Methods in Enzymology. Elsevier, 1984;121-126.
• 22. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem. 1988;34(3):497-500.
• 23. Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun. 1976;71(4):952-958.
• 24. 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.
• 25. Lowry OH, Rosebrough NJ, Farr AL, et al. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-275.
• 26. Jiang X, Baucom C, Elliott RL, Mitochondrial Toxicity of Azithromycin Results in Aerobic Glycolysis and DNA Damage of Human Mammary Epithelia and Fibroblasts. Antibiotics (Basel). 2019;8(3):110.
• 27. Kuzu M, Kandemir FM, Yildirim S, et al. Morin attenuates doxorubicin-induced heart and brain damage by reducing oxidative stress, inflammation and apoptosis. Biomed Pharmacother. 2018;106:443-453.
• 28. Rohym HH, Hemeda MS, Elsayed AM, et al. Interleukin-10 levels in azithromycin-induced cardiac damage and the protective role of combined selenium and vitamin E treatment. Toxicol Rep. 2024;14:101860.
• 29. Ma T, Kandhare AD, Mukherjee-Kandhare AA, et al. Fisetin, a plant flavonoid ameliorates doxorubicin-induced cardiotoxicity in experimental rats: the decisive role of caspase-3, COX-II, cTn-I, iNOs and TNF-α. Mol Biol Rep. 2019;46(1):105-118.
• 30. Caglayan C, Kandemir FM, Yildirim S, et al. Rutin protects mercuric chloride-induced nephrotoxicity via targeting of aquaporin 1 level, oxidative stress, apoptosis and inflammation in rats. J Trace Elem Med Biol. 2019;54:69-78.
• 31. Akaras N, Kandemir FM, Şimşek H, et al. Antioxidant, antiinflammatory, and antiapoptotic effects of rutin in spleen toxicity induced by sodium valproate in rats. Türk Doğa ve Fen Dergisi. 2023b;12(2):138-144.
• 32. Küçükler S, Caglayan C, Özdemir S, et al. Hesperidin counteracts chlorpyrifos-induced neurotoxicity by regulating oxidative stress, inflammation, and apoptosis in rats. Metab Brain Dis. 2024;39(4):509-522.
• 33. Benzer F, Kandemir FM, Ceribasi S, et al. Chemotherapeutic agent-induced nephrotoxicity in rabbits: protective role of grape seed extract. Int J Pharmacol. 2012;8(1):39-45.
• 34. Keleş ON, Can S, Cigsar G, et al. Hepatoprotective Effects of B-1,3-(D)-Glucan on Bortezomib-Induced Liver Damage in Rats. Kafkas Univ Vet Fak Derg. 2014;20(6):929-938.
• 35. Aksu EH, Kandemir FM, Yıldırım S, et al. Palliative effect of curcumin on doxorubicin-induced testicular damage in male rats. J Biochem Mol Toxicol. 2019;33(10):e22384.
• 36. 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.
• 37. Kankılıç NA, Şimşek H, Akaras N, et al. Protective effects of naringin on colistin-induced damage in rat testicular tissue: Modulating the levels of Nrf-2/HO-1, AKT-2/FOXO1A, Bax/Bcl2/Caspase-3, and Beclin-1/LC3A/LC3B signaling pathways. J Biochem Mol Toxicol. 2024b;38:e23643.
• 38. Akaras N, Gür C, Caglayan C, et al. Protective effects of naringin against oxaliplatin-induced testicular damage in rats: Involvement of oxidative stress, inflammation, endoplasmic reticulum stress, apoptosis, and histopathology. Iran J Basic Med Sci. 2024a;27:466-474.
• 39. Kandemir FM, Ileriturk M, Gur C. Rutin protects rat liver and kidney from sodium valproate-induce damage by attenuating oxidative stress, ER stress, inflammation, apoptosis and autophagy. Mol Biol Rep. 2022;49(7):6063-6074.
• 40. Kankılıç NA, Küçükler S, Gür C, et al. Naringin protects against paclitaxel‐induced toxicity in rat testicular tissues by regulating genes in pro‐inflammatory cytokines, oxidative stress, apoptosis, and JNK/MAPK signaling pathways. J Biochem Mol Toxicol. 2024c;38(7):e23751.
• 41. Yilmaz S, Gur C, Kucukler S, et al. Zingerone attenuates sciatic nerve damage caused by sodium arsenite by inhibiting NF-κB, caspase-3, and ATF-6/CHOP pathways and activating the Akt2/FOXO1 pathway. Iran J Basic Med Sci. 2024a;27(4):485-491.
• 42. Aydin M, Cevik A, Kandemir FM, et al. Evaluation of hormonal change, biochemical parameters, and histopathological status of uterus in rats exposed to 50-Hz electromagnetic field. Toxicol Ind Health. 2009;25(3):153-158.
• 43. Ekı̇ncı̇-Akdemı̇r FN, Yildirim S, Kandemı̇r FM, et al. The effects of casticin and myricetin on liver damage induced by methotrexate in rats. Iran J Basic Med Sci. 2018;21(12):1281-1288.
• 44. Akaras N, Gür C, Şimşek H, et al. Effects of quercetin on cypermethrin-induced stomach injury: The role of oxidative stress, inflammation, and apoptosis. Gümüşhane University Journal of Health Sciences. 2023c;12(2):556-566.
• 45. Taştan Bal T, Akaras N, Demir Ö, et al. Protective effect of astaxanthin and metformin in the liver of rats in which the polycystic ovary syndrome model was formed by giving letrozole. Iran J Basic Med Sci. 2023;26:688-694.
• 46. Şimşek H, Gür C, Küçükler S, et al. Carvacrol Reduces mercuric chloride-induced testicular toxicity by regulating oxidative stress, inflammation, apoptosis, autophagy, and histopathological changes. Biol Trace Elem Res. 2024;202(10):4605-4617.
• 47. Akaras N, Kucukler S, Gur C, et al. Sinapic acid protects against lead acetate-induced lung toxicity by reducing oxidative stress, apoptosis, inflammation, and endoplasmic reticulum stress damage. Environ Toxicol. 2024b;39(7):3820-3832.
• 48. Darendelioglu E, Caglayan C, Küçükler S, et al. 18β-glycyrrhetinic acid Mitigates bisphenol A-induced liver and renal damage: Inhibition of TNF-α/NF-κB/p38-MAPK, JAK1/STAT1 pathways, oxidative stress and apoptosis. Food Chem Toxicol. 2025;196:115218.
• 49. Aksu EH, Kandemir FM, Küçükler S, et al. Improvement in colistin-induced reproductive damage, apoptosis, and autophagy in testes via reducing oxidative stress by chrysin. J Biochem Mol Toxicol. 2018;32(11):e22201.
• 50. Saleh DO, Elbaset MA, Ahmed KA, et al. Chrysin mitigates cyclophosphamide-triggered cardiotoxicity in rats: Insights into cardioprotection via treg expression modulation and inos downregulation. Toxicol Rep. 2025;14:102007.