Eugenol attenuates paclitaxel-induced cardiotoxicity by modulating autophagy-related markers in rats

Document Type : Original Article

Authors

1 Department of Histology and Embryology, Faculty of Medicine, Kirsehir Ahi Evran University, 40100 Kirsehir, Türkiye

2 Department of Medical Pharmacology, Faculty of Medicine, Kirsehir Ahi Evran University, 40100 Kirsehir, Türkiye

3 Department of Histology and Embryology, Faculty of Medicine, Malatya Turgut Ozal University, 44210 Malatya, Türkiye

4 Department of Physiology, Faculty of Medicine, Kirsehir Ahi Evran University, 40100 Kirsehir, Türkiye

5 Department of Fertilization and Artificial Inseminatıon, Faculty of Veterinary Medicine, Selcuk University, 42250 Konya, Türkiye

10.22038/ijbms.2026.89478.19317

Abstract

Objective(s): Paclitaxel (PTX) is a commonly used chemotherapeutic agent that causes cardiotoxicity characterized by oxidative stress, inflammation, and mitochondrial dysfunction, which disrupts autophagy and apoptosis in cardiomyocytes. This study investigated the therapeutic potential of eugenol (EUG), a natural anti-oxidant and anti-inflammatory compound, against PTX-induced cardiac damage.
Materials and Methods: Thirty-six male Wistar rats were randomly assigned to six groups: Control, EUG5, EUG25, PTX, PTX+EUG5, and PTX+EUG25. Hemodynamic parameters (systolic and diastolic blood pressure and heart rate), serum cardiac biomarkers (troponin T and brain natriuretic peptide), histopathological alterations, and immunohistochemical expression of autophagy-related proteins (mTOR, ULK1, and Atg13) were evaluated.
Results: PTX administration significantly reduced arterial blood pressure and increased serum cardiac injury biomarkers, accompanied by marked myocardial structural damage. Histopathological analysis revealed myocardial degeneration, inflammation, edema, and tissue disorganization in the PTX group. In PTX-exposed rats treated with EUG, arterial blood pressure was higher, and serum cardiac injury biomarkers were lower than in the PTX group, accompanied by reduced histopathological scores. PTX exposure was associated with decreased mTOR expression and increased ULK1 and Atg13 immunoreactivity, while EUG-treated PTX groups showed values closer to those of the control group for these autophagy-related markers.
Conclusion: EUG administration was associated with reduced biochemical and histopathological indicators of cardiac injury in PTX-exposed rats, along with changes in autophagy-related markers. These findings demonstrate that EUG treatment coincided with attenuation of PTX-induced cardiac injury at the biochemical and histopathological levels, suggesting its potential experimental value in models of chemotherapy-associated cardiotoxicity.

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Main Subjects


Zhu L, Chen L. Progress in research on paclitaxel and tumor immunotherapy. Cell Mol Biol Lett 2019; 24:40. 
Yu DL, Lou ZP, Ma FY, Najafi M. The interactions of paclitaxel with tumour microenvironment. Int Immunopharmacol 2022; 105:108555. 
Bertolini D, Pizzi C, Donal E, Galli E. Cancer and heart failure: Dangerous liaisons. J Cardiovasc Dev Dis 2024; 11:263. 
Zhang K, Heidrich FM, DeGray B, Boehmerle W, Ehrlich BE. Paclitaxel accelerates spontaneous calcium oscillations in cardiomyocytes by interacting with NCS-1 and the InsP3R. J Mol Cell Cardiol 2010; 49: 829–835.
Nagy A, Börzsei D, Hoffmann A, Törok S, Veszela M, Almasi N et al. A comprehensive overview on chemotherapy-induced cardiotoxicity: Insights into the underlying inflammatory and oxidative mechanisms. Cardiovasc Drugs Ther 2024. doi:10.1007/s10557-024-07574-0.
Zhang J, Xiang Q, Wu M, Lao YZ, Xian YF, Xu HX et al. Autophagy regulators in cancer. Int J Mol Sci 2023; 24:10944.
Harborne JB, Baxter H. Phytochemical Dictionary. London: Taylor & Francis; 1993.
Özarslan M, Avcıoğlu NH, Can DB, Çalışkan A. Biofilm formation of Candida albicans on occlusal device materials and antibiofilm effects of chitosan and eugenol. J Prosthet Dent 2024; 131:144.e1–144.e7.
Barot J, Saxena B. Therapeutic effects of eugenol in a rat model of traumatic brain injury: A behavioral, biochemical, and histological study. J Tradit Complement Med 2021; 11:318–327. 
Miyazawa M, Hisama M. Suppression of chemical mutagen-induced SOS response by alkylphenols from clove (Syzygium aromaticum) in Salmonella typhimurium TA1535/pSK1002 umu test. J Agric Food Chem 2001; 49:4019–4025.
Pramod K, Ansari SH, Ali J. Eugenol: A natural compound with versatile pharmacological actions. Nat Prod Commun 2010; 5:1999–2006.
Damasceno ROS, Pinheiro JLS, Rodrigues LHM, Gomes RC, Duarte ABS, Emídio JJ, et al. Anti-inflammatory and anti-oxidant activities of eugenol: An update. Pharmaceuticals (Basel) 2024; 17:1505. 
Fathy M, Abdel-Latif R, Abdelgwad YM, Othman OA, Abdel-Razik AH, Dandekar T, et al. Nephroprotective potential of eugenol in a rat experimental model of chronic kidney injury: Targeting NOX, TGF-β, and Akt signaling. Life Sci 2022; 308:120957. 
Feng W, Jin L, Xie Q, Huang L, Jiang Z, Ji Y et al. Eugenol protects the transplanted heart against ischemia/reperfusion injury in rats by inhibiting the inflammatory response and apoptosis. Exp Ther Med 2018; 16:3464–3470. 
Filomeni G, De Zio D, Cecconi F. Oxidative stress and autophagy: The clash between damage and metabolic needs. Cell Death Differ 2015; 22:377–388.
Kaarniranta K, Blasiak J, Liton P, Boulton M, Klionsky DJ, Sinha D. Autophagy in age-related macular degeneration. Autophagy 2023; 19:388–400.
Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol 2020; 21:183–203. 
Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of ULK1. Nat Cell Biol 2011; 13:132–141.
Zhang X, Zhang H, Gao Y, Hao Z, Liu J, Zhou G et al. Forsythoside A regulates autophagy and apoptosis through the AMPK/mTOR/ULK1 pathway and alleviates inflammatory damage in MAC-T cells. Int Immunopharmacol 2023; 118:110053. 
Shaernejad S, Nosrat A, Baeeri M, Goradel NH, SeyedSadeghi M, Akbairani M et al. Role of hesperidin/hesperetin against chemotherapy-induced cardiotoxicity: A systematic review of nonclinical studies. Cancer Cell Int 2025; 25:1–13.
Devi S, Chauhan S, Mannan A, Singh TG. Targeting cardiovascular risk factors with eugenol: An anti-inflammatory perspective. Inflammopharmacology 2024; 32:307–317. 
Yakut S, Atcalı T, Çaglayan C, Ulucan A, Kandemir FM, Kara A et al. Therapeutic potential of silymarin in mitigating paclitaxel-induced hepatotoxicity and nephrotoxicity: Insights into oxidative stress, inflammation, and apoptosis in rats. Balkan Med J 2024; 41:193–204. 
Semis HS, Kandemir FM, Kaynar O, Dogan T, Arikan SM. The protective effects of hesperidin against paclitaxel-induced peripheral neuropathy in rats. Life Sci 2021; 287:120104. 
Koçak S, Kalkan KT, Aydın ÖS, Öztürk K. Cardioprotective effects of carvacrol in the isoproterenol-induced myocardial infarction model. BMC Pharmacol Toxicol 2025; 26:132. 
Aly E, El-Mashad ABI, Tantawy AA, Amin AA. A comparative study on the cardiopulmonary protective effect of propolis versus coenzyme Q10 on paclitaxel-induced toxicity. J Adv Vet Res 2023; 14:59–64.
Ruifrok AC, Johnston DA. Quantification of histochemical staining by color deconvolution. Anal Quant Cytol Histol 2001; 23:291–299.
Joshi AM, Prousi GS, Bianco C, Malla M, Guha A, Shah M et al. Microtubule inhibitors and cardiotoxicity. Curr Oncol Rep 2021; 23:30.
Ekholm E, Rantanen V, Antila K, Salminen E. Paclitaxel changes sympathetic control of blood pressure. Eur J Cancer 1997; 33:1419–1424.
Altin C, Sade LE, Demirtas S, Karacaglar E, Kanyilmaz S, Simsek V et al. Effects of paclitaxel and carboplatin combination on mechanical myocardial and microvascular functions: A transthoracic Doppler echocardiography and two-dimensional strain imaging study. Echocardiography 2015; 32:238–247. 
Rowinsky EK, McGuire WP, Guarnieri T, Fisherman JS, Christian MC, Donehower R C. Cardiac disturbances during the administration of taxol. J Clin Oncol 1991; 9:1704–1712.
Liu XY, Nie YK, Liu Y, Chen M. Cardiovascular protective properties of the natural product eugenol. Eur J Pharmacol 2025; 1003:177929. 
Peixoto-Neves D, Wang Q, Leal-Cardoso JH, Rossoni LV, Jaggar JH. Eugenol dilates mesenteric arteries and reduces systemic blood pressure by activating endothelial cell TRPV4 channels. Br J Pharmacol 2015; 172:3484–3494. 
Damiani CEN, Moreira CM, Zhang HT, Creazzo TL, Vassallo DV. Effects of eugenol, an essential oil, on the mechanical and electrical activities of cardiac muscle. J Cardiovasc Pharmacol 2004; 44:688–695.
Aktaş İ, Gur FM, Bilgiç S. Protective effect of misoprostol against paclitaxel-induced cardiac damage in rats. Prostaglandins Other Lipid Mediat 2024; 171:106813. 
El-Sayed EM, Mansour AM, Abd El-Aziz GS. Melatonin mitigates paclitaxel-induced cardiotoxicity in rats through modulation of oxidative stress, inflammation, and apoptosis. Life Sci 2023; 316:121369. 
Zhang Y, Liu X, Wang H, Li Y. Resveratrol protects against paclitaxel-induced myocardial injury by suppressing oxidative stress and inflammatory signaling in rats. Cardiovasc Toxicol 2022; 22:541–551. 
Liu C, Wang X, Xu S, Liu M, Cao X. Regulation of autophagy: Insights into O-GlcNAc modification mechanisms. Life Sci 2025; 123547. 
Zou L, Liao M, Zhen Y, Zhu S, Chen X, Zhang J et al. Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications. Acta Pharm Sin B 2022; 12:3743–3782.