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Effectiveness of intratympanic Epigallocatechin-3-gallate injection on Cisplatin-induced hearing loss in rats
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: 22 December 2025
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Cisplatin is an imperative drug in the treatment of a wide range of cancers. However, it has various side effects including ototoxicity causing bilateral sensorineural hearing loss. Despite lacking a clearly defined mechanism, Reactive Oxygen Species (ROS) production and damage to Outer Hair Cells (OHCs) have been implicated as possible culprits. The ideal otoprotective drug would target inflammation and oxidative stress without compromising cisplatin's efficacy. This study aimed to scrutinize whether intratympanic Epigallocatechin-3-Gallate (EGCG) exhibits a protective effect against cisplatin-related ototoxicity. Twenty-four adult male Wistar rats (8–10 weeks, 200–250 g) were randomly divided into four groups (n = 6 per group): Cisplatin, EGCG, Cisplatin+EGCG, and Control. Cisplatin (15 mg/kg) was administered intraperitoneally, and/or EGCG (10 mg/mL, 200 μL) was injected transtympanically into the right ear, depending on group assignment. Control rats received intratympanic distilled water. After 72 h, auditory function was assessed by Auditory Brain Response (ABR), followed by histopathological and Signal Transducer and Activator of Transcription-1 (STAT1) immunohistochemistry evaluation of cochlear sections. All animals underwent baseline otoscopy and ABR to rule out pre-existing hearing impairment. Data were analyzed using repeated measures of Analysis of Variance (ANOVA) and paired t-tests for ABR thresholds, and Kruskal–Wallis/Mann–Whitney tests for histopathological and Immunohistochemistry (IHC) scoring. Statistical significance was defined as p < 0.05. EGCG injections failed to prevent hearing threshold increases in the Cisplatin group. According to histopathologic and STAT-1 IHC evaluation in the treatment group, reduced OHC damage, apoptosis, and cochlear hyperemia were observed. Administration of EGCG alleviated apoptosis and prevented OHCs damage in animals. However, it could not prevent hearing loss significantly.
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1. Ghosh S. Cisplatin: the first metal based anticancer drug. J Biol Res 2019;88:102925. DOI: https://doi.org/10.1016/j.bioorg.2019.102925
2. Nagy JL, Adelstein DJ, Newman CW, et al. Cisplatin ototoxicity: the importance of baseline audiometry. Am J Clin Oncol 1999;22:305-8. DOI: https://doi.org/10.1097/00000421-199906000-00020
3. Lanvers-Kaminsky C, Zehnhoff-Dinnesen A, Parfitt R, et al. Drug-induced ototoxicity: mechanisms, pharmacogenetics, and protective strategies. J Clin Pharm Ther 2017;101:491-500. DOI: https://doi.org/10.1002/cpt.603
4. Laurell G, Bagger-Sjöbäck D. Degeneration of the organ of Corti following intravenous administration of cisplatin. Acta Otolaryngol 1991;111:891-8. DOI: https://doi.org/10.3109/00016489109138427
5. Yurtsever KN, Baklaci D, Guler I, et al. The protective effect of platelet rich plasma against cisplatin-induced ototoxicity. J Biol Res 2020;31:e506-e9. DOI: https://doi.org/10.1097/SCS.0000000000006645
6. Gozeler MS, Akdemir F, Yildirim S, et al. Levosimendan ameliorates cisplatin-induced ototoxicity: rat model. Int J Pediatr Otorhinolaryngol 2019;122:70-5. DOI: https://doi.org/10.1016/j.ijporl.2019.04.004
7. Hill GW, Morest DK, Parham K. Cisplatin-induced ototoxicity: effect of intratympanic dexamethasone injections. Otol Neurotol 2008;29:1005. DOI: https://doi.org/10.1097/MAO.0b013e31818599d5
8. Hyppolito MA, de Oliveira JA, Rossato M. Cisplatin ototoxicity and otoprotection with sodium salicylate. Ear Nose Throat J 2006;263:798-803. DOI: https://doi.org/10.1007/s00405-006-0070-6
9. Borse V, Al Aameri RF, Sheehan K, et al. Epigallocatechin-3-gallate, a prototypic chemopreventative agent for protection against cisplatin-based ototoxicity. Cell Physiol Biochem 2017;8:e2921-e. DOI: https://doi.org/10.1038/cddis.2017.314
10. Chtourou Y, Aouey B, Kebieche M, et al. Protective role of naringin against cisplatin induced oxidative stress, inflammatory response and apoptosis in rat striatum via suppressing ROS-mediated NF-κB and P53 signaling pathways. Food Chem Toxicol 2015;239:76-86. DOI: https://doi.org/10.1016/j.cbi.2015.06.036
11. Minami SB, Sha S-H, Schacht J. Antioxidant protection in a new animal model of cisplatin-induced ototoxicity. Hear Res 2004;198:137-43. DOI: https://doi.org/10.1016/j.heares.2004.07.016
12. Lawenda BD, Kelly KM, Ladas EJ, et al. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst 2008;100:773-83. DOI: https://doi.org/10.1093/jnci/djn148
13. Kaur T, Borse V, Sheth S, et al. Adenosine A1 receptor protects against cisplatin ototoxicity by suppressing the NOX3/STAT1 inflammatory pathway in the cochlea. J Neurosci 2016;36:3962-77. DOI: https://doi.org/10.1523/JNEUROSCI.3111-15.2016
14. Maeda Y, Fukushima K, Omichi R, et al. Time courses of changes in phospho-and total-MAP kinases in the cochlea after intense noise exposure. PLoS One 2013;8:e58775. DOI: https://doi.org/10.1371/journal.pone.0058775
15. Mukherjea D, Jajoo S, Sheehan K, et al. NOX3 NADPH oxidase couples transient receptor potential vanilloid 1 to signal transducer and activator of transcription 1-mediated inflammation and hearing loss. J Neurosci 2011;14:999-1010. DOI: https://doi.org/10.1089/ars.2010.3497
16. Koromilas AE, Sexl V. The tumor suppressor function of STAT1 in breast cancer. J Signal Transduct 2013;2:e23353. DOI: https://doi.org/10.4161/jkst.23353
17. Wang F, Zhang L, Liu J, et al. Highly expressed STAT1 contributes to the suppression of stemness properties in human paclitaxel-resistant ovarian cancer cells. J Cell Biochem 2020;12:11042. DOI: https://doi.org/10.18632/aging.103317
18. Borse V. Oral administration of Epigallocatechin-3-Gallate (EGCG) is a potential therapeutic for cisplatin-induced hearing loss. Southern Illinois University at Carbondale; 2017.
19. Freyer DR, Chen L, Krailo MD, et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2017;18:63-74. DOI: https://doi.org/10.1016/S1470-2045(16)30625-8
20. Campbell KC, Rehemtulla A, Sunkara P, et al. Oral D-methionine protects against cisplatin-induced hearing loss in humans: phase 2 randomized clinical trial in India. Int J Audiol 2022;61:621-31. DOI: https://doi.org/10.1080/14992027.2021.1983215
21. Schmitt NC, Rubel EW, Nathanson NM. Cisplatin-induced hair cell death requires STAT1 and is attenuated by epigallocatechin gallate. J Neurosci 2009;29:3843-51. DOI: https://doi.org/10.1523/JNEUROSCI.5842-08.2009
22. Cavet ME, Harrington KL, Vollmer TR, et al. Anti-inflammatory and anti-oxidative effects of the green tea polyphenol epigallocatechin gallate in human corneal epithelial cells. Mol Vis 2011;17:533.
23. Darra E, Shoji K, Mariotto S, et al. Protective effect of epigallocatechin-3-gallate on ischemia/reperfusion-induced injuries in the heart: STAT1 silencing flavonoid. J Nutr 2007;2:307-10. DOI: https://doi.org/10.1007/s12263-007-0060-3
24. Khan N, Afaq F, Saleem M, et al. Targeting multiple signaling pathways by green tea polyphenol-epigallocatechin-3-gallate. Cancer Res 2006;66:2500-5. DOI: https://doi.org/10.1158/0008-5472.CAN-05-3636
25. Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol 2011;82:1807-21. DOI: https://doi.org/10.1016/j.bcp.2011.07.093
26. Noack V, Pak K, Jalota R, et al. An antioxidant screen identifies candidates for protection of cochlear hair cells from gentamicin toxicity. Front Cell Neurosci 2017;11:242. DOI: https://doi.org/10.3389/fncel.2017.00242
27. Liu H, Hao J, Li K. Current strategies for drug delivery to the inner ear. J Pharm Sci Biomed 2013;3:86-96. DOI: https://doi.org/10.1016/j.apsb.2013.02.003
28. García-Berrocal J, Nevado J, Ramírez-Camacho R, et al. The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear. J Laryngol Otol 2007;152:1012-20. DOI: https://doi.org/10.1038/sj.bjp.0707405
29. Kaur T, Mukherjea D, Sheehan K, et al. Short interfering RNA against STAT1 attenuates cisplatin-induced ototoxicity in the rat by suppressing inflammation. Cell Death Dis 2011;2:e180. DOI: https://doi.org/10.1038/cddis.2011.63
30. Qi S, Wang C, Song D, et al. Intraperitoneal injection of -epigallocatechin-3-gallate protects against light-induced photoreceptor degeneration in the mouse retina. Mol Vis 2017;23:171.
31. Overbeck GW, Church MW. Effects of tone burst frequency and intensity on the auditory brainstem response (ABR) from albino and pigmented rats. Hear Res 1992;59:129-37. DOI: https://doi.org/10.1016/0378-5955(92)90110-9
32. Somdaş MA, Güntürk İ, Balcıoğlu E, et al. Protective effect of N-acetylcysteine against cisplatin ototoxicity in rats: a study with hearing tests and scanning electron microscopy. Braz J Otorhinolaryngol 2020;86:30-7. DOI: https://doi.org/10.1016/j.bjorl.2018.08.002
33. Zolfagharzadeh V, Ai J, Soltani H, et al. Sustain release of loaded insulin within biomimetic hydrogel microsphere for sciatic tissue engineering in vivo. J Biol Med 2023;225:687-700. DOI: https://doi.org/10.1016/j.ijbiomac.2022.11.133
34. Rybak LP. Mechanisms of cisplatin ototoxicity and progress in otoprotection. Curr Opin Otolaryngol Head Neck Surg 2007;15:364-9. DOI: https://doi.org/10.1097/MOO.0b013e3282eee452
35. De Freitas MR, Figueiredo AA, de Castro Brito GA, et al. The role of apoptosis in cisplatin-induced ototoxicity in rats. Hear Res 2009;75:745-52. DOI: https://doi.org/10.1016/S1808-8694(15)30528-0
36. Marshak T, Steiner M, Kaminer M, et al. Prevention of cisplatin-induced hearing loss by intratympanic dexamethasone: a randomized controlled study. Otol Neurotol 2014;150:983-90. DOI: https://doi.org/10.1177/0194599814524894
37. Lee S-Y, Kim J, Oh S, et al. Contralateral spreading of substances following intratympanic nanoparticle-conjugated gentamicin injection in a rat model. Sci Rep 2020;10:18636. DOI: https://doi.org/10.1038/s41598-020-75725-y
38. Chen Y, Gu J, Liu Y, et al. Epigallocatechin gallate-loaded tetrahedral DNA nanostructures as a novel inner ear drug delivery system. Front Bioeng Biotechnol 2022;14:8000-11. DOI: https://doi.org/10.1039/D1NR07921B
39. Sheth S, Mukherjea D, Rybak LP, et al. Mechanisms of cisplatin-induced ototoxicity and otoprotection. Front Cell Neurosci 2017;11:338. DOI: https://doi.org/10.3389/fncel.2017.00338
40. Prayuenyong P, Baguley DM, Kros CJ, et al. Preferential cochleotoxicity of cisplatin. Front Integr Neurosci 2021;15:695268. DOI: https://doi.org/10.3389/fnins.2021.695268
How to Cite
Effectiveness of intratympanic Epigallocatechin-3-gallate injection on Cisplatin-induced hearing loss in rats. (2025). Journal of Biological Research - Bollettino Della Società Italiana Di Biologia Sperimentale. https://doi.org/10.4081/jbr.2025.13692
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