A Review: “Pharmaceutical Induced Ototoxicity”

Abstract

Ototoxicity, defined as drug-induced damage to the auditory and vestibular systems, manifests as hearing loss, tinnitus, dizziness, and balance disorders, representing a critical challenge in clinical practice and pharmaceutical development. This review aims to consolidate advancements in the understanding of pharmaceutical-induced ototoxicity, focusing on its mechanisms, diagnostic methodologies, and preventive strategies. A comprehensive analysis of existing literature was conducted, encompassing clinical findings and experimental data on the ototoxic effects of major drug classes, including aminoglycosides, platinum-based chemotherapeutics, and loop diuretics. The review evaluates the underlying biochemical mechanisms and explores innovative approaches for mitigating ototoxic effects. Ototoxicity predominantly results from oxidative stress, mitochondrial dysfunction, disruption of calcium homeostasis, and activation of inflammatory pathways. Significant progress has been achieved in the development of therapeutic drug monitoring protocols, antioxidant therapies, and targeted drug delivery systems, including nanoparticles and hydrogels. Emerging technologies, such as gene-editing and caspase inhibitors, demonstrate potential for preserving hair cell integrity and mitigating auditory damage. Early detection and management of ototoxicity are paramount for maintaining auditory and vestibular function. This review provides a comprehensive framework for clinicians, researchers, and pharmaceutical professionals to address ototoxic effects effectively and highlights promising directions for future research and therapeutic development.

Keywords

• Hearing loss
• cisplatin
• aminoglycosides
• oxidative stress
• auditory hair cells

References

1. [1] Zong Y, Chen F, Li S, Zhang H. (−)-Epigallocatechin-3-gallate (EGCG) prevents aminoglycosides-induced ototoxicity via anti-oxidative and anti-apoptotic pathways. Int J Pediatr Otorhinolaryngol. 2021; 150: 110920. https://doi.org/10.1016/j.ijporl.2021.110920.
2. [2] Oltulu C, Dasman M. Oxidative Stress Induced Toxicity. In: Isik M, editor. Recent Advances in Molecular Biology and Biochemistry: Biyomit; 2023. p. 283-96.
3. [3] Tan WJ, Song L. Role of mitochondrial dysfunction and oxidative stress in sensorineural hearing loss. Hear Res. 2023; 434: 108783. https://doi.org/10.1016/j.heares.2023.108783.
4. [4] Gao Z, Chen Y, Guan M-X. Mitochondrial DNA mutations associated with aminoglycoside induced ototoxicity. J Otol. 2017; 12(1): 1-8. https://doi.org/10.1016/j.joto.2017.02.001.
5. [5] Szczepek AJ. Ototoxicity: old and new foes. Adv Clin Audiol. 2017; 29: 233-249. http://doi.org/10.5772/66933.
6. [6] Mohammadipour A, Abudayyak M. Hippocampal toxicity of metal base nanoparticles. Is there a relationship between nanoparticles and psychiatric disorders? Rev Environ Health. 2022; 37(1): 35-44. https://doi.org/10.1515/reveh-2021-0006.
7. [7] Tang Q, Wang X, Jin H, Mi Y, Liu L, Dong M, Chen Y, Zou Z. Cisplatin-induced ototoxicity: Updates on molecular mechanisms and otoprotective strategies. Eur J Pharm Biopharm. 2021; 163: 60-71. https://doi.org/10.1016/j.ejpb.2021.03.008.
8. [8] Fettiplace R, Nam J-H. Tonotopy in calcium homeostasis and vulnerability of cochlear hair cells. Hear Res. 2019; 376: 11-21. https://doi.org/10.1016/j.heares.2018.11.002.

9. [9] Ding D, Liu H, Qi W, Jiang H, Li Y, Wu X, Sun H, Gross K, Salvi R. Ototoxic effects and mechanisms of loop diuretics. J Otol. 2016; 11(4): 145-156. https://doi.org/10.1016/j.joto.2016.10.001.
10. [10] Fan T, Xiang M-Y, Zhou R-Q, Li W, Wang L-Q, Guan P, Li G-L, Wang Y, Li J. Effect of sodium salicylate on calcium currents and exocytosis in cochlear inner hair cells: Implications for Tinnitus Generation. Neurosci Bull. 2021; 38: 69-80. https://doi.org/10.1007/s12264-021-00747-z.
11. [11] Kros CJ, Steyger PS. Aminoglycoside- and Cisplatin-Induced Ototoxicity: Mechanisms and Otoprotective Strategies. Cold Spring Harb Perspect Med. 2019;9(11):a033548. https://doi.org/10.1101/cshperspect.a033548.
12. [12] Sheppard A, Hayes SH, Chen GD, Ralli M, Salvi R. Review of salicylate-induced hearing loss, neurotoxicity, tinnitus and neuropathophysiology. Acta Otorhinolaryngol Ital. 2014;34(2):79-93.
13. [13] Bulut E, Budak M, Öztürk L, Türkmen MT, Uzun C, Sipahi T. DNA methylation of the prestin gene and outer hair cell electromotileresponse of the cochlea in salicylate administration. Turk J Med Sci. 2017; 47(5): 1626-33. https://doi.org/10.3906/sag-1604-137.
14. [14] Eroglu S, Cevizci R, Turan Dizdar H, Tansuker HD, Bulut E, Dilci A, Ustun S, Sirvanci S, Kaya OT, Bayazit D, Cakir BO, Oktay MF, Bayazit YA. Association of Conductive Hearing Loss with the Structural Changes in the Organ of Corti. ORL J Otorhinolaryngol Relat Spec. 2021;83(4):272-279. https://doi.org/10.1159/000513871.
15. [15] Ortekin SG, Kocyigit M, Yagiz R, Tas A, Bulut E, Koten M, Kanter M, Karasalihoglu AR. Assessment of protective effect of ascorbic acid in cisplatin ototoxicity on guinea pigs with electrophysiological tests and ultrastructural study: A Preliminary Study. Int J Surg Med. 2020; 5(2): 88-93. https://doi.org/10.5455/ijsm.Assessment-protective-effect-ascorbic-acid.
16. [16] Selimoglu E. Aminoglycoside-induced ototoxicity. Curr Pharm Des. 2007; 13(1): 119-126. https://doi.org/10.2174/138161207779313731.
17. [17] Hailey DW, Esterberg R, Linbo TH, Rubel EW, Raible DW. Fluorescent aminoglycosides reveal intracellular trafficking routes in mechanosensory hair cells. J Clin Invest. 2017; 127(2): 472-486. https://doi.org/10.1172/jci85052.
18. [18] Dillard LK, Martinez RX, Perez LL, Fullerton AM, Chadha S, McMahon CM. Prevalence of aminoglycoside-induced hearing loss in drug-resistant tuberculosis patients: A systematic review. J Infect. 2021; 83(1): 27-36. https://doi.org/10.1016/j.jinf.2021.05.010.
19. [19] Ben Romdhane H, Ben Fredj N, Chaabane A, Ben Aicha S, Chadly Z, Ben Fadhel N, Boughattas N, Aouam K. Interest of therapeutic drug monitoring of aminoglycosides administered by a monodose regimen. Nephrol Ther. 2019;15(2):110-114. https://doi.org/10.1016/j.nephro.2018.08.004.
20. [20] Bera S, Mondal D. Antibacterial efficacies of nanostructured aminoglycosides. ACS omega. 2022; 7(6): 4724-4734. https://doi.org/10.1021/acsomega.1c04399.
21. [21] Ishikawa M, García-Mateo N, Čusak A, López-Hernández I, Fernández-Martínez M, Müller M, Rüttiger L, Singer W, Löwenheim H, Kosec G. Lower ototoxicity and absence of hidden hearing loss point to gentamicin C1a and apramycin as promising antibiotics for clinical use. Sci Rep. 2019; 9(1): 2410. https://doi.org/10.1038/s41598-019-38634-3.
22. [22] Ding D, Allman BL, Salvi R. Review: ototoxic characteristics of platinum antitumor drugs. Anat Rec (Hoboken). 2012;295(11):1851-1867. https://doi.org/10.1002/ar.22577.
23. [23] So H, Kim H, Lee JH, Park C, Kim Y, Kim E, Kim JK, Yun KJ, Lee KM, Lee HY, Moon SK, Lim DJ, Park R. Cisplatin cytotoxicity of auditory cells requires secretions of proinflammatory cytokines via activation of ERK and NF-kappaB. J Assoc Res Otolaryngol. 2007;8(3):338-355. https://doi.org/10.1007/s10162-007-0084-9.
24. [24] Prayuenyong P, Baguley DM, Kros CJ, Steyger PS. Preferential Cochleotoxicity of Cisplatin. Front Neurosci. 2021;15:695268. https://doi.org/10.3389/fnins.2021.695268.
25. [25] Nikitkina YY, Kryukov A, Kunel’skaya N, Temnov A. Hearing loss when taking cisplatin, depending on the dose. Russ Otorhinolaryngol. 2023;22(5):53–59. https://doi.org/10.18692/1810-4800-2023-5-53-59.
26. [26] Zhang F-Y, Xue Y-X, Liu W-J, Yao Y-L, Ma J, Chen L, Shang X-L. Changes in the Numbers of Ribbon Synapses and Expression of RIBEYE in Salicylate-Induced Tinnitus. Cell Physiol Biochem. 2014; 34(3): 753-767. https://doi.org/10.1159/000363040.
27. [27] Dillard LK, Fullerton AM, McMahon CM. Ototoxic hearing loss from antimalarials: A systematic narrative review. Travel Med Infect Dis. 2021; 43: 102117. https://doi.org/10.1016/j.tmaid.2021.102117.
28. [28] Uzun C, Koten M, Adalı M, Yorulmaz F, Yağız R, Karasalihoğlu A. Reversible ototoxic effect of azithromycin and clarithromycin on transiently evoked otoacoustic emissions in guinea pigs. J Laryngol Otol. 2001; 115: 622-628. https://doi.org/10.1258/0022215011908676.
29. [29] Uzun C. Tinnitus due to clarithromycin. J Laryngol Otol.. 2003; 117: 1006-1007. https://doi.org/10.1258/002221503322683984.
30. [30] Ikeda AK, Prince AA, Chen JX, Lieu JE, Shin JJ. Macrolide‐associated sensorineural hearing loss: a systematic review. The Laryngoscope. 2018; 128(1): 228-236. https://doi.org/10.1002/lary.26799.
31. [31] Riga M, Psarommatis I, Korres S, Lyra C, Papadeas E, Varvutsi M, Ferekidis E, Apostolopoulos N. The effect of treatment with vincristine on transient evoked and distortion product otoacoustic emissions. Int J Pediatr Otorhinolaryngol. 2006; 70(6): 1003-1008. https://doi.org/10.1016/j.ijporl.2005.10.011.
32. [32] Yoon Y, Jung K, Sadun A, Shin H-C, Koh J. Ethambutol-induced vacuolar changes and neuronal loss in rat retinal cell culture: mediation by endogenous zinc. Toxicol Appl Pharmacol. 2000; 162 2: 107-114. https://doi.org/10.1006/TAAP.1999.8846.
33. [33] Brown A, Lupo P, Okcu M, Lau C, Rednam S, Scheurer M. SOD2 genetic variant associated with treatment-related ototoxicity in cisplatin-treated pediatric medulloblastoma. Cancer Med. 2015; 4: 1679-1686. https://doi.org/10.1002/cam4.516.
34. [34] Güven SG, Erdoğan H, Arslan M, Ersoy O, Bulut E, Çilingir Kaya ÖT, Şirvancı S, Uzun C. The Effects of Memantine on Cisplatin-Induced Ototoxicity. Audiol Neurotol. 2024: 1-15. https://doi.org/10.1159/000542496.
35. [35] van Gendt MJ, Koka K, Kalkman RK, Stronks HC, Briaire JJ, Litvak L, Frijns JHM. Simulating intracochlear electrocochleography with a combined model of acoustic hearing and electric current spread in the cochlea. J Acoust Soc Am. 2020;147(3):2049. https://doi.org/10.1121/10.0000948.
36. [36] Yilmaz A, Uckaya F, Bayindir N, Guler EM, Toprak A, Kocyigit A, Esrefoglu M, Topcu G. Comparing healing effect against ulcerative colitis and toxicological effects of Rosmarinus officinalis: A comprehensive in vivo study of an edible plant in rats. J Food Biochem. 2022; 46(11): e14299. https://doi.org/10.1111/jfbc.14299.
37. [37] He F, Huang X, Wei G, Lin X, Zhang W, Zhuang W, He W, Zhan T, Hu H, Yang H. Regulation of ACSL4-Catalyzed Lipid Peroxidation Process Resists Cisplatin Ototoxicity. Oxid Med Cell Longev. 2022;2022:3080263. https://doi.org/10.1155/2022/3080263.
38. [38] Zhu RZ, Li BS, Gao SS, Seo JH, Choi B-M. Luteolin inhibits H2O2-induced cellular senescence via modulation of SIRT1 and p53. Korean J Physiol Pharmacol. 2021; 25(4): 297-305. https://doi.org/10.4196/kjpp.2021.25.4.297.
39. [39] Yilmaz A, Koca M, Ercan S, Acar OO, Boga M, Sen A, Kurt A. Amelioration potential of synthetic oxime chemical cores against multiple sclerosis and Alzheimer's diseases: Evaluation in aspects of in silico and in vitro experiments. J Mol Struct. 2024; 1318: 139193. https://doi.org/10.1016/j.molstruc.2024.139193.
40. [40] Kang BC, Yi J, Kim SH, Pak JH, Chung JW. Dexamethasone treatment of murine auditory hair cells and cochlear explants attenuates tumor necrosis factor-α-initiated apoptotic damage. PLoS One. 2023 ;18(9):e0291780. https://doi.org/10.1371/journal.pone.0291780.
41. [41] Tsinaslanidou Z, Tsaligopoulos M, Angouridakis N, Vital V, Kekes G, Constantinidis J. The Expression of TNFα, IL-6, IL-2 and IL-8 in the Serum of Patients with Idiopathic Sudden Sensorineural Hearing Loss: Possible Prognostic Factors of Response to Corticosteroid Treatment. Audiol Neurotol Extra. 2016; 6(1): 9-19. https://doi.org/10.1159/000442016.
42. [42] Shih CP, Kuo CY, Lin YY, Lin YC, Chen HK, Wang H, Chen HC, Wang CH. Inhibition of Cochlear HMGB1 Expression Attenuates Oxidative Stress and Inflammation in an Experimental Murine Model of Noise-Induced Hearing Loss. Cells. 2021;10(4):810. https://doi.org/10.3390/cells10040810.
43. [43] Lee JH, Oh SH, Kim TH, Go YY, Song J-J. Anti-apoptotic effect of dexamethasone in an ototoxicity model. Biomater Res. 2017; 21(1): 4. https://doi.org/10.1186/s40824-017-0090-x.
44. [44] Li Y, Xu H, Shi J, Li C, Li M, Zhang X, Xue Q, Qiu J, Cui L, Sun Y, Song X, Chen L. Regulation of the p53/SLC7A11/GPX4 Pathway by Gentamicin Induces Ferroptosis in HEI-OC1 Cells. Otol Neurotol. 2024; 45(8):947-953. https://doi.org/10.1097/mao.0000000000004271.
45. [45] Liu Z, Zhang H, Hong G, Bi X, Hu J, Zhang T, An Y, Guo N, Dong F, Xiao Y, Li W, Zhao X, Chu B, Guo S, Zhang X, Chai R, Fu X. Inhibition of Gpx4-mediated ferroptosis alleviates cisplatin-induced hearing loss in C57BL/6 mice. Mol Ther. 2024; 32(5): 1387-1406. https://doi.org/10.1016/j.ymthe.2024.02.029.
46. [46] Zhan T, Xiong H, Pang J, Zhang W, Ye Y, Liang Z, Huang X, He F, Jian B, He W, Gao Y, Min X, Zheng Y, Yang H. Modulation of NAD+ biosynthesis activates SIRT1 and resist cisplatin-induced ototoxicity. Toxicol Lett. 2021;349:115-123. https://doi.org/10.1016/j.toxlet.2021.05.013.
47. [47] Lin SCY, Thorne PR, Housley GD, Vlajkovic SM. Purinergic Signaling and Aminoglycoside Ototoxicity: The Opposing Roles of P1 (Adenosine) and P2 (ATP) Receptors on Cochlear Hair Cell Survival. Front Cell Neurosci. 2019;13:207. https://doi.org/10.3389/fncel.2019.00207.
48. [48] Bulut E, Arslan M, Uzun C. Cochlear origin of tinnitus and outer hair cell motor protein Prestin as a biomarker for tinnitus. Med Hypotheses. 2025; 194: 111528. https://doi.org/10.1016/j.mehy.2024.111528.
49. [49] Zhang Y, Fang Q, Wang H, Qi J, Sun S, Liao M, Wu Y, Hu Y, Jiang P, Cheng C, Qian X, Tang M, Cao W, Xiang S, Zhang C, Yang J, Gao X, Ying Z, Chai R. Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage. Autophagy. 2022; 19: 75-91. https://doi.org/10.1080/15548627.2022.2062872.
50. [50] Liu Y, Yu Y, Chu H, Bing D, Wang S, Zhou L-Q, Chen J, Chen Q, Pan C, Sun Y-B, Cui Y. 17-DMAG induces Hsp70 and protects the auditory hair cells from kanamycin ototoxicity in vitro. Neurosci Lett. 2015; 588: 72-77. https://doi.org/10.1016/j.neulet.2014.12.060.
51. [51] Song B, Anderson D, Schacht J. Protection from gentamicin ototoxicity by iron chelators in guinea pig in vivo. J Pharmacol Exp Ther. 1997; 282 1: 369-377. https://doi.org/10.1016/S0022-3565(24)36819-3.
52. [52] Özel H, Özdoğan F, Gürgen S, Esen E, Genç S, Selçuk A. Comparison of the protective effects of intratympanic dexamethasone and methylprednisolone against cisplatin-induced ototoxicity. J Laryngol Otol. 2016; 130(3): 225-234. https://doi.org/10.1017/s0022215115003473.
53. [53] Tas A, Bulut E, Tas M, Yagiz R, Turan P, Huseyinoglu A, Karasalihoglu AR. Effects of intratympanic steroid on cisplatin ototoxicity: an electrophysiological and ultrastructural study. Int J Hematol Oncol. 2018; 28(2): 104-111. https://doi.org/10.4999/uhod.181742.
54. [54] Chen Y, Gu J, Liu J, Tong L, Shi F, Wang X, Wang X, Yu D, Wu H. Dexamethasone-loaded injectable silk-polyethylene glycol hydrogel alleviates cisplatin-induced ototoxicity. Int J Nanomedicine. 2019; 4211-4127. https://doi.org/10.2147/ijn.s195336.
55. [55] Wang X, Chen Y, Tao Y, Gao Y, Yu D, Wu H. A666-conjugated nanoparticles target prestin of outer hair cells preventing cisplatin-induced hearing loss. Int J Nanomedicine. 2018; 7517-7531. https://doi.org/10.2147/ijn.s170130.
56. [56] Yüksel Aslıer NG, Tağaç AA, Durankaya SM, Çalışır M, Ersoy N, Kırkım G, Yurdakoç K, Bağrıyanık HA, Yılmaz O, Sütay S, Güneri EA. Dexamethasone-loaded chitosan-based genipin-cross-linked hydrogel for prevention of cisplatin induced ototoxicity in Guinea pig model. Int J Pediatr Otorhinolaryngol. 2019; 122: 60-69. https://doi.org/10.1016/j.ijporl.2019.04.003.
57. [57] Davies C, Bergman J, Misztal C, Ramchandran R, Mittal J, Bulut E, Shah V, Mittal R, Eshraghi AA. The Outcomes of Cochlear Implantation in Usher Syndrome: A Systematic Review. J Clin Med. 2021;10(13):2915. https://doi.org/10.3390/jcm10132915.
58. [58] Cai J, Wu X, Li X, Ma C, Xu L, Guo X, Li J, Wang H, Han Y. Allicin Protects against Cisplatin-Induced Stria Vascularis Damage: Possible Relation to Inhibition of Caspase-3 and PARP-1-AIF-Mediated Apoptotic Pathways. ORL J Otorhinolaryngol Relat Spec. 2019;81(4):202-214. https://doi.org/10.1159/000500557.
59. [59] Kim YJ, Lee J-S, Kim H, Jang JH, Choung Y-H. Gap junction-mediated intercellular communication of cAMP prevents CDDP-induced ototoxicity via cAMP/PKA/CREB pathway. Int J Mol Sci. 2021; 22(12): 6327. https://doi.org/10.3390/ijms22126327.
60. [60] Guan M, Fang Q, He Z, Li Y, Qian F, Qian X, Lu L, Zhang X, Liu D, Qi J, Zhang S, Tang M, Gao X, Chai R. Inhibition of ARC decreases the survival of HEI-OC-1 cells after neomycin damage in vitro. Oncotarget. 2016;7(41):66647-66659. https://doi.org/10.18632/oncotarget.11336.