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CC BY-NC-ND 4.0 · Int Arch Otorhinolaryngol 2020; 24(01): e47-e52
DOI: 10.1055/s-0039-1698782
Original Research
Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil

Otoprotection Mechanisms Against Oxidative Stress Caused by Cisplatin

Maiara Santos Gonçalves 
1   Department of Phonoaudiology, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
,
Aron Ferreira da Silveira
2   Department of Morphology, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
,
Adriana de Andrade Batista Murashima
3   Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirao Preto, SP, Brazil
,
Maria Rossato
3   Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirao Preto, SP, Brazil
,
Miguel Angelo Hippolito
3   Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirao Preto, SP, Brazil
› Author Affiliations
Further Information

Publication History

04 July 2019

07 September 2019

Publication Date:
09 January 2020 (online)

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Abstract

Introduction Cisplatin damages the auditory system and is related to the generation of free radicals. Glutathione peroxidase is an endogenous free radicals remover.

Objective To investigate the mechanisms involved in otoprotection by N-acetylcysteine through the expression of glutathione peroxidase in outer hair cells from rats treated with cisplatin.

Methods Male Wistar rats were intraperitoneally injected with cisplatin (8 mg/Kg) and/or received oral administration by gavage of N-acetylcysteine (300 mg/Kg) for 3 consecutive days. On the 4th day, the animals were euthanized and beheaded. The tympanic bullae were removed and prepared for scanning electron microscopy and immunofluorescence.

Results Among the groups exposed to ototoxic doses of cisplatin, there was an increase in glutathione peroxidase immunostaining in two groups, the one exposed to cisplatin alone, and the group exposed to both cisplatin and N-acetylcysteine.

Conclusion The expression of glutathione peroxidase in the outer hair cells of rats exposed to cisplatin showed the synthesis of this enzyme under cellular toxicity conditions.

Keywords

cisplatin - toxicity - free radicals - cochlea - oxidative stress
 

  • References

  • 1 Riga MG, Chelis L, Kakolyris S. , et al. Transtympanic injections of N-acetylcysteine for the prevention of cisplatin-induced ototoxicity: a feasible method with promising efficacy. Am J Clin Oncol 2013; 36 (01) 1-6
    CrossrefPubMedGoogle Scholar
  • 2 Somani SM, Husain K, Jagannathan R, Rybak LP. Amelioration of cisplatin-induced oto and nephrotoxicity by protective agents. Ann Neurosci 2001; 8: 101-113
    Google Scholar
  • 3 Rybak LP. Mechanisms of cisplatin ototoxicity and progress in otoprotection. Curr Opin Otolaryngol Head Neck Surg 2007; 15 (05) 364-369
    CrossrefPubMedGoogle Scholar
  • 4 McKeage MJ. Comparative adverse effect profiles of platinum drugs. Drug Saf 1995; 13 (04) 228-244
    CrossrefPubMedGoogle Scholar
  • 5 Casares C, Ramírez-Camacho R, Trinidad A, Roldán A, Jorge E, García-Berrocal JR. Reactive oxygen species in apoptosis induced by cisplatin: review of physiopathological mechanisms in animal models. Eur Arch Otorhinolaryngol 2012; 269 (12) 2455-2459
    CrossrefPubMedGoogle Scholar
  • 6 Dickey DT, Wu YJ, Muldoon LL, Neuwelt EA. Protection against cisplatin-induced toxicities by N-acetylcysteine and sodium thiosulfate as assessed at the molecular, cellular, and in vivo levels. J Pharmacol Exp Ther 2005; 314 (03) 1052-1058
    CrossrefPubMedGoogle Scholar
  • 7 Schweitzer VG. Cisplatin-induced ototoxicity: the effect of pigmentation and inhibitory agents. Laryngoscope 1993; 103 (4 Pt 2): 1-52
    PubMedGoogle Scholar
  • 8 van Ruijven MWM, de Groot JCMJ, Klis SFL, Smoorenburg GF. The cochlear targets of cisplatin: an electrophysiological and morphological time-sequence study. Hear Res 2005; a; 205 (1-2): 241-248
    CrossrefPubMedGoogle Scholar
  • 9 Rybak LP, Husain K, Morris C, Whitworth C, Somani S. Effect of protective agents against cisplatin ototoxicity. Am J Otol 2000; 21 (04) 513-520
    Google Scholar
  • 10 Campbell KCM, Kalkanis J, Glatz R. Ototoxicity: mechanisms, protective agents and monitoring. Curr Opin Otol Head Neck Surg 2000; 8: 436-440
    Google Scholar
  • 11 Feghali JG, Liu W, Van De Water TR. L-n-acetyl-cysteine protection against cisplatin-induced auditory neuronal and hair cell toxicity. Laryngoscope 2001; 111 (07) 1147-1155
    CrossrefPubMedGoogle Scholar
  • 12 Rybak LP, Mukherjea D, Jajoo S, Ramkumar V. Cisplatin ototoxicity and protection: clinical and experimental studies. Tohoku J Exp Med 2009; 219 (03) 177-186
    CrossrefPubMedGoogle Scholar
  • 13 Holdiness MR. Clinical pharmacokinetics of N-acetylcysteine. Clin Pharmacokinet 1991; 20 (02) 123-134
    CrossrefPubMedGoogle Scholar
  • 14 Neuwelt EA, Pagel MA, Hasler BP, Deloughery TG, Muldoon LL. Therapeutic efficacy of aortic administration of Nacetylcysteine against bone marrow toxicity after intracarotid administration of alkylator, with or without glutathione depletion in a rat model. Cancer Res 2001; 61: 7868-7874
    PubMedGoogle Scholar
  • 15 Strayer DS, Rubin E. Cell adaptation, cell injury and cell death. In: Rubin R, Strauer DS. Rubin's Pathology: clinicopathologic foundations of medicine, 6th edn. Philadelphia: Lippincott Williams & Wilkins; 2012: 01-46
    Google Scholar
  • 16 Jero J, Coling DE, Lalwani AK. The use of Preyer's reflex in evaluation of hearing in mice. Acta Otolaryngol 2001; 121 (05) 585-589
    CrossrefPubMedGoogle Scholar
  • 17 De Freitas MR, Figueiredo AA, Brito GAC. , et al. The role of apoptosis in cisplatin-induced ototoxicity in rats. Rev Bras Otorrinolaringol (Engl Ed) 2009; 75 (05) 745-752
    Google Scholar
  • 18 Hyppolito MA, Oliveira JAA, Rossato M, Holanda F. Cisplatin ototoxicity and otoprotetor to cilliated cells by ginkgo biloba extract: anatomic and eletrophisiologic study. Rev Bras Otorrinolaringol (Engl Ed) 2003; 69 (04) 504-511
    CrossrefGoogle Scholar
  • 19 Hyppolito MA, de Oliveira AA, Lessa RM, Rossato M. [Amifostine otoprotection to cisplatin ototoxicity: a guinea pig study using otoacoustic emission distortion products (DPOEA) and scanning electron microscopy]. Rev Bras Otorrinolaringol (Engl Ed) 2005; 71 (03) 268-273
    CrossrefGoogle Scholar
  • 20 Gutteridge JM, Halliwell B. Antioxidants: Molecules, medicines, and myths. Biochem Biophys Res Commun 2010; 393 (04) 561-564
    CrossrefPubMedGoogle Scholar
  • 21 Rybak LP, Whitworth CA. Ototoxicity: therapeutic opportunities. Drug Discov Today 2005; 10 (19) 1313-1321
    CrossrefPubMedGoogle Scholar
  • 22 Wu YJ, Muldoon LL, Neuwelt EA. The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J Pharmacol Exp Ther 2005; 312 (02) 424-431
    CrossrefPubMedGoogle Scholar
  • 23 Thomas Dickey D, Muldoon LL, Kraemer DF, Neuwelt EA. Protection against cisplatin-induced ototoxicity by N-acetylcysteine in a rat model. Hear Res 2004; 193 (1-2): 25-30
    CrossrefPubMedGoogle Scholar
  • 24 Muldoon LL, Pagel MA, Kroll RA. , et al. Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity. Clin Cancer Res 2000; 6 (01) 309-315
    PubMedGoogle Scholar
  • 25 Neuwelt EA, Pagel MA, Kraemer DF, Peterson DR, Muldoon LL. Bone marrow chemoprotection without compromise of chemotherapy efficacy in a rat brain tumor model. J Pharmacol Exp Ther 2004; 309 (02) 594-599
    CrossrefPubMedGoogle Scholar