Background/Aims: Cisplatin is a chemotherapeutic agent. The use of remote ischemic preconditioning (RIPC) was proposed after the observation that ischemic preconditioning of a cardiac vascular area could protect another completely distinctly. Methods: This is an experimental study. Male Wistar rats were anesthetized, and they underwent a hearing evaluation via measurement of the brainstem auditory evoked potential (BSAEP). Then, cisplatin was administered intraperitoneally (IP) at a dose of 8 mg/kg/day for 4 consecutive days to group 1, whereas saline solution was administered IP to group 2. In groups 3 and 4, ischemia of the right hind paw was performed for 10 min, followed by reperfusion for 30 min, after which cisplatin or saline was administered IP to group 3 or group 4, respectively. Afterwards, all animals were evaluated via the BSAEP. The right cochlea was dissected for immunohistochemistry. Results: RIPC lowered the increase in BSAEP of the animals treated with cisplatin (p = 0.0146). Weight loss decreased in the animals subjected to RIPC (p < 0.005). In group 3, RIPC reversed immunostaining for tumor necrosis factor-α and inducible nitric oxide synthase in the stria vascularis injured by cisplatin (p < 0.05). Conclusion: RIPC protects against systemic toxicity and ototoxicity induced by cisplatin in rats.

1.
Schacht J, Talaska AE, Rybak LP: Cisplatin and aminoglycoside antibiotics: hearing loss and its prevention. Anat Rec (Hoboken) 2012;295:1837-1850.
2.
Rybak LP, Mukherjea D, Jajoo S, Ramkumar V: Cisplatin ototoxicity and protection: clinical and experimental studies. Tohoku J Exp Med 2009;219:177-186.
3.
Chang J, Jung HH, Yang JY, Lee S, Choi J, Im GJ, Chae SW: Protective effect of metformin against cisplatin-induced ototoxicity in an auditory cell line. J Assoc Res Otolaryngol 2014;15:149-158.
4.
Borges GC, Baraúna GN, Lopes Filho OC, Borges RHM: Ototoxicidade causada pela cisplatina em crianças. Estudo retrospectivo. Braz J Otorhinolaryngol 2001;67:292-295.
5.
Marshak T, Steiner M, Kaminer M, Levy L, Shupak A: Prevention of cisplatin-induced hearing loss by intratympanic dexamethasone: a randomized controlled study. Otolaryngol Head Neck Surg 2014;150:983-990.
6.
Li Y, Womer RB, Silber JH: Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose. Eur J Cancer 2004;40:2445-2451.
7.
Yancey A, Harris MS, Egbelakin A, Gilbert J, Pisoni DB, Renbarger J: Risk factors for cisplatin-associated ototoxicity in pediatric oncology patients. Pediatr Blood Cancer 2012;59:144-148.
8.
Rednam S, Scheurer ME, Adesina A, Lau CC, Okcu MF: Glutathione S-transferase P1 single nucleotide polymorphism predicts permanent ototoxicity in children with medulloblastoma. Pediatr Blood Cancer 2013;60:593-598.
9.
Mandic A, Hansson J, Linder S, Shoshan MC: Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. J Biol Chem 2003;278:9100-9106.
10.
Chirtes F, Albu S: Prevention and restoration of hearing loss associated with the use of cisplatin. Biomed Res Int 2014;2014:925485.
11.
Waissbluth S, Salehi P, He X, Daniel SJ: Systemic dexamethasone for the prevention of cisplatin-induced ototoxicity. Eur Arch Otorhinolaryngol 2013;270:1597-1605.
12.
So H, Kim H, Kim Y, Kim E, Pae HO, Chung HT, Kim HJ, Kwon KB, Lee KM, Lee H-Y, Moon S-K, Park R: Evidence that cisplatin-induced auditory damage is attenuated by downregulation of pro-inflammatory cytokines via Nrf2/HO-1. J Assoc Res Otolaryngol 2008;9:290-306.
13.
Rybak LP, Whitworth CA, Mukherjea D, Ramkumar V: Mechanisms of cisplatin-induced ototoxicity and prevention. Hear Res 2007;226:157-167.
14.
So H, Kim H, Lee J-H, Park C, Kim Y, Kim E, Kim J-K, Yun K-J, Lee K-M, Lee H-Y, Moon S-K, Lim DJ, Park R: Cisplatin cytotoxicity of auditory cells requires secretions of proinflammatory cytokines via activation of ERK and NF-κB. J Assoc Res Otolaryngol 2007;8:338-355.
15.
Lopez-Gonzalez MA, Guerrero JM, Rojas F, Delgado F: Ototoxicity caused by cisplatin is ameliorated by melatonin and other antioxidants. J Pineal Res 2000;28:73-80.
16.
Kalkanis JG, Whitworth C, Rybak LP: Vitamin E reduces cisplatin ototoxicity. Laryngoscope 2004;114:538-542.
17.
Feghali JG, Liu W, Van De Water TR: L-N-acetyl-cysteine protection against cisplatin-induced auditory neuronal and hair cell toxicity. Laryngoscope 2001;111:1147-1155.
18.
Lynch ED, Gu R, Pierce C, Kil J: Reduction of acute cisplatin ototoxicity and nephrotoxicity in rats by oral administration of allopurinol and ebselen. Hear Res 2005;201:81-89.
19.
Campbell KC, Meech RP, Rybak LP, Hughes LF: D-Methionine protects against cisplatin damage to the stria vascularis. Hear Res 1999;138:13-28.
20.
Hyppolito MA, Oliveira JAAD, Rossato M, Holanda F: Ototoxicidade da cisplatina e otoproteção pelo extrato de Ginkgo biloba às células ciliadas externas: estudo anatômico e eletrofisiológico. Rev Bras Otorrinolaringol 2003;69:504-511.
21.
Huang X, Whitworth CA, Rybak LP: Ginkgo biloba extract (EGb 761) protects against cisplatin-induced ototoxicity in rats. Otol Neurotol 2007;28:828-833.
22.
Teranishi MA, Nakashima T: Effects of trolox, locally applied on round windows, on cisplatin-induced ototoxicity in guinea pigs. Int J Pediatr Otorhinolaryngol 2003;67:133-139.
23.
Cho SI, Lee JE, Do NY: Protective effect of silymarin against cisplatin-induced ototoxicity. Int J Pediatr Otorhinolaryngol 2014;78:474-478.
24.
Freitas MR: Caracterização morfofuncional da ototoxicidade por cisplatina em ratos: Avaliação do papel da apoptose e da otoproteção por amifostina. Fortaleza, Universidade Federal do Ceará, 2006, pp 169f.
25.
Murry CE, Jennings RB, Reimer KA: Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-1136.
26.
Tapuria N, Kumar Y, Habib MM, Abu Amara M, Seifalian AM, Davidson BR: Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury - a review. J Surg Res 2008;150:304-330.
27.
Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P: Regional ischemic “preconditioning” protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 1993;87:893-899.
28.
Boyko VV, Pisetska ME, Tyshchenko OM, Skoryi DI, Kozlova TV, Gorgol NI, Volchenko IV: Role of ischemic preconditioning in hepatic ischemia-reperfusion injury. Hepatobiliary Surg Nutr 2014;3:179-184.
29.
Tahir M, Arshid S, Heimbecker AM, Castro MS, Souza Montero EF, Fontes B, Fontes W: Evaluation of the effects of ischemic preconditioning on the hematological parameters of rats subjected to intestinal ischemia and reperfusion. Clinics (Sao Paulo) 2015;70:61-68.
30.
Otani H: Ischemic preconditioning: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 2008;10:207-247.
31.
Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, Vogel M, Sorensen K, Redington AN, MacAllister R: Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation 2002;106:2881-2883.
32.
Schmidt MR, Sloth AD, Johnsen J, Bøtker HE: Remote ischemic conditioning: the cardiologist's perspective. J Cardiovasc Med (Hagerstown) 2012;13:667-674.
33.
Küntscher MV, Schirmbeck EU, Menke H, Klar E, Gebhard MM, Germann G: Ischemic preconditioning by brief extremity ischemia before flap ischemia in a rat model. Plast Reconstr Surg 2002;109:2398-2404.
34.
Kocman EA, Ozatik O, Sahin A, Guney T, Kose AA, Dag I, Alatas O, Cetin C: Effects of ischemic preconditioning protocols on skeletal muscle ischemia-reperfusion injury. J Surg Res 2015;193:942-952.
35.
Souza Filho MV, Loiola RT, Rocha EL, Simão AF, Gomes AS, Souza MH, Ribeiro RA: Hind limb ischemic preconditioning induces an anti-inflammatory response by remote organs in rats. Braz J Med Biol Res 2009;42:921-929.
36.
Hsu SM, Raine L, Fanger H: Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 1981;29:577-580.
37.
Savaj S, Savoj J, Jebraili I, Sezavar SH: Remote ischemic preconditioning for prevention of contrast-induced acute kidney injury in diabetic patients. Iran J Kidney Dis 2014;8:457-460.
38.
Wang Y, Shen J, Xiong X, Xu Y, Zhang H, Huang C, Tian Y, Jiao C, Wang X, Li X: Remote ischemic preconditioning protects against liver ischemia-reperfusion injury via heme oxygenase-1-induced autophagy. PLoS One 2014;9:e98834.
39.
Zografos TA, Katritsis GD, Tsiafoutis I, Bourboulis N, Katsivas A, Katritsis DG: Effect of one-cycle remote ischemic preconditioning to reduce myocardial injury during percutaneous coronary intervention. Am J Cardiol 2014;113:2013-2017.
40.
Freitas MR, de Castro Brito GA, de Carvalho JV Jr, Gomes RM Jr, Barreto Martins MJ, de Albuquerque Ribeiro R: Light microscopy study of cisplatin-induced ototoxicity in rats. J Laryngol Otol 2009;123:590-597.
41.
Cappaert NL, Klis SF, Wijbenga J, Smoorenburg GF: Acceleration of cisplatin ototoxicity by perilymphatic application of 4-methylthiobenzoic acid. Hear Res 2005;203:80-87.
42.
Choi SJ, Kim SW, Lee JB, Lim HJ, Kim YJ, Tian C, So HS, Park R, Choung YH: Gingko biloba extracts protect auditory hair cells from cisplatin-induced ototoxicity by inhibiting perturbation of gap junctional intercellular communication. Neuroscience 2013;244:49-61.
43.
Kim SJ, Park C, Han AL, Youn MJ, Lee JH, Kim Y, Kim ES, Kim HJ, Kim JK, Lee HK, Chung SY, So H, Park R: Ebselen attenuates cisplatin-induced ROS generation through Nrf2 activation in auditory cells. Hear Res 2009;251:70-82.
44.
Freitas MR, Silva VC, Brito GA, Carvalho Junior JV, Gomes Junior RM, Ribeiro Rde A: Distortion-product otoacoustic emissions and auditory brainstem responses sensitivity assessment in cisplatin-induced ototoxicity in rats. Braz J Otorhinolaryngol 2009;75:476-484.
45.
Knight KR, Kraemer DF, Winter C, Neuwelt EA: Early changes in auditory function as a result of platinum chemotherapy: use of extended high-frequency audiometry and evoked distortion product otoacoustic emissions. J Clin Oncol 2007;25:1190-1195.
46.
Adam AN: Some mechanisms of the protective effect of ischemic preconditioning on rat liver ischemia-reperfusion injury. Int J Gen Med 2014;7:483-489.
47.
Modun D, Giustarini D, Tsikas D: Nitric oxide-related oxidative stress and redox status in health and disease. Oxid Med Cell Longev 2014;2014:129651.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.