Effect of Transtympanic Injection of Melatonin on Cisplatin-Induced Ototoxicity

Mehmet Gokhan Demir, Niyazi Altintoprak, Sedat Aydin, Ebru Kosemihal, Kayhan Basak
2016 The Journal of International Advanced Otology  
Original Article Cisplatin is a well-known chemotherapeutic substance that is commonly used in head and neck cancer treatment. As is the nature of various cancer drugs, cisplatin has many side effects, including bone marrow toxicity, renal toxicity, gastrointestinal toxicity, peripheral neuropathy, and ototoxicity. These clinical side effects are mostly dose-dependent. Formation of ototoxicity depends on the outer cells of the cochlea indirectly and damage of the auditory neurons directly [1] .
more » ... The decrease in the antioxidant protection of the organ of corti and the increase in the synthesis of reactive oxygen species (ROS) level [2] [3] [4] play roles in cisplatin toxicity. In the cochlea, the levels of glutathione, glutathione peroxidase, and reductase decrease, and the levels of superoxide dismutase, catalase, and malondialdehyde increase [4] . However, the cochlea's protective upregulation mechanism mitigates the ototoxic effects of cisplatin [5] . Many antioxidants prevented the ototoxic effects of cisplatin such as amifostine, D-methionine, 4-methylthiobenzoic acid, sodium thiosulfate, and superoxide dismutase [2, 6, 7] . Cochlear destruction by ROS has been found on the outer hair cells and at the intraperilymphatic level [7, 8] . Melatonin is a secreted pineal gland hormone synthesized in the circadian rhythm, mainly in the dark. It has a neuroendocrinoimmunological role in the human body. The melatonin cycle affects the central nervous system, retina, cochlea, immune system, and Harderian gland through the melatonin receptors of these organ systems [9] [10] [11] [12] . In addition, the antioxidant role of melatonin is well known [13] . The objective of our study is to scrutinize the antioxidant effect of intratympanic melatonin on cisplatin-induced ototoxicity. MATERIALS and METHODS Animals Healthy adult male Wistar albino rats weighing up to 180-320 g were obtained from Marmara University Research Center for the study. The rats were preserved under ideal laboratory conditions [temperature (21±1°C), humidity (70±10%), and 12 h light-dark cy-This study was presented at the 3 rd Congress of European ORL-HNS, 7-11 June 2015, Prague, Czech Republic. OBJECTIVE: Cisplatin is a chemotherapeutic agent that is widely used in cancer treatment. Numerous side effects have been detected, one of which is ototoxicity. Melatonin, a product of the pineal gland, has a neuroendocrinoimmunological role in vertebrates. In the present study, we investigated the effects of melatonin on cisplatin-induced ototoxicity. MATERIALS and METHODS: Twenty-four Wistar albino rats were divided into three groups. Group 1 was administered both intraperitoneal and transtympanic saline; Group 2, 12 mg/kg of intraperitoneal single-dose cisplatin and transtympanic saline; and Group 3, 12 mg/kg of intraperitoneal single-dose cisplatin and 0.1 mg/mL of transtympanic melatonin for 5 days. Before and after the procedure, distortion product otoacoustic emissions and auditory brainstem responses of all the rats were measured. At the end of the procedure, the cochleas of the rats were investigated at the microscopic level. RESULTS: Group 3 had lesser threshold shift in otoacoustic emissions and auditory brainstem responses at all frequencies than Group 2 (p<0.005). The difference was not significant between Group 1 and Group 3. On the microscopic level, more epithelial loss and less TNF staining were detected in Group 2 than in Group 3. CONCLUSION: As an antioxidant and immune modulator, melatonin is effective against cisplatin ototoxicity. Both hearing thresholds and tissue investigations supported this conclusion. Melatonin can also be used to treat cisplatin ototoxicity using transtympanic local application in lower doses.
doi:10.5152/iao.2015.1094 pmid:26915150 fatcat:5cwqab3kwbfpnhkiodyrcro4iu