Protective effect of trimetazidine on amikacin-induced ototoxicity in rats Fadlullah Aksoy a , Remzi Dogan a, *, Orhan Ozturan a , Sabri Baki Eren a , Bayram Veyseller a , Alev Pektas b , O ¨ nder Hu ¨ seyinbas c a Bezmialem Vakif University, Department of Otorhinolaryngology, Fatih, Istanbul, Turkey b Bezmialem Vakif University, Faculty of Health Sciences, Department of Audiology, Fatih, Istanbul, Turkey c Bezmialem Vakif University, Research Center, Fatih, Istanbul, Turkey 1. Introduction Ototoxicity is a clinical condition, usually brought about by the detrimental effects of some chemical agent on the auditory and balance functions of the ear [1]. More than 130 agents are known to have ototoxic effects, with aminoglycoside (AG) and macrolide antibiotics, loop diuretics, NSAIDs, antineoplastic and antimalarial drugs taking the lead [1]. While amikacin (AK), kanamycin and neomycin cause damage primarily to the cochlea, streptomycin and gentamicin primarily cause vestibular damage [2]. Cochlear damage may lead to permanent hearing loss, and vestibular damage may lead to vertigo, ataxia and/or nystagmus [3]. AK is a semi-synthetic AG, produced by the acetylation of kanamycin A. The specific properties of its structure make it resistant to bacterial enzymes which can inactivate natural AGs such as gentamicin, kanamycin and tobramycin, thus it has the broadest spectrum among all AGs. AK is a frequently preferred antibiotic due to its rapid action, broad spectrum, lower bacterial resistance, its synergetic effects with beta-lactam antibiotics, and its lower cost [4]. However, 10–80% of patients who are treated with AK are reported to suffer from its ototoxic effects. The hearing loss is typically neurosensorial, nonsyndromic, bilateral, progres- sive, and is a high-frequency hearing loss [5]. Since the hair cells of the cochlea cannot regenerate, the hearing loss is irreversible [6]. AK ototoxicity is brought about by the drug’s excitotoxic effects, caused by impairment of mitochondrial protein synthesis and overactivation of glutamatergic receptors (N-methyl-D-aspartate), which increase the formation of free radicals and induce apoptosis [7,8]. There have been numerous studies of oxidative stress leading to sensory neural hearing loss [9–11]. Experimental studies have shown that antioxidant agents may prevent AG ototoxicity [12–16]. International Journal of Pediatric Otorhinolaryngology 78 (2014) 663–669 A R T I C L E I N F O Article history: Received 22 September 2013 Received in revised form 20 January 2014 Accepted 22 January 2014 Available online 5 February 2014 Keywords: ABR Amikacin DPOAE Oxidative status Trimetazidine A B S T R A C T Objective: Aminoglycoside antibiotics are known to have ototoxic effects and may induce sensorineural hearing loss. This study investigated the protective effect of trimetazidine, which has antioxidant and cytoprotective properties, against amikacin ototoxicity. Methods: Thirty-two male rats were divided into four groups – amikacin, amikacin + trimetazidine, trimetazidine, and control groups. Trimetazidine, 10 mg/kg per day, was given for 14 days by oral gavage. Amikacin, 600 mg/kg per day, was also given for 14 days, by the intramuscular route. Distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) tests were applied to the rats for hearing assessment. At the termination of the study, the biochemical parameters were calculated to evaluate the oxidative status. Results: The DPOAE values of the amikacin group were significantly lower on the 7th and 14th days than those of the trimetazidine + amikacin group and there was an increase in the ABR thresholds. The ABR thresholds for the amikacin group on the 7th and 14th days were significantly higher than the levels on the first day of the study, while there was no significant increase in those values in the trimetazidine + amikacin group. The total oxidant status (TOS) and oxidant status index (OSI) values of the amikacin group were significantly higher than those of the trimetazidine + amikacin group. The total antioxidant status (TAS) values of the amikacin group were lower than those of the trimetazidine + amikacin group. Conclusions: The audiologic tests and biochemical parameters investigated in this study both point to the protective effect of trimetazidine against amikacin-induced ototoxicity. ß 2014 Elsevier Ireland Ltd. All rights reserved. * Corresponding author at: Bezmialem Vakif University, Medical Faculty, Department of Otorhinolaryngology, Fatih, Istanbul, Turkey. Tel.: +90 505 7915844; fax: +90 212 533 2326. E-mail address: dr.remzidogan@gmail.com (R. Dogan). Contents lists available at ScienceDirect International Journal of Pediatric Otorhinolaryngology jo ur n al ho m ep ag e: ww w.els evier .c om /lo cat e/ijp o r l 0165-5876/$ – see front matter ß 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijporl.2014.01.031