Abstract
Previous studies have described the effects of zingerone (ZO) on cisplatin (CXP)-induced injury to the kidneys, liver, and other organs but not to the cochlea. This study aimed to investigate the effects of ZO on CXP-induced ototoxicity. Eight-week-old Sprague–Dawley rats were used and divided into a control group, a CXP group, and a CXP + ZO group. Rats in the CXP group received 5 mg/kg/day CXP intraperitoneally for five days. Rats in the CXP + ZO group received 5 mg/kg/day CXP intraperitoneally for five days and 50 mg/kg/day ZO intraperitoneally for seven days. Auditory brainstem response thresholds (ABRTs) were measured before (day 0) and after (day 10) drug administration. Cochlear histology was examined using hematoxylin and eosin (H&E) staining and cochlear whole mounts. The expression levels of cytochrome P450 (CYP)1A1, CYP1B1, inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NFκB), tumor necrosis factor alpha (TNFα), and interleukin 6 (IL6) were estimated using quantitative reverse transcription-polymerase chain reaction. The expression levels of heme oxygenase 1 (HO1) and caspase 3 were analyzed via Western blotting. The auditory thresholds at 4, 8, and 16 kHz were attenuated in the CXP + ZO group compared with the CXP group. The mRNA expression levels of CYP1A1, CYP1B1, iNOS, NFκB, TNFα, and IL6 were lower in the CXP + ZO group than in the CXP group. The protein expression levels of HO1 and caspase 3 were lower in the CXP + ZO group than in the CXP group. Cotreatment with ZO exerted otoprotective effects against CXP-induced cochlear injury via antioxidative and anti-inflammatory activities involving CYPs, iNOS, NFκB, and TNFα.
Highlights
Oxidative stress combined with inflammation in the cochlea is one of the main pathophysiologies of cochlear hearing loss [1,2,3]
Cisplatin (CXP)-induced ototoxicity is accompanied by increases in the levels of reactive oxygen species; the inflammatory molecules tumor necrosis factor alpha (TNFα), interleukin 1β (IL1β), and interleukin 6 (IL6); and nuclear factor kappa B (NFκB) [4,5,6]
This histological damage is associated with shifts in the auditory brainstem response (ABR) threshold (ABRT) and optoacoustic emissions, which have been characterized as dose-dependent, and with irreversible hearing loss [10,11]
Summary
Oxidative stress combined with inflammation in the cochlea is one of the main pathophysiologies of cochlear hearing loss [1,2,3]. Activation of NFκB increases the levels of proinflammatory cytokines, such as TNFα, IL1β, and IL6, in the cochlea [7] These oxidative stress responses and inflammatory responses induce apoptosis activation by activating caspase 3 [8]. Animal studies have shown that these ototoxic injuries are initiated by the degeneration and loss of cochlear outer hair cells and are accompanied by neuronal death and spiral ganglion cell degeneration. This histological damage is associated with shifts in the auditory brainstem response (ABR) threshold (ABRT) and optoacoustic emissions, which have been characterized as dose-dependent, and with irreversible hearing loss [10,11]. The clinical use of these agents has been impeded by the questionable and potentially toxic effects of human doses
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