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Abstract
Previous preclinical studies have demonstrated the otoprotective effects of resveratrol (RV) at low doses. This study aimed to investigate the dose-dependent effects of RV in rats with cisplatin (CXP)-induced hearing loss. Sprague-Dawley rats (8-weeks old) were divided into six treatment groups (n = 12/group) and treated as follows: control, 0.5 mg/kg RV, 50 mg/kg RV, CXP, 0.5 mg/kg RV + CXP), and 50 mg/kg RV + CXP groups. CXP (3 mg/kg) was intraperitoneally injected for 5 days. RV (0.5 or 50 mg/kg) was intraperitoneally injected for 10 days from the first day of CXP administration. Auditory brainstem response (ABR) thresholds were measured before and within 3 days at the end of the drug administration. Cochlear tissues were harvested, and the outer hair cells were examined using cochlear whole mounts. The mRNA expression of NFκB, IL6, IL1β, and CYP1A1, and protein levels of aryl hydrocarbon receptor (AhR) and cytosolic and nuclear receptor for advanced glycation endproducts (RAGE) were evaluated. The ABR threshold increased in the 50 mg/kg RV and CXP groups at 4, 8, 16, and 32 kHz. The 0.5 mg/kg RV + CXP group demonstrated decreased hearing thresholds at 4 and 32 kHz compared to the CXP group. Cochlear whole-mount analysis revealed loss of outer hair cells in the 50 mg/kg RV and CXP groups and partial prevention of these cells in the 0.5 mg/kg RV + CXP group. The mRNA expressions of NFκB, IL6, and IL1β were increased in the 50 mg/kg RV and CXP groups compared to the control group. In contrast, these levels were decreased in the 0.5 mg/kg RV + CXP group compared to the CXP group. The mRNA expression of CYP1A1 was increased in the CXP group, while it was decreased in the 0.5 mg/kg RV + CXP group compared to the control group. The protein levels of AhR and cytosolic RAGE decreased in the 0.5 mg/kg RV group. Low-dose RV had partial otoprotective effects on CXP ototoxicity. The otoprotective effects of RV may be mediated through anti-oxidative (CYP1A1 and RAGE) and anti-inflammatory (NFκB, IL6, and IL1β) responses. High-dose RV exerted an inflammatory response and did not ameliorate CXP-induced ototoxicity.
Highlights
Resveratrol is a natural polyphenol abundant in grape skin [1]
The 50 mg/kg RV + CXP group demonstrated increased hearing threshold after CXP injection at 4, 8, 16, and 32 kHz, and the hearing thresholds after drug administration were not significantly different from those of the CXP group
+ CXP group demonstrated increased hearing threshold after CXP injection at 4, 8, 16, and 32 kHz, but the hearing thresholds after drug administration were lower than those of the CXP group at 4 and 32 kHz (29.09 ± 1.46 vs. 37.50 ± 2.14 dB SPL, p = 0.008 (p = 0.02, vs. CXP group, unpaired t-test) for 4 kHz, 35.91 ± 1.82 vs. 46.25 ± 4.91 dB SPL, p = 0.034 for 8 kHz, 33.64 ± 1.55 vs. 41.88 ± 4.76 dB SPL, p = 0.071 for 16 kHz, and 41.82 ±
Summary
Resveratrol (trans-3,40 ,5,-trihydroxystilbene, RV) is a natural polyphenol abundant in grape skin [1]. A moderate dose of RV has been reported to have protective effects on cardiovascular diseases through anti-oxidative effects, mediated by scavenging peroxyl radicals and impeding lipid peroxidation, and anti-inflammatory effects, via several target molecules, including nuclear factor kappa B (NFκB) [3]. Increasing evidence supports the anti-proliferative and anti-angiogenic effects of RV, and RV-mediated effects have been implicated in multiple conditions, from cardiovascular and neurodegenerative diseases to cancer and longevity [4]. The effects of RV vary depending on its bioavailability and dose. The absorptive efficiency is influenced by the constituents, and only about 1.7–1.9% of orally administered resveratrol was accounted for as biologically active free polyphenol [6]. The dose-dependent effects of RV have been reported to include anti-apoptotic and cardioprotective effects at low doses and pro-apoptotic and vascular endothelial injuries at high doses [8]
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