Abstract
Cisplatin (cis-diammine-dichloroplatinum; CDDP) is an anticancer drug that induces significant hearing loss and balance dysfunction as side effects. Cilostazol (CS, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3, 4-dihydro-2-(1H)-quinolinone) has neuroprotective and antioxidant effects, whereas Ginkgo biloba extract (GbE) has preventive effects on CDDP-induced hearing loss in rats, and GbE enhances the antiatherogenic effect of CS by inhibiting the generation of reactive oxygen species (ROS). The purpose of this study was to investigate the effects of renexin (RXN), which contains GbE and CS, against CDDP-induced cochleo-vestibular dysfunction in rats and to elucidate the mechanism underlying the protective effects of RXN on auditory cells. Rats intraperitoneally injected with CDDP exhibited an increase in hearing threshold and vestibular dysfunction, which agreed with hair cell damage in the Organ of Corti and otoliths. However, these impairments were significantly prevented in a dose-dependent manner by pre- and co-treatment with RXN, and these preventive effects in RXN-treated rats were more prominent than those in GbE-treated rats. In a CDDP pharmacokinetic study, platinum concentration was very similar between CDDP-only treated and RXN+CDDP cotreated rats. RXN markedly attenuated CDDP-induced intracellular ROS and significantly reduced CDDP-activated expression of p-extracellular regulated kinase (ERK), BAX, cytochrome c, cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase, but increased BCL-XL expression. These results show that RXN may have a synergistic effect by strongly protecting hearing and vestibular dysfunction induced by CDDP by inhibiting ROS production, mitochondrial pathways and the ERK pathway, without interfering with CDDP pharmacokinetics. Therefore, RXN could potentially be used to reduce CDDP-related hearing loss and dizziness.
Highlights
Induced ototoxicity causes hair cell loss by inducing apoptosis in the cochlea
The present study investigated the protective effects of renexin (RXN), which is a combination of Ginkgo biloba extract (GbE) and CS, against CDDP-induced hearing loss and vestibular toxicity in rats, and explored the mechanism of the protective effect of RXN in the House Ear Institute-Organ of Corti 1 (HEI-OC1) auditory cell line
Hearing thresholds at 16 and 32 kHz were normal in the control group during the experimental period, but increased in all CDDP-administrated animals after 5 days (Supplementary Figure 1a)
Summary
Induced ototoxicity causes hair cell loss by inducing apoptosis in the cochlea. CDDP primarily damages the outer and inner hair cells, induces degeneration of the stria vascularis, and remarkably reduces the number of spiral ganglion cells.[4]. CS functions as a platelet aggregation inhibitor[16] and vasodilator,[17] and is mainly used for treating patients with peripheral arterial disease[18] and intermittent claudication.[19] Previous studies have demonstrated that CS inhibits apoptosis under several conditions.[20,21,22] Kim et al.[23] reported a protective effect of CS against lipopolysaccharide-induced apoptosis in human umbilical vein endothelial cells, by scavenging hydroxyl radicals and intracellular reactive oxygen species (ROS) with the reduction in tumor necrosis factor-a formation and by increasing Bcl-2 protein expression, and decreasing Bax protein and cytochrome c release. The present study investigated the protective effects of renexin (RXN), which is a combination of GbE and CS, against CDDP-induced hearing loss and vestibular toxicity in rats, and explored the mechanism of the protective effect of RXN in the House Ear Institute-Organ of Corti 1 (HEI-OC1) auditory cell line
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