Gentamicin-induced Ototoxicity Research Articles

Is Gentamicin-Induced Ototoxicity Reversible with Delayed Administration of Nigella Sativa Oil? An Experimental Study

Is Gentamicin-Induced Ototoxicity Reversible with Delayed Administration of Nigella Sativa Oil? An Experimental Study

Ivacaftor attenuates gentamicin-induced ototoxicity through the CFTR-Nrf2-HO1/NQO1 pathway

ABSTRACT Objectives Gentamicin is one of the most common ototoxic drugs that can lower patients' quality of life. Oxidative stress is a key factors inducing sensory hair cell death during gentamicin administration. So far, there are no effective drugs to prevent or treat gentamicin- induced hearing loss. A recent study found cystic fibrosis transmembrane conductance regulator (CFTR) as a new target to modulate cellular oxidative balance. The objective of this study was to estimate the effect of the CFTR activator ivacaftor on gentamicin-induced ototoxicity and determine its mechanism. Methods The hair cell count was analyzed by Myosin 7a staining. Apoptosis was analyzed by TUNEL Apoptosis Kit. Cellular reactive oxygen species (ROS) level was detected by DCFH-DA probes. The Nrf2 related proteins expression levels were analyzed by western blot. Results An in vitro cochlear explant model showed that gentamicin caused ROS accumulation in sensory hair cells and induced apoptosis, and this effect was alleviated by pretreatment with ivacaftor. Western blotting showed that ivacaftor administration markedly increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The protective effect of ivacaftor was abolished by the Nrf2 inhibitor ML385. Discussion Our results indicate the protective role of the CFTR-Nrf2-HO1/NQO1 pathway in gentamicin-induced ototoxicity. Ivacaftor may be repositioned or repurposed towards aminoglycosides-induced hearing loss.

Protective effects of nigella sativa oil against gentamicin-induced ototoxicity in rats: A dose-ranging study.

Aminoglycosides are relatively potent antibiotics used against some life-threatening infections but contribute to ototoxicity. Although the beneficial effects of high-dose nigella sativa oil (NSO) on ototoxicity in the form of intratympanic or oral use have been demonstrated, no variable-dose studies have been conducted on this subject. We aimed to investigate the potential protective effect of different doses of intraperitoneal (i.p.) NSO on Gentamicin (GM)-induced ototoxicity with auditory brainstem responses (ABR) testing. Thirty adult male Sprague-Dawley rats (300-400 gr) were used in this study. Rats were randomly divided into 5 groups, with six animals in each group: All the groups received GM (120mg/kg i.p) for ten days. Group 1: 0.9% saline solution (0.3ml/kg i.p.), Group 2: NSOL (low dose 0.1ml/kg i.p.), Group 3: NSOM (median dose 0.3ml/kg i.p.), Group 4: NSOH (high dose 3ml/kg i.p.), Group 5: NSOML (late onset median dose 0.3ml/kg i.p) were given for fifteen days. But death occurred in 3 rats in group 4 and they were excluded from the study. The pretreatment and posttreatment ABR testings were performed. The posttreatment ABR results were compared with the pretreatment values. A significant difference was found in group 1 (p:0,002), group 2 (p: 0,040), and group 4 (p: 0,027). When the posttreatment tests were compared with each other, there was a significant difference between groups 1 and 2 (p<0,001), groups 1 and 3 (p<0,001), and groups 1 and 5 (p<0,001). The administration of 0.1ml/kg and 3ml/kg dose of NSO does not prevent ototoxicity. The 0.3ml/kg dose of NSO effectively prevents GM-induced ototoxicity within both prophylactic and therapeutic use.

Salicylate attenuates gentamicin-induced ototoxicity and facilitates the recovery in the basilar papilla of the lizard Podarcis siculus

It is known that ototoxicity is the main cause of toxicity induced by aminoglycoside antibiotics. Effects on cochlea and vestibule in vertebrates are variable, depending on the typology of the aminoglycoside and the animal model examined. Despite this, they are routinely used to prevent postoperative and urinary tract infections and in the treatment of tuberculosis and cystic fibrosis. Gentamicin causes hearing loss by damaging stereocilia and by causing degeneration of hair cells due to free radical formation and eventual activation of caspase-dependent pathways. Its toxicity increases with the frequency of administration, dose concentration, and duration of treatment. Turnover of new hair cells may occur spontaneously, throughout life, or may be triggered by an acoustic or ototoxic insult to replace dead cells. Turnover and repair of damage are common in fish and amphibians and in birds' vestibule. In contrast, in the papilla basilaris of birds, and in the vestibule of mammals, hair cell regeneration is activated only after damage. Sensory epithelium repair and hair cell regeneration also occur in the reptiles’ vestibule, but no data is available on regeneration or repair in the basilar papilla, involved in sound perception. The purpose of this work is therefore to assess the damage induced by gentamicin on the papilla basilaris of a reptile model organism, the Lacertidae Podarcis siculus. Recovery was also evaluated 3, 8 and 18 days after the end of exposure, in absence of gentamicin and in presence of the otoprotective salicylate. Scanning electron microscopy (SEM) was carried out to check for morphological damage while the occurrence of cell proliferation events was evaluated by fluorescence microscopy, after administration of 5-Bromo-2′-deoxyuridine (BrdU). Results show that salicylate administration facilitates recovery and reduces damage to hair cells after gentamicin treatment. Following the incorporation of bromodeoxyuridine, we demonstrated that sensory epithelium repair and hair cell regeneration have occurred, and that the recovery is due to either proliferation of the supporting cells and/or self-repair of hair cell bundles in the weakly damaged sensory cells.

Ameliorative effect of taxifolin on gentamicin-induced ototoxicity via down-regulation of apoptotic pathways in mouse cochlear UB/OC-2 cells.

Taxifolin is a flavanonol with efficacious cytoprotective properties, such as anti-inflammatory, antioxidant, anticancer, hepatoprotective, and nephroprotective effects. However, the potential protective effects of taxifolin against gentamicin-induced ototoxicity have not been confirmed. In this study, the possible mechanisms underlying the effects of taxifolin on gentamicin-induced death of UB/OC-2 cochlear cells were investigated. Mouse cochlear UB/OC-2 cells with or without taxifolin pretreatment were exposed to gentamicin, and the effects on cytotoxicity, reactive oxygen species (ROS) production, mitochondrial permeability transition, and apoptotic marker expression were examined using biochemical techniques, flow cytometry, western blotting, and fluorescent staining. Little or no apparent effect of taxifolin on cell viability was observed at concentrations less than 40 μM. Further investigations showed that gentamicin significantly inhibited cell viability in a concentration-dependent manner. Pretreatment with taxifolin attenuated gentamicin-induced lactate dehydrogenase release, as well as cellular cytotoxicity. In addition, taxifolin significantly prevented gentamicin-induced cell damage by decreasing ROS production, stabilizing mitochondrial membrane potential, and downregulating the mitochondrial pathway of apoptosis. In summary, pretreatment with taxifolin is effective for mitigating gentamicin-induced apoptotic cell death mediated by the mitochondrial pathway. Our data suggest that taxifolin provides a new approach to combat gentamicin-induced ototoxicity.

Bisdemethoxycurcumin-mediated Attenuation of Apoptosis Prevents Gentamicin-induced Ototoxicity in Mouse Cochlear UB/OC-2 Cells.

Gentamicin has been widely prescribed since the last two decades despite its ototoxicity and nephrotoxicity. Bisdemethoxycurcumin (BDMC) is an affordable and safe curcuminoid with medicinal properties. We aimed to understand the effects of BDMC on the gentamicin-induced hair cell damage in mouse cochlear UB/OC-2 cells, in order to elucidate the therapeutic potential of BDMC against gentamicin-induced ototoxicity. We quantified the cell membrane potential and examined the regulators and cascade proteins in the intrinsic pathway of hair cell apoptosis. Mouse cochlear UB/OC-2 cells were treated with BDMC before exposure to gentamicin. The effects of BDMC on hair cell viability, mitochondrial function, and apoptosis-related proteins were examined by flow cytometry, western blot, and fluorescent staining. Our results revealed that BDMC reversed gentamicin-mediated cycle arrest at the G2/M phase, stabilizing the mitochondrial membrane potential, decreasing cleaved caspase proteins, and successfully reversing hair cell apoptosis. BDMC is a potential agent for reducing gentamicin-induced ototoxicity.

Targeting Autophagy Induction as A possible Protective Mechanism by Verapamil Compared to Rapamycin (Sirolimus) Against Gentamicin -Induced Ototoxicity in Guinea Pigs

Background: Ototoxicity is a harmful feature of the cochlea or auditory nerve and sometimes vestibularapparatus. Gentamicin is known to cause irreversible bilateral ototoxicity. Autophagy induction hasbeen proposed as a target for prevention of gentamicin ototoxicity. Aim of the work: to investigate thepossible protective effect of autophagy induction by verapamil compared to rapamycin. Methods: Thisexperiment was conducted on 32 male guinea pigs. At the beginning each animal’s hearing status wasassessed using auditory brainstem response (ABR) audiometry. Then, they were divided into 4 equalgroups: Group 1: control group, Group 2: untreated gentamicin-induced ototoxicity group. Group 3:gentamicin-induced ototoxicity treated concomitantly with rapamycin. Group 4: gentamicin-inducedototoxicity treated concomitantly with verapamil. At the end of the experiment, ABR was repeatedthen the animals were sacrificed, and blood samples were obtained for assaying of reduced glutathioneand malondialdehyde levels. The left cochlea was processed for scanning electron microscope, whilethe right cochlea was processed for histopathology and LC3-II immunohistochemistry. Results:Verapamil revealed superiority compared to rapamycin proved by significant improvement in ABR,histopathological results, in addition to its antioxidant effect. Conclusion: verapamil could be suggestedas a potential therapeutic approach to decrease gentamicin ototoxicity.

Effects of Moringa Extract on Aminoglycoside-Induced Hair Cell Death and Organ of Corti Damage.

Moringa extract, a naturally occurring anti-oxidant, protects against aminoglycoside-induced hair cell death and hearing loss within the organ of Corti. Reactive oxygen species (ROS) arise primarily in the mitochondria and have been implicated in aminoglycoside-induced ototoxicity. Mitochondrial dysfunction results in loss of membrane potential, release of caspases, and cell apoptosis. Moringa extract has not previously been examined as a protective agent for aminoglycoside-induced ototoxicity. Putative otoprotective effects of moringa extract were investigated in an organotypic model using murine organ of Corti explants subjected to gentamicin-induced ototoxicity. Assays evaluated hair cell loss, cytochrome oxidase expression, mitochondrial membrane potential integrity, and caspase activity. In vitro application of moringa conferred significant protection from gentamicin-induced hair cell loss at dosages from 25 to 300 μg/mL, with dosages above 100 μg/mL conferring near complete protection. Assays demonstrated moringa extract suppression of ROS, preservation of cytochrome oxidase activity, and reduction in caspase production. Moringa extract demonstrated potent antioxidant properties with significant protection against gentamicin ototoxicity in cochlear explants.

Effect of Rutin on Gentamicin-Induced Ototoxicity in Rats: A Biochemical and Histopathological Examination

Effect of Rutin on Gentamicin-Induced Ototoxicity in Rats: A Biochemical and Histopathological Examination

XIAP inhibits gentamicin-induced hair cell damage and ototoxicity through the caspase-3/9 pathway

Gentamicin (GM), an aminoglycoside antibiotic, is one commonly used clinical drugs with ototoxic side effects. One of the most principal mechanisms of its ototoxicity is that GM can activate caspase-mediated cell death pathways in the cochlea. Since the anti-apoptotic protein known as X-linked Inhibitor of Apoptosis Protein (XIAP) has been reported to directly bind to activated caspase protein and inhibit their activities, we hypothesized that it might protect cochlea hair cells from GM ototoxicity. To evaluate this hypothesis, postnatal day 2–3 (P2-3) transgenic (TG) mice, in which XIAP gene is over-expressed under a pure C57BL/6J genetic background was constructed. We first extracted the cochlea tissue of normal mice and treated them with different concentrations of GM, and the number of hair cells were observed to determine the concentration of GM used in subsequent experiments. Next, we used Western Blot experiment to examine the effect of GM on XIAP protein expression in normal mouse cochlea, and then Western Blot and RT-PCR experiments were used to identify the transgenic mice. Finally, immunofluorescence assays were used to detect the effect of GM on the expression of caspase protein and verify the protective effect of XIAP. We found that GM at a concentration of 0.5 mM significantly affected the function of cochlea hair cells, up-regulating the expression of cleaved-caspase-3 and cleaved-caspase-9 protein but down-regulating XIAP protein. In the cochlea tissues of TG mice, this effect of GM was suppressed, and the destruction of hair cells was significantly reduced, and the cleaved-caspase-3 and cleaved-caspase-9 proteins were significantly suppressed. These results suggested that XIAP reduces GM-induced ototoxicity and caspase-3/9 pathway is associated with this process.

Theophylline alleviates gentamicin-induced cytotoxicity to sensory hair cells by maintaining HDAC2 expression

Sensorineural hearing loss is a health problem with global prevalence. Aminoglycoside antibiotics, for instance gentamicin, may cause ototoxicity in mammals as a result of apoptosis and elevated oxidative stress in cochlear hair cells. Our study aimed to examine the potential effects of theophylline, an HDAC2 agonist, on gentamicin-induced cytotoxicity to sensory hair cells. Mouse cochlear explants and HEI-OC1 cells were in vitro cultured and challenged by gentamicin to induce ototoxicity, with or without theophylline. Cochlear hair cells were evaluated by fluorescent microscopy, and their mechanotransduction was assessed by electrophysiology. Expression levels of HDAC2 and apoptosis pathway factors were also evaluated following gentamicin and theophylline treatments. The functional role of HDAC2 in this setting was investigated by siRNA targeted silencing. Theophylline protected cochlear hair cells from ototoxicity induced by gentamicin, in terms of preserving cochlear structure and mechanotransduction ability, and preventing the activation of the intrinsic apoptosis pathway dose-dependently. HDAC2 expression was downregulated by gentamicin, which could be restored by theophylline. HDAC2 silencing in HEI-OC1 cells negated the beneficial effect of theophylline against gentamicin-induced growth defect and apoptosis activation. Theophylline protects sensory hair cells from gentamicin ototoxicity by maintaining HDAC2 expression. Our study thereby discovers a critical role of HDAC2 in gentamicin-induced ototoxicity, which could shine light on potential therapeutic options for treatment against sensorineural hearing loss.

Icariin Treatment Protects Against Gentamicin-Induced Ototoxicity via Activation of the AMPK-SIRT3 Pathway.

Ototoxicity is a serious health problem that greatly affects millions of people worldwide. This condition is caused by the entry of aminoglycosides into auditory hair cells, subsequently inducing reactive oxygen species (ROS) production and accumulation. Several strategies have been adopted to overcome irreversible ROS-induced hair cell loss in mammals. In recent years, icariin, a major active component of the traditional herb Epimedium, has been widely studied and revealed to have antioxidant, anti-inflammatory, and anti-apoptotic properties. In this study, we found that icariin pretreatment improved the survival rate of gentamicin-treated House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and cochlear explants. Icariin remarkably suppressed HEI-OC1 cell apoptosis and inhibited ROS production in cells. Notably, icariin upregulated PGC-1α (SIRT3 promoter) and SIRT3 expression in HEI-OC1 cells. In addition, SIRT3 inhibition significantly attenuated the anti-apoptotic effect of icariin. We also found that icariin can increase AMPK phosphorylation. Further studies showed that inhibition of SIRT3 activity had no significant effect on AMPK phosphorylation. Furthermore, the AMPK inhibitor compound C significantly suppressed SIRT3 expression, meaning that AMPK, as an upstream molecule, regulates SIRT3 expression. Meanwhile, inhibition of AMPK activity significantly reduced the protective effect of icariin on gentamicin ototoxicity. Based on these results, icariin exerts its protective effect on gentamicin-induced ototoxicity via activation of the AMPK-SIRT3 signaling pathway, thus providing a new strategy for treating ototoxicity caused by aminoglycoside antibiotics.

Does Calcium Dobesilate Have Therapeutic Effect on Gentamicin-induced Cochlear Nerve Ototoxicity? An Experimental Study.

The ototoxic effects of aminoglycosides are well known. Gentamicin carries a substantial risk of hearing loss. Gentamicin is widely used to combat life-threatening infections, despite its ototoxic effects. Calcium dobesilate is a pharmacologically active agent used to treat many disorders due to its vasoprotective and antioxidant effects. We investigated the therapeutic role of calcium dobesilate against gentamicin-induced cochlear nerve ototoxicity in an animal model. Thirty-two Sprague Dawley rats were divided into four groups: Gentamicin, Gentamicin + Calcium Dobesilate, Calcium Dobesilate, and Control. Preoperative and postoperative hearing thresholds were determined using auditory brainstem response thresholds with click and 16-kHz tone-burst stimuli. Histological analysis of the tympanic bulla specimens was performed under light and transmission electron microscopy. The histological findings were subjected to semiquantitative grading, of which the results were compared between the groups. Gentamicin + Calcium Dobesilate group had, on average, 27 dB better click-evoked hearing than Gentamicin group (p < 0.01), whereas the difference was not significant with 16-kHz tone-burst stimuli (p > 0.01). Histologically examining the Control and Calcium Dobesilate groups revealed normal ultrastructural appearances. The Gentamicin group showed the most severe histological alterations including myelin destruction, total axonal degeneration, and edema. The histological evidence of damage was significantly reduced in the Gentamicin + Calcium Dobesilate group compared with the Gentamicin group. Adding oral calcium dobesilate to systemic gentamicin was demonstrated to exert beneficial effects on click-evoked hearing thresholds, as supported by the histological findings.

Dihydromyricetin Protects Against Gentamicin-Induced Ototoxicity via PGC-1α/SIRT3 Signaling in vitro.

Aminoglycoside-induced ototoxicity can have a major impact on patients’ quality of life and social development problems. Oxidative stress affects normal physiologic functions and has been implicated in aminoglycoside-induced inner ear injury. Excessive accumulation of reactive oxygen species (ROS) damages DNA, lipids, and proteins in cells and induces their apoptosis. Dihydromyricetin (DHM) is a natural flavonol with a wide range of health benefits including anti-inflammatory, antitumor, and antioxidant effects; however, its effects and mechanism of action in auditory hair cells are not well understood. The present study investigated the antioxidant mechanism and anti-ototoxic potential of DHM using House Ear Institute-Organ of Corti (HEI-OC)1 auditory cells and cochlear explant cultures prepared from Kunming mice. We used gentamicin to establish aminoglycoside-induced ototoxicity models. Histological and physiological analyses were carried out to determine DHM’s pharmacological effects on gentamicin-induced ototoxicity. Results showed DHM contributes to protecting cells from apoptotic cell death by inhibiting ROS accumulation. Western blotting and quantitative RT-PCR analyses revealed that DHM exerted its otoprotective effects by up-regulating levels of peroxisome proliferator activated receptor γ-coactivator (PGC)-1α and Sirtuin (SIRT)3. And the role of PGC-1α and SIRT3 in the protective effects of DHM was evaluated by pharmacologic inhibition of these factors using SR-18292 and 3-(1H-1,2,3-triazol-4-yl) pyridine, respectively, which indicated DHM’s protective effect was dependent on activation of the PGC-1α/SIRT3 signaling. Our study is the first report to identify DHM as a potential otoprotective drug and provides a basis for the prevention and treatment of hearing loss caused by aminoglycoside antibiotic-induced oxidative damage to auditory hair cells.

Exosomes derived from mouse inner ear stem cells attenuate gentamicin-induced ototoxicity in vitro through the miR-182-5p/FOXO3 axis.

Gentamicin-induced cochlear hair cell ototoxicity, such as oxidative stress and apoptosis, could be attenuated by mouse inner ear stem cells (IESCs). However, it is still unclear whether such protective effects could be mediated by exosomes derived from IESCs (IESCs-ex). In the present study, HEI-OC1 cells were exposed to gentamicin (2 mM) to establish an ototoxicity model and further treated with exosomes isolated from miR-182-5p transferred or non-transferred IESCs. IESCs-ex improved HEI-OC1 cell viability, as assayed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide method, and alleviated the oxidative stress response induced by the gentamicin treatment, as confirmed by measuring the malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase levels. IESCs-ex increased relative miR-182-5p expression and decreased FOXO3 expression in the gentamicin-exposed HEI-OC1 cells. Furthermore, exosomes derived from miR-182-5p mimics that were pre-treated with IESCs could increase miR-182-5p and Bcl-2 expressions and decrease FOXO3 and Bax expressions in gentamicin-exposed HEI-OC1 cells. All of these results indicate that IESCs-ex could attenuate gentamicin-induced HEI-OC1 cell apoptosis and oxidative stress through the miR-182-5p/FOXO3 axis.

Otoprotective Effect of 2,3,4',5-Tetrahydroxystilbene-2-O-β-d-Glucoside on Gentamicin-Induced Apoptosis in Mouse Cochlear UB/OC-2 Cells.

Excessive levels of reactive oxygen species (ROS) lead to mitochondrial damage and apoptotic cell death in gentamicin-induced ototoxicity. 2,3,4’,5-Tetrahydroxystilbene-2-O-β-d-glucoside (THSG), a bioactive constituent, isolated from Polygonum multiflorum Thunb., exhibits numerous biological benefits in treating aging-related diseases by suppressing oxidative damage. However, its protective effect on gentamicin-induced ototoxicity remains unexplored. Therefore, here, we aimed to investigate the otoprotective effect of THSG on gentamicin-induced apoptosis in mouse cochlear UB/OC-2 cells. We evaluated the effect of gentamicin and THSG on the ROS level, superoxide dismutase (SOD) activity, mitochondrial membrane potential, nuclear condensation, and lactate dehydrogenase (LDH) release, and the expression of apoptosis-related proteins was assessed to understand the molecular mechanisms underlying its preventive effects. The findings demonstrated that gentamicin increased ROS generation, LDH release, and promoted apoptotic cell death in UB/OC-2 cells. However, THSG treatment reversed these effects by suppressing ROS production and downregulating the mitochondrial-dependent apoptotic pathway. Additionally, it increased the SOD activity, decreased the expression of apoptosis-related proteins, alleviated the levels of the apoptotic cells, and impaired cytotoxicity. To the best of our knowledge, this is the first study to demonstrate that THSG could be a potential therapeutic option to attenuate gentamicin-induced ototoxicity.

Telmisartan Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro

Background: Telmisartan is an angiotensin II receptor blocker that has pleiotropic effects and protective properties in different cell types. Moreover, telmisartan has also shown partial agonism on the peroxisome proliferator-activated receptor γ (PPAR-γ). Auditory hair cells (HCs) express PPAR-γ, and the protective role of PPAR-γ agonists on HCs has been shown. Objectives: The objective of this study was to investigate the effects of telmisartan on gentamicin-induced ototoxicity in vitro. Methods: Cochlear explants were exposed to gentamicin with or without telmisartan, and/or GW9662, an irreversible PPAR-γ antagonist. Results: Telmisartan protected auditory HCs against gentamicin-induced ototoxicity. GW9662 completely blocked this protective effect, suggesting that it was mediated by PPAR-γ signaling. Exposure to GW9662 or telmisartan alone was not toxic to auditory HCs. Conclusions: We found that telmisartan, via PPAR-γ signaling, protects auditory HCs from gentamicin-induced ototoxicity. Therefore, telmisartan could potentially be used in the future to prevent or treat sensorineural hearing loss.

A new active peptide from Neptunea arthritica cumingii exerts protective effects against gentamicin-induced sensory-hair cell injury in zebrafish

Gentamicin is commonly used for effective treatment of severe Gram-negative bacterial infections. However, its use is being increasingly restricted owing to the ototoxic effects attributed to it. Gentamicin-induced ototoxicity is thought to be related with apoptosis induced by reactive oxygen species (ROS). In this study, we found a novel active peptide from Neptunea arthritica cumingii with otoprotective effects and no significant embryotoxic effects. The combined application of gentamicin and this novel active peptide helped sensory-hair cells to protect themselves from lethal ROS accumulation. This, in turn, reduced the expression of three genes (caspase-3, caspase-9, Bax), and thereby, the sensory-hair cell apoptosis promoted by ROS accumulation upon gentamicin administration. Our findings provided new insights into the prevention of gentamicin-induced hearing loss.

Baicalin attenuates gentamicin-induced cochlear hair cell ototoxicity.

Gentamicin can lead to cochlear hair cells associated ototoxicity by inducing apoptosis and oxidative stress, which can be alleviated by baicalin, one flavonoid extracted from the root of Scutellaria baicalensis. The role of baicalin in protecting gentamicin-induced hearing loss is unclear. Interference with oxidative stress was investigated in this study using House Ear Institute-Organ of Corti1 (HEI-OC1) cells, which were simultaneously treated with baicalin (0-400μm) and gentamicin (0.2 or 1mm). MTT was used to assay cell viability and apoptosis was detected with Annexin V-fluorescein isothiocyanate staining. The production of reactive oxygen species was indicated by 2,7-dichlorofluorescein diacetate fluorescence intensity and mitochondrial depolarization was assayed by JC1-mitochondrial membrane potential assay. Poly(ADP-ribose) polymerase (PARP), cleaved-caspase 3 and cleaved-PARP expression were analyzed with western blot. Baicalin improved the viability of HEI-OC1 cells and significantly reduced the oxidative stress and mitochondrial depolarization compared with the gentamicin treatment group. Gentamicin treatment increased the activation of PARP and caspase-3, while such an increase could be downregulated by baicalin. Baicalin attenuates gentamicin-induced cochlear hair cells ototoxicity, and such inhibition may be mediated by the regulation of reactive oxygen species production, mitochondrial depolarization, and caspase-3 and PARP activation.

Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review.

Mitochondrial dysfunction is associated with the etiologies of sensorineural hearing loss, such as age-related hearing loss, noise- and ototoxic drug-induced hearing loss, as well as hearing loss due to mitochondrial gene mutation. Mitochondria are the main sources of reactive oxygen species (ROS) and ROS-induced oxidative stress is involved in cochlear damage. Moreover, the release of ROS causes further damage to mitochondrial components. Antioxidants are thought to counteract the deleterious effects of ROS and thus, may be effective for the treatment of oxidative stress-related diseases. The administration of mitochondria-targeted antioxidants is one of the drug delivery systems targeted to mitochondria. Mitochondria-targeted antioxidants are expected to help in the prevention and/or treatment of diseases associated with mitochondrial dysfunction. Of the various mitochondria-targeted antioxidants, the protective effects of MitoQ and SkQR1 against ototoxicity have been previously evaluated in animal models and/or mouse auditory cell lines. MitoQ protects against both gentamicin- and cisplatin-induced ototoxicity. SkQR1 also provides auditory protective effects against gentamicin-induced ototoxicity. On the other hand, decreasing effect of MitoQ on gentamicin-induced cell apoptosis in auditory cell lines has been controversial. No clinical studies have been reported for otoprotection using mitochondrial-targeted antioxidants. High-quality clinical trials are required to reveal the therapeutic effect of mitochondria-targeted antioxidants in terms of otoprotection in patients.